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Nagafuji K, Ito Y, Miyamoto T, Eto T, Kamimura T, Kato K, Miyazaki Y, Wake A, Kohno K, Takase K, Imamura Y, Uchida N, Tanimoto K, Kawano N, Kurokawa T, Kondo Y, Fujisaki T, Tsukada J, Yonemoto K, Akashi K. Clinical Impact of Continuous Dasatinib Administration on the Prognosis of Patients With BCR::ABL1 Acute Lymphoblastic Leukemia: Result of the Prospective MRD2014 Study Conducted by Fukuoka Blood and Marrow Transplantation Group (FBMTG). Eur J Haematol 2025; 114:1001-1010. [PMID: 40052397 DOI: 10.1111/ejh.14407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 02/26/2025] [Accepted: 02/27/2025] [Indexed: 05/07/2025]
Abstract
AIM To assess the efficacy of continuous dasatinib in improving outcomes for adult patients with BCR::ABL1 ALL. METHODS The prospective, multicenter ALL/MRD2014 trial introduced a modified protocol compared to the MRD2008 trial, incorporating continuous dasatinib use and reduced chemotherapy intensity. RESULTS Among the 164 adult ALL patients enrolled (2014-2019), 61 were Philadelphia-positive (Ph+) (median age 50 years; 38 males, 23 females). Post-induction, 96.7% achieved complete remission (CR). The 3-year event-free survival (EFS) and overall survival (OS) were 51% and 76%, respectively. Patients undergoing allo-HSCT in CR1 had improved outcomes, with a 3-year EFS of 64% and OS of 87%. MRD-negative patients before transplantation exhibited superior survival (EFS: 71% vs. 29%; OS: 94% vs. 57%). Comparison with the MRD2008 trial revealed similar outcomes, with the MRD2014 trial achieving a 3-year EFS of 51% and OS of 76% vs. 52% and 84% in MRD2008. Although not statistically significant, the MRD2014 trial showed trends of increased relapse (CIR: 39% vs. 26%, p = 0.305) and reduced non-relapse mortality (NRM: 10% vs. 21%, p = 0.181). CONCLUSION The ALL/MRD2014 trial underscores the importance of MRD status and allo-HSCT in Ph+ ALL. Continuous dasatinib-based regimens offer favorable outcomes in MRD-negative patients. TRIAL REGISTRATION This study was registered with the UMIN Clinical Trials Registry (UMIN-CTR), number UMIN000012382.
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Affiliation(s)
- Koji Nagafuji
- Division of Hematology & Oncology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yoshikiyo Ito
- Department of Hematology, Imamura General Hospital, Kagoshima, Japan
| | - Toshihiro Miyamoto
- Hematology/Respiratory Medicine, Faculty of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Tetsuya Eto
- Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
| | - Tomohiko Kamimura
- Department of Hematology, HaraSanshin General Hospital, Fukuoka, Japan
| | - Koji Kato
- Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
| | | | - Atsuhi Wake
- Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations, Toranomon Hospital, Kawasaki, Japan
| | - Kentaro Kohno
- Department of Hematology and Oncology, Japan Community Health Care Organization Kyushu Hospital, Kitakyushu, Japan
| | - Ken Takase
- Department of Hematology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Yutaka Imamura
- Division of Hematology, Our Lady of the Snow Social Medical Corporation St. Mary's Hospital, Kurume, Japan
| | - Naoyuki Uchida
- Department of Hematology, Federation of National Public Service Personnel Mutual aid Associations Toranomon Hospital, Tokyo, Japan
| | - Kazuki Tanimoto
- Department of Hematology and Oncology, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan
| | - Noriaki Kawano
- Department of Hematology, Miyazaki Prefectural Hospital, Miyazaki, Japan
| | - Toshiro Kurokawa
- Department of Hematology, Toyama Red Cross Hospital, Toyama, Japan
| | - Yukio Kondo
- Department of Hematology, Toyama Prefectural Central Hospital, Toyama, Japan
| | - Tomoaki Fujisaki
- Department of Hematology, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Junichi Tsukada
- Department of Hematology, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Koji Yonemoto
- Division of Biostatistics, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Koichi Akashi
- Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
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Foà R. Ph-Positive Acute Lymphoblastic Leukemia - 25 Years of Progress. N Engl J Med 2025; 392:1941-1952. [PMID: 40367376 DOI: 10.1056/nejmra2405573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Affiliation(s)
- Robin Foà
- Department of Translational and Precision Medicine, Sapienza University, Rome
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Nishiwaki S, Terakura S, Morishita T, Goto T, Inagaki Y, Miyao K, Fukushima N, Hirano D, Tange N, Kurahashi S, Kuwatsuka Y, Kasai M, Iida H, Ozeki K, Sawa M, Nishida T, Kiyoi H. Post-transplant TKIs for Ph+ ALL: practices to date and clinical significance. Int J Hematol 2025; 121:494-503. [PMID: 39821010 DOI: 10.1007/s12185-025-03917-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 01/19/2025]
Abstract
Post-transplant tyrosine kinase inhibitors (TKIs) show promise in preventing relapse after allogeneic hematopoietic cell transplantation (allo-HCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, their real-world use and efficacy remain unclear. A comprehensive study across seven centers included Ph+ALL patients who underwent allo-HCT between 2002 and 2022. Post-transplant TKIs were administered in 28% of patients (49 of 173 transplanted in complete remission): 7% as prophylaxis during complete molecular remission (CMR), and 21% in response to measurable residual disease (MRD) positivity. Median first post-transplant TKI duration was 13.7 months for the prophylactic group and 4.0 months for the MRD-triggered group. Prophylactic TKIs appear particularly beneficial for patients not in CMR at allo-HCT, showing a trend towards higher 5-year relapse-free survival (RFS) compared to those not receiving prophylactic TKIs (100% vs. 73%; P = 0.11). Significant RFS differences were observed between the prophylactic, non-TKI, and MRD-triggered groups. However, patients with white blood cell counts <15000/µl at diagnosis and no additional chromosomal abnormalities-an MRD-triggered high efficacy cluster-demonstrated comparable 5-year RFS regardless of TKI strategy (100% vs. 85% vs. 80%; P = 0.87). This cluster highlights the potential effectiveness of MRD-triggered TKI administration in select low-risk patients, suggesting tailored TKI strategies based on risk factors.
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Affiliation(s)
- Satoshi Nishiwaki
- Department of Advanced Medicine, Nagoya University Hospital, 65 Tsurumai-cho Showa-ku, Nagoya, 4668560, Japan.
| | - Seitaro Terakura
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takanobu Morishita
- Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan
- Department of Blood and Marrow Transplantation and Cellular Therapy, Fujita Health University, Toyoake, Japan
| | - Tatsunori Goto
- Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan
| | - Yuichiro Inagaki
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Kotaro Miyao
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Nobuaki Fukushima
- Department of Hematology and Oncology, JA Aichi Konan Kosei Hospital, Konan, Japan
| | - Daiki Hirano
- Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Naoyuki Tange
- Department of Hematology and Oncology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Shingo Kurahashi
- Division of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi, Japan
| | - Yachiyo Kuwatsuka
- Department of Advanced Medicine, Nagoya University Hospital, 65 Tsurumai-cho Showa-ku, Nagoya, 4668560, Japan
| | - Masanobu Kasai
- Department of Hematology and Oncology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Hiroatsu Iida
- Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Kazutaka Ozeki
- Department of Hematology and Oncology, JA Aichi Konan Kosei Hospital, Konan, Japan
| | - Masashi Sawa
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Tetsuya Nishida
- Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan
| | - Hitoshi Kiyoi
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Kong J, Zheng FM, Yan CH, Wang JZ, Fu HX, Wang ZD, Suo P, Hu GH, Lv M, Chen H, Mo XD, Xu LP, Zhang XH, Huang XJ, Wang Y. Efficacy and safety of olverembatinib as maintenance therapy after allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Ann Hematol 2025; 104:801-808. [PMID: 39815121 PMCID: PMC11868191 DOI: 10.1007/s00277-025-06198-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/07/2025] [Indexed: 01/18/2025]
Abstract
Experience using olverembatinib as maintenance therapy in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) after allogeneic hematopoietic cell transplantation (allo-HCT) is limited. We retrospectively collected data from 26 patients with Ph+ ALL who received only olverembatinib as maintenance therapy after allo-HCT. Olverembatinib was administered as prophylaxis in 18 patients (69.2%), and preemptively in 8 patients (30.8%). The median time of olverembatinib initiation after transplantation was 2.5 months (range, 1-7.3). The median starting dose of olverembatinib was 35 mg qod (range, 15-40). The median duration of olverembatinib treatment was 12.5 months (range, 6-23). Olverembatinib maintenance treatment was discontinued in 8 patients (8/26,30%), seven stopped the drug for a long-lasting BCR-ABL1 negativity and 1 for recurrent fever associated with the drug. BCR-ABL1 turned positive in 3 patients in 2, 3 and 6 months after discontinuation. During olverembatinib treatment, three patients developed grade ≥ 3 hematologic side effects, which resolved with dose interruption or dose reduction. The median follow-up time after allo-HCT were 17.75 months (range 7-31). The hematologic relapse rate was 7.7% (2/26), with no event in the preemptive group. The 3-year probability of overall survival and relapse free survival after allo-HCT was 91.7% and 79.1%, respectively. Only one patient in prophylaxis group died of central central nervous system (CNS) relapse. Thus, our data suggest that olverembatinib is effective and safe as maintenance treatment in patients with Ph+ ALL who underwent allo-HSCT. The main adverse effect was hematologic toxicity, which was tolerated.
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Affiliation(s)
- Jun Kong
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Feng-Mei Zheng
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Chen-Hua Yan
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Jing-Zhi Wang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Hai-Xia Fu
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Zhi-Dong Wang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Pan Suo
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Guan-Hua Hu
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Meng Lv
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Huan Chen
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Xiao-Dong Mo
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Lan-Ping Xu
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Xiao-Hui Zhang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
| | - Xiao-Jun Huang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China
| | - Yu Wang
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Peking University, Beijing, China.
- Institute of Hematology, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, People's Republic of China.
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Tachibana T, Tanaka M, Noguchi Y, Najima Y, Sadato D, Harada Y, Tamai Y, Doki N, Nakajima H. Successful treatment of two cases with Philadelphia-chromosome positive acute lymphoblastic leukemia who relapsed after allogeneic stem cell transplantation and the treatments with novel immunotherapies and ponatinib. Hematology 2024; 29:2360843. [PMID: 38828928 DOI: 10.1080/16078454.2024.2360843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/21/2024] [Indexed: 06/05/2024] Open
Abstract
The outcomes of relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant to new drugs such as tyrosine kinase inhibitors, inotuzumab ozogamicin (InO) and blinatumomab are dismal. We treated two cases of Ph+ALL resistant to these drugs that achieved long-term survival after treatment with chimeric antigen receptor (CAR)-T cell therapy or a second allogeneic hematopoietic stem cell transplantation (HCT) with a sequential conditioning regimen. Case 1: A 15-year-old boy was diagnosed with Ph+ALL. Despite the second HCT after the treatment of ponatinib and blinatumomab, hematological relapse occurred. InO was ineffective and he was transferred to a CAR-T center. After the CAR-T cell therapy, negative measurable residual disease (MRD) was achieved and maintained for 38 months without maintenance therapy. Case 2: A 21-year-old man was diagnosed with Ph+ALL. Hematological relapse occurred after the first HCT. Despite of the treatment with InO, ponatinib, and blinatumomab, hematological remission was not achieved. The second HCT was performed using a sequential conditioning regimen with clofarabine. Negative MRD was subsequently achieved and maintained for 42 months without maintenance therapy. These strategies are suggestive and helpful to treat Ph+ALL resistant to multiple immunotherapies.
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Affiliation(s)
| | - Masatsugu Tanaka
- Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan
| | - Yuma Noguchi
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Yuho Najima
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Daichi Sadato
- Clinical Research Support Center, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Yuka Harada
- Clinical Research Support Center, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Yotaro Tamai
- Division of Hematology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Hideaki Nakajima
- Department of Hematology and Clinical Immunology, Yokohama City University School of Medicine, Yokohama, Japan
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Terakawa T, Hayasaka Y, Umeki Y, Ikeda M, Matsuoka Y, Mizuki M, Matsui S, Nakahara W, Matsunaga H, Morris S, Nishida T, Sakaki T, Yoshimoto T, Ueda S. Tyrosine Kinase Inhibitor-induced Cerebrovascular Occlusion Presenting with Moyamoya Disease-like Stenosis of the Circle of Willis. Intern Med 2024; 63:2977-2981. [PMID: 38462515 PMCID: PMC11604399 DOI: 10.2169/internalmedicine.3337-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 01/30/2024] [Indexed: 03/12/2024] Open
Abstract
Vascular occlusive events are notable adverse effects of tyrosine kinase inhibitors (TKIs), which are promising treatments for chronic myeloid leukemia (CML). We herein report the case of a patient with CML who developed cerebrovascular occlusion of the circle of Willis during TKI treatment. Our patient did not meet the diagnostic criteria for moyamoya disease due to the insignificant development of moyamoya vessels. The lack of moyamoya vessel development may be explained by the suppression of tyrosine kinases that are responsible for angiogenesis. Cerebrovascular occlusion of the circle of Willis, without significant development of moyamoya vessels, may be an important phenotype of TKI-associated vasculopathy.
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Affiliation(s)
- Takuya Terakawa
- Department of Hematology, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Yuya Hayasaka
- Department of Hematology, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Yuka Umeki
- Department of Hematology, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Mako Ikeda
- Department of Hematology, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Yoshiki Matsuoka
- Department of Hematology, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Masanari Mizuki
- Department of Hematology, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Shogo Matsui
- Department of Hematology, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Wataru Nakahara
- Department of Hematology, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Hitomi Matsunaga
- Department of Hematology, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Shayne Morris
- Department of Neurosurgery, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Takeo Nishida
- Department of Neurosurgery, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Takayuki Sakaki
- Department of Neurosurgery, Japan Community Health Care Organization Osaka Hospital, Japan
| | - Takeshi Yoshimoto
- Department of Neurology, National Cerebral and Cardiovascular Center, Japan
| | - Shuji Ueda
- Department of Hematology, Hyogo Prefectural Nishinomiya Hospital, Japan
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7
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Kurosawa S, Fukuda T, Ichinohe T, Hashii Y, Kanda J, Goto H, Kato K, Yoshimitsu M, Ishimaru F, Sato A, Onizuka M, Matsuo K, Ito Y, Yanagisawa A, Ohbiki M, Tabuch K, Atsuta Y, Arai Y. Center effect on allogeneic hematopoietic stem cell transplantation outcomes for B-cell acute lymphoblastic leukemia. Cytotherapy 2024; 26:1185-1192. [PMID: 38804991 DOI: 10.1016/j.jcyt.2024.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/03/2024] [Accepted: 05/03/2024] [Indexed: 05/29/2024]
Abstract
This nationwide study retrospectively examined the center effect on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult B-cell acute lymphoblastic leukemia. The cohort analyses were separated into Philadelphia chromosome (Ph)-positive and -negative cases. The patients were divided into low- and high-volume groups according to the number of allo-HSCTs at each facility. The primary endpoint was 5-year overall survival (OS). This study included 1156 low-volume and 1329 high-volume Ph-negative and 855 low-volume and 926 high-volume Ph-positive cases. In Ph-negative cases, 5-year OS was significantly higher in the high-volume centers at 52.7% (95% confidence interval [CI]: 49.9-55.5) versus 46.8% (95% CI: 43.8-49.7) for the low-volume centers (P < 0.01). Multivariate analysis identified high volume as a favorable prognostic factor (hazard ratio [HR]: 0.81 [95% CI: 0.72-0.92], P < 0.01). Subgroup analysis in Ph-negative cases revealed that the center effects were more evident in patients aged ≥40 years (HR: 0.72, 95% CI: 0.61-0.86, P < 0.01) and those receiving cord blood transplantation (HR: 0.62, 95% CI: 0.48-0.79, P < 0.01). In Ph-positive cases, no significant difference was observed between the high and low-volume centers for 5-year OS (59.5% [95% CI: 56.2-62.7] vs. 54.9% [95% CI: 51.3-58.3], P = 0.054). In multivariate analysis, center volume did not emerge as a significant prognostic indicator. This study showed center effects on survival in Ph-negative but not in Ph-positive cases, highlighting the heterogeneity of the center effect in allo-HSCT for B-cell acute lymphoblastic leukemia. Collaborative efforts among transplant centers and further validation are essential to improve outcomes.
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Affiliation(s)
- Shuhei Kurosawa
- Department of Hematology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.
| | - Takahiro Fukuda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | | | - Junya Kanda
- Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hideki Goto
- Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan
| | - Koji Kato
- Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Makoto Yoshimitsu
- Department of Hematology and Rheumatology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Fumihiko Ishimaru
- Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan
| | - Atsushi Sato
- Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai, Japan
| | - Makoto Onizuka
- Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Japan
| | - Keitaro Matsuo
- Division Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Isehara, Japan
| | - Yuri Ito
- Department of Medical Statistics, Research & Development Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Atsumi Yanagisawa
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan
| | - Marie Ohbiki
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan; Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan; Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ken Tabuch
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan
| | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan; Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yasuyuki Arai
- Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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8
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Othman T, Koller P, Tsai NC, Yang D, Pourhassan H, Agrawal V, Ngo D, Chen J, Farol L, Spielberger R, Sahebi F, Al Malki MM, Cai JL, Sandhu KS, Mansour J, Salhotra A, Ali H, Aribi A, Arslan S, Marcucci G, Forman SJ, Stein AS, Nakamura R, Pullarkat V, Aldoss I, Mei M. Toxicities associated with tyrosine kinase inhibitor maintenance following allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Am J Hematol 2024; 99:1680-1690. [PMID: 38804599 DOI: 10.1002/ajh.27378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 04/29/2024] [Accepted: 05/12/2024] [Indexed: 05/29/2024]
Abstract
Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common.
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Affiliation(s)
- Tamer Othman
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Paul Koller
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Ni-Chun Tsai
- Department of Computational and Quantitative Sciences, Beckman Research Institute, City of Hope, Duarte, California, USA
| | - Dongyun Yang
- Department of Computational and Quantitative Sciences, Beckman Research Institute, City of Hope, Duarte, California, USA
| | - Hoda Pourhassan
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Vaibhav Agrawal
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Dat Ngo
- Department of Pharmacy, City of Hope National Medical Center, California, Duarte, USA
| | - Jason Chen
- Department of Pharmacy, City of Hope National Medical Center, California, Duarte, USA
| | - Leonardo Farol
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Ricardo Spielberger
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Firoozeh Sahebi
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Monzr M Al Malki
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Ji-Lian Cai
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Karamjeet S Sandhu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Joshua Mansour
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Amandeep Salhotra
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Haris Ali
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Ahmed Aribi
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Shukaib Arslan
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Guido Marcucci
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Stephen J Forman
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Anthony S Stein
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Ryotaro Nakamura
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Vinod Pullarkat
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Ibrahim Aldoss
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Matthew Mei
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
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9
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Khawaji ZY, Khawaji NY, Alahmadi MA, Elmoneim AA. Prediction of Response to FDA-Approved Targeted Therapy and Immunotherapy in Acute Lymphoblastic Leukemia (ALL). Curr Treat Options Oncol 2024; 25:1163-1183. [PMID: 39102166 DOI: 10.1007/s11864-024-01237-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2024] [Indexed: 08/06/2024]
Abstract
OPINION STATEMENT Acute lymphoblastic leukemia (ALL) represents the predominant cancer in pediatric populations, though its occurrence in adults is relatively rare. Pre-treatment risk stratification is crucial for predicting prognosis. Important factors for assessment include patient age, white blood cell (WBC) count at diagnosis, extramedullary involvement, immunophenotype, and cytogenetic aberrations. Minimal residual disease (MRD), primarily assessed by flow cytometry following remission, plays a substantial role in guiding management plans. Over the past decade, significant advancements in ALL outcomes have been witnessed. Conventional chemotherapy has remarkably reduced mortality rates; however, its intensive nature raises safety concerns and has led to the emergence of treatment-resistant cases with recurrence of relapses. Consequently, The U.S. Food and Drug Administration (FDA) has approved several novel treatments for relapsed/refractory ALL due to their demonstrated efficacy, as indicated by improved complete remission and survival rates. These treatments include tyrosine kinase inhibitors (TKIs), the anti-CD19 monoclonal antibody blinatumomab, anti-CD22 inotuzumab ozogamicin, anti-CD20 rituximab, and chimeric antigen receptor (CAR) T-cell therapy. Identifying the variables that influence treatment decisions is a pressing necessity for tailoring therapy based on heterogeneous patient characteristics. Key predictive factors identified in various observational studies and clinical trials include prelymphodepletion disease burden, complex genetic abnormalities, and MRD. Furthermore, the development of serious adverse events following treatment could be anticipated through predictive models, allowing for appropriate prophylactic measures to be considered. The ultimate aim is to incorporate the concept of precision medicine in the field of ALL through valid prediction platform to facilitate the selection of the most suitable treatment approach.
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Affiliation(s)
| | | | | | - Abeer Abd Elmoneim
- Women and Child Health Department, Taibah University, Madinah, Kingdom of Saudi Arabia
- 2nd Affiliation: Pediatric Department, Faculty of Medicine, Sohag University, Sohag, Egypt
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10
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Sohn SK, Lee JM, Jang Y, Lee Y, Na J, Cho HJ, Moon JH, Baek DW. Is intensive chemotherapy and allogeneic stem cell transplantation mandatory for curing Philadelphia chromosome-positive acute lymphoblastic leukemia in young patients in the era of multitarget agents? Expert Rev Hematol 2024; 17:353-359. [PMID: 38755522 DOI: 10.1080/17474086.2024.2357273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 05/15/2024] [Indexed: 05/18/2024]
Abstract
INTRODUCTION The treatment outcomes for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) have improved with various tyrosine kinase inhibitors (TKIs) and bispecific T-cell engagers. Although allogeneic stem cell transplantation (allo-SCT) is the standard treatment for young patients with Ph+ALL, its role remains debatable in the era of TKIs and blinatumomab. AREAS COVERED There are some issues regarding Ph+ALL. First, do young patients require intensive chemotherapy (IC) in the era of multitarget agents? Second, which TKI is preferred for frontline therapy? Third, should allo-SCT be performed in patients achieving complete remission with ponatinib and IC? Fourth, can chemo-free treatment lead to a cure without allo-SCT? We searched relevant literature from the last 30 years on PubMed; reviewed the role of chemo-free therapies and combinations of ponatinib and IC; and assessed the necessity of allo-SCT in young patients with Ph+ALL. EXPERT OPINION Allo-SCT may not be needed, even in young patients with Ph+ALL treated with ponatinib-based IC or combined ponatinib and blinatumomab as frontline therapy. When adopting a ponatinib-based chemo-minimized regimen for induction, allo-SCT is needed with posttransplant ponatinib maintenance. Continuous exposure to ponatinib at pre- or post-transplant is regarded as one of the most important factor for the success of treatment.
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Affiliation(s)
- Sang Kyun Sohn
- Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Jung Min Lee
- Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Youngeun Jang
- Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Yunji Lee
- Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Jihyun Na
- Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Hee Jeong Cho
- Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Joon Ho Moon
- Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Dong Won Baek
- Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea
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11
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Shaykh N, Patel F, Stachler L, Ali K, Tripathi V, Rai O, Jacob R. A Case of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in a 26-Year-Old Pregnant Woman. Cureus 2024; 16:e60679. [PMID: 38903380 PMCID: PMC11187471 DOI: 10.7759/cureus.60679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 05/20/2024] [Indexed: 06/22/2024] Open
Abstract
Acute lymphoblastic leukemia (ALL) is an uncommon and rapidly progressing blood cancer originating in the bone marrow, characterized by the abnormal proliferation of immature lymphocytes. Although most cases of ALL are observed in children, the disease pattern shows two peaks: one in early childhood and another around the age of 50. Approximately a fifth to a third of adults diagnosed with ALL exhibit cytogenetic abnormalities involving the Philadelphia chromosome. Despite the existence of several studies on Philadelphia chromosome-positive ALL (Ph+ ALL), our case accentuates the use of a multi-disciplinary approach to treatment and involves a patient from a unique demographic.
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Affiliation(s)
- Natalie Shaykh
- Internal Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, USA
| | - Falguni Patel
- Internal Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, USA
| | - Luke Stachler
- Internal Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, USA
| | - Kabeer Ali
- Internal Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, USA
| | - Vanshika Tripathi
- Internal Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, USA
| | - Oshin Rai
- Internal Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, USA
| | - Rafik Jacob
- Internal Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, USA
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12
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Nishiwaki S, Sugiura I, Fujisawa S, Hatta Y, Atsuta Y, Doki N, Kurahashi S, Ueda Y, Dobashi N, Maeda T, Matsumura I, Tanaka M, Kako S, Ichinohe T, Fukuda T, Ohtake S, Ishikawa Y, Miyazaki Y, Kiyoi H. Utility of allogeneic stem cell transplantation for adult Ph+ALL with complete molecular remission. Am J Hematol 2024; 99:806-815. [PMID: 38314662 DOI: 10.1002/ajh.27237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/25/2023] [Accepted: 01/21/2024] [Indexed: 02/06/2024]
Abstract
This study aimed to investigate the usefulness of allogeneic stem cell transplantation (allo-SCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in the first complete remission (CR1) with complete molecular remission (CMR). We compared the outcomes between Ph+ALL patients who did or did not undergo allo-SCT in CR1. We included patients enrolled in the prospective clinical studies in the tyrosine kinase inhibitor era conducted by the Japan Adult Leukemia Study Group, who achieved CMR within 3 months. A total of 147 patients (allo-SCT: 101; non-SCT: 46) were eligible for this analysis. In the multivariate analyses, allo-SCT was significantly associated with both superior overall survival (OS) (adjusted hazard ratio (aHR): 0.54; 95% CI: 0.30-0.97; p = .04) and relapse-free survival (RFS) (aHR: 0.21; 95% CI: 0.12-0.38; p < .001). The 5-year adjusted OS and RFS were 73% and 70% in the allo-SCT cohort, whereas they were 50% and 20% in the non-SCT cohort. Despite the higher non-relapse mortality (aHR: 3.49; 95% CI: 1.17-10.4; p = .03), allo-SCT was significantly associated with a lower relapse rate (aHR: 0.10; 95% CI: 0.05-0.20; p < .001). In addition, allo-SCT was also associated with superior graft-versus-host disease-free, relapse-free survival (aHR: 0.43; 95% CI: 0.25-0.74; p = .002). Propensity score-matched analyses confirmed the results of the multivariate analyses. In patients who achieved CMR within 3 months, allo-SCT in CR1 had superior survival and lower relapse compared with the non-SCT cohort.
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Affiliation(s)
- Satoshi Nishiwaki
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Isamu Sugiura
- Division of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi, Japan
| | - Shin Fujisawa
- Department of Hematology, Yokohama City University Medical Center, Yokohama, Japan
| | - Yoshihiro Hatta
- Department of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
| | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan
- Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Shingo Kurahashi
- Division of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi, Japan
| | - Yasunori Ueda
- Department of Hematology/Oncology, Kurashiki Central Hospital, Kurashiki, Japan
| | - Nobuaki Dobashi
- Division of Clinical Oncology/Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomoya Maeda
- Department of Hemato-Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Itaru Matsumura
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Masatsugu Tanaka
- Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan
| | - Shinichi Kako
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Takahiro Fukuda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | | | - Yuichi Ishikawa
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasushi Miyazaki
- Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Hitoshi Kiyoi
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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13
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van Outersterp I, Boer JM, van de Ven C, Reichert CEJ, Boeree A, Kruisinga B, de Groot-Kruseman HA, Escherich G, Sijs-Szabo A, Rijneveld AW, den Boer ML. Tyrosine kinase inhibitor resistance in de novo BCR::ABL1-positive BCP-ALL beyond kinase domain mutations. Blood Adv 2024; 8:1835-1845. [PMID: 38386975 PMCID: PMC11007435 DOI: 10.1182/bloodadvances.2023012162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 02/05/2024] [Accepted: 02/06/2024] [Indexed: 02/24/2024] Open
Abstract
ABSTRACT A better understanding of ABL1 kinase domain mutation-independent causes of tyrosine kinase inhibitor (TKI) resistance is needed for BCR::ABL1-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Although TKIs have dramatically improved outcomes, a subset of patients still experiences relapsed or refractory disease. We aimed to identify potential biomarkers of intrinsic TKI resistance at diagnosis in samples from 32 pediatric and 19 adult patients with BCR::ABL1-positive BCP-ALL. Reduced ex vivo imatinib sensitivity was observed in cells derived from newly diagnosed patients who relapsed after combined TKI and chemotherapy treatment compared with cells derived from patients who remained in continuous complete remission. We observed that ex vivo imatinib resistance was inversely correlated with the amount of (phosphorylated) BCR::ABL1/ABL1 protein present in samples that were taken at diagnosis without prior TKI exposure. This suggests an intrinsic cause of TKI resistance that is independent of functional BCR::ABL1 signaling. Simultaneous deletions of IKZF1 and CDKN2A/B and/or PAX5 (IKZF1plus), as well as deletions of PAX5 alone, were related to ex vivo imatinib resistance. In addition, somatic lesions involving ZEB2, SETD2, SH2B3, and CRLF2 were associated with reduced ex vivo imatinib sensitivity. Our data suggest that the poor prognostic value of IKZF1(plus) deletions is linked to intrinsic mechanisms of TKI resistance other than ABL1 kinase domain mutations in newly diagnosed pediatric and adult BCR::ABL1-positive BCP-ALL.
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Affiliation(s)
| | - Judith M. Boer
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Cesca van de Ven
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | | | - Aurelie Boeree
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Brian Kruisinga
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | | | - Gabriele Escherich
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Aniko Sijs-Szabo
- Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Anita W. Rijneveld
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Monique L. den Boer
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Pediatric Oncology and Hematology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
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14
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Foà R, Bassan R, Elia L, Piciocchi A, Soddu S, Messina M, Ferrara F, Lunghi M, Mulè A, Bonifacio M, Fracchiolla N, Salutari P, Fazi P, Guarini A, Rambaldi A, Chiaretti S. Long-Term Results of the Dasatinib-Blinatumomab Protocol for Adult Philadelphia-Positive ALL. J Clin Oncol 2024; 42:881-885. [PMID: 38127722 PMCID: PMC10927329 DOI: 10.1200/jco.23.01075] [Citation(s) in RCA: 55] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 09/17/2023] [Accepted: 10/16/2023] [Indexed: 12/23/2023] Open
Abstract
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report the long-term results of the frontline trial with dasatinib and blinatumomab in induction/consolidation (GIMEMA LAL2116, D-ALBA) for adult Philadelphia-positive ALL (Ph+ ALL), which enrolled 63 patients of all ages. At a median follow-up of 53 months, disease-free survival, overall survival, and event-free survival are 75.8%, 80.7%, and 74.6%, respectively. No events have occurred among early molecular responders. A significantly worse outcome was recorded for IKZF1plus patients. Twenty-nine patients-93.1% being in molecular response (ie, complete molecular response or positive nonquantifiable) after dasatinib/blinatumomab-never received chemotherapy/transplant and continued with a tyrosine kinase inhibitor only; 28 patients remain in long-term complete hematologic response (CHR). An allogeneic transplant was carried out in first CHR mainly in patients with persistent minimal residual disease; 83.3% of patients are in continuous CHR. The transplant-related mortality was 12.5% for patients transplanted in first CHR and 13.7% overall. Nine relapses and six deaths have occurred. ABL1 mutations were found in seven cases. The final analysis of the D-ALBA study shows that a chemotherapy-free induction/consolidation regimen on the basis of a targeted strategy (dasatinib) and immunotherapy (blinatumomab) is effective in inducing durable long-term hematologic and molecular responses in adult Ph+ ALL, paving the way for a new era in the management of these patients.
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Affiliation(s)
- Robin Foà
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Renato Bassan
- Hematology Unit, Ospedale dell’Angelo and Ospedale Ss Giovanni e Paolo, Mestre Venezia, Italy
| | - Loredana Elia
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Alfonso Piciocchi
- GIMEMA Data Center, Fondazione GIMEMA Franco Mandelli Onlus, Rome, Italy
| | - Stefano Soddu
- GIMEMA Data Center, Fondazione GIMEMA Franco Mandelli Onlus, Rome, Italy
| | - Monica Messina
- GIMEMA Data Center, Fondazione GIMEMA Franco Mandelli Onlus, Rome, Italy
| | | | - Monia Lunghi
- Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Antonino Mulè
- UOC Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy
| | - Massimiliano Bonifacio
- Department of Engineering for Innovation Medicine, Section of Innovation Biomedicine, Hematology Area—University of Verona, Verona, Italy
| | - Nicola Fracchiolla
- UOC Oncoematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano, Milan, Italy
| | | | - Paola Fazi
- GIMEMA Data Center, Fondazione GIMEMA Franco Mandelli Onlus, Rome, Italy
| | - Anna Guarini
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Alessandro Rambaldi
- Hematology and Bone Marrow Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Sabina Chiaretti
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
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15
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Hidaka M, Inokuchi K, Uoshima N, Takahashi N, Yoshida N, Ota S, Nakamae H, Iwasaki H, Watanabe K, Kosaka Y, Komatsu N, Meguro K, Najima Y, Eto T, Kondo T, Kimura S, Yoshida C, Ishikawa Y, Sawa M, Hata T, Horibe K, Iida H, Shimomura T, Dobashi N, Sugiura I, Makiyama J, Miyagawa N, Sato A, Ito R, Matsumura I, Kanakura Y, Naoe T. Development and evaluation of a rapid one-step high sensitivity real-time quantitative PCR system for minor BCR-ABL (e1a2) test in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Jpn J Clin Oncol 2024; 54:153-159. [PMID: 37986553 PMCID: PMC10849185 DOI: 10.1093/jjco/hyad156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 10/25/2023] [Indexed: 11/22/2023] Open
Abstract
OBJECTIVE Minimal residual disease assessment of BCR-ABL messenger ribonucleic acid levels is crucial in Philadelphia chromosome-positive acute lymphoblastic leukemia for prognosis and treatment planning. However, accurately quantifying minor BCR-ABL transcripts, which comprise 70% of Philadelphia chromosome-positive acute lymphoblastic leukemia cases, lacks a national-approved method. METHODS We developed the "Otsuka" minor BCR-ABLmessenger ribonucleic acid assay kit with exceptional precision (0.00151%). Minor BCR-ABL messenger ribonucleic acid levels were analyzed in 175 adults, 36 children with acute lymphoblastic leukemia and 25 healthy individuals to evaluate the kit's performance. RESULTS The "Otsuka" kit showed high concordance with a commonly used chimeric gene screening method, indicating reliable detection of positive cases. Quantitative results demonstrated a robust correlation with both a laboratory-developed test and a diagnostic research product. The "Otsuka" kit performs comparably or even surpass to conventional products, providing valuable insights into Philadelphia chromosome-positive acute lymphoblastic leukemia pathology. CONCLUSIONS The 'Otsuka" minor BCR-ABL messenger ribonucleic acid assay kit exhibits excellent performance in quantifying minor BCR-ABL transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia patients. Our results align well with established screening methods and show a strong correlation with laboratory-developed tests and diagnostic research products. The "Otsuka" kit holds great promise as a valuable tool for understanding Philadelphia chromosome-positive acute lymphoblastic leukemia pathology and guiding effective treatment strategies.
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Affiliation(s)
- Michihiro Hidaka
- Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan
| | - Koiti Inokuchi
- Department of Hematology, Nippon Medical School, Tokyo, Japan
| | - Nobuhiko Uoshima
- Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan
| | - Naoto Takahashi
- Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Nao Yoshida
- Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Aichi Medical Center Nagoya First Hospital, Aichi, Japan
| | - Shuichi Ota
- Department of Hematology, Sapporo Hokuyu Hospital, Hokkaido, Japan
| | - Hirohisa Nakamae
- Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hiromi Iwasaki
- Department of Hematology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Kenichiro Watanabe
- Department of Hematology and Oncology, Shizuoka Children’s Hospital, Shizuoka, Japan
| | - Yoshiyuki Kosaka
- Department of Hematology and Oncology, Center of Childhood Cancer, Hyogo Prefectural Kobe Children’s Hospital, Hyogo, Japan
| | - Norio Komatsu
- Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kuniaki Meguro
- Department of Hematology, National Hospital Organization Sendai Medical Center, Miyagi, Japan
| | - Yuho Najima
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Tetsuya Eto
- Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
| | - Takeshi Kondo
- Blood Disorders Center, Aiiku Hospital, Hokkaido, Japan
| | - Shinya Kimura
- Department of Hematology, Respiratory Medicine and Oncology, Saga University, Saga, Japan
| | - Chikashi Yoshida
- Department of Hematology, National Hospital Organization Mito Medical Center, Ibaraki, Japan
| | - Yuichi Ishikawa
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Masashi Sawa
- Department of Hematology and Oncology, Anjo Kosei Hospital, Aichi, Japan
| | - Tomoko Hata
- Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan
| | - Keizo Horibe
- Department of Pediatrics, National Hospital Organization Nagoya Medical Center, Aichi, Japan
| | - Hiroatsu Iida
- Department of Hematology, National Hospital Organization Nagoya Medical Center, Aichi, Japan
| | - Takeshi Shimomura
- Department of Hematology, National Hospital Organization Hiroshimanishi Medical Center, Hiroshima, Japan
| | - Nobuaki Dobashi
- Department of Clinical Oncology and Hematology, The Jikei University Daisan Hospital, Tokyo, Japan
| | - Isamu Sugiura
- Department of Hematology and Oncology, Toyohashi Municipal Hospital, Aichi, Japan
| | - Junya Makiyama
- Department of Hematology/Oncology, Institute of Medical Science, The University of Tokyo Hospital, Tokyo, Japan
| | - Naoyuki Miyagawa
- Division of Hematology/Oncology, Kanagawa Children’s Medical Center, Kanagawa, Japan
| | - Asuka Sato
- Diagnostic Division, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan
| | - Ryuta Ito
- Diagnostic Division, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan
| | - Itaru Matsumura
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka, Japan
| | | | - Tomoki Naoe
- National Hospital Organization Nagoya Medical Center, Aichi, Japan
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16
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Oh I, Hatano K, Ikeda T, Toda Y, Minakata D, Kawaguchi S, Morita K, Yamamoto C, Ashizawa M, Sato K, Kameda K, Gomyo A, Misaki Y, Kawamura S, Kimura S, Kobayashi H, Sato H, Nakasone H, Ohmine K, Fujiwara S, Kako S, Kanda Y. Phase 2 trial of induction with dasatinib and consolidation with hyper-CVAD plus dasatinib followed by allografting for Ph-positive acute lymphoblastic leukemia in adults. Leuk Res 2024; 137:107438. [PMID: 38278044 DOI: 10.1016/j.leukres.2024.107438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 11/20/2023] [Accepted: 01/08/2024] [Indexed: 01/28/2024]
Affiliation(s)
- Iekuni Oh
- Department of Hematology, Yuai Memorial Hospital, Koga 306-0232, Japan
| | - Kaoru Hatano
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Takashi Ikeda
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Yumiko Toda
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Daisuke Minakata
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Shinichiro Kawaguchi
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Kaoru Morita
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Chihiro Yamamoto
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Masahiro Ashizawa
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Kazuya Sato
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Kazuaki Kameda
- Division of Hematology, Department of Medicine, Jichi Medical University Saitama Medical Center, Saitama 330-8503, Japan
| | - Ayumi Gomyo
- Division of Hematology, Department of Medicine, Jichi Medical University Saitama Medical Center, Saitama 330-8503, Japan
| | - Yukiko Misaki
- Division of Hematology, Department of Medicine, Jichi Medical University Saitama Medical Center, Saitama 330-8503, Japan
| | - Shunto Kawamura
- Division of Hematology, Department of Medicine, Jichi Medical University Saitama Medical Center, Saitama 330-8503, Japan
| | - Shunichi Kimura
- Division of Hematology, Department of Medicine, Jichi Medical University Saitama Medical Center, Saitama 330-8503, Japan
| | - Hiroyuki Kobayashi
- Department of Hematology, Nasu Red Cross Hospital, Tochigi 324-8686, Japan
| | - Hiroyuki Sato
- Department of Hematology, Saitama Red Cross Hospital, Saitama 330-8553, Japan
| | - Hideki Nakasone
- Division of Hematology, Department of Medicine, Jichi Medical University Saitama Medical Center, Saitama 330-8503, Japan
| | - Ken Ohmine
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Shinichiro Fujiwara
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Shinichi Kako
- Division of Hematology, Department of Medicine, Jichi Medical University Saitama Medical Center, Saitama 330-8503, Japan
| | - Yoshinobu Kanda
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan; Division of Hematology, Department of Medicine, Jichi Medical University Saitama Medical Center, Saitama 330-8503, Japan.
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17
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Yoon JH, Lee S. Diagnostic and therapeutic advances in adults with acute lymphoblastic leukemia in the era of gene analysis and targeted immunotherapy. Korean J Intern Med 2024; 39:34-56. [PMID: 38225824 PMCID: PMC10790045 DOI: 10.3904/kjim.2023.407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/03/2023] [Accepted: 12/23/2023] [Indexed: 01/17/2024] Open
Abstract
Acute lymphoblastic leukemia (ALL) is one of the most rapidly changing hematological malignancies with advanced understanding of the genetic landscape, detection methods of minimal residual disease (MRD), and the development of immunotherapeutic agents with good clinical outcomes. The annual incidence of adult ALL in Korea is 300-350 patients per year. The WHO classification of ALL was revised in 2022 to reflect the molecular cytogenetic features and suggest new adverse- risk subgroups, such as Ph-like ALL and ETP-ALL. We continue to use traditional adverse-risk features and cytogenetics, with MRD-directed post-remission therapy including allogeneic hematopoietic cell transplantation. However, with the introduction of novel agents, such as ponatinib, blinatumomab, and inotuzumab ozogamicin incorporated into frontline therapy, good MRD responses have been achieved, and overall survival outcomes are improving. Accordingly, some clinical trials have suggested a possible era of chemotherapy-free or transplantation-free approaches in the near future. Nevertheless, relapse of refractory ALL still occurs, and some poor ALL subtypes, such as Ph-like ALL and ETP-ALL, are unsolved problems for which novel agents and treatment strategies are needed. In this review, we summarize the currently applied diagnostic and therapeutic practices in the era of advanced genetic analysis and targeted immunotherapies in United States and Europe and introduce real-world Korean data.
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Affiliation(s)
- Jae-Ho Yoon
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seok Lee
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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18
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Tozawa N, Yamashita T, Nara M, Fujioka Y, Ikeda S, Kobayashi T, Kobayashi I, Kitadate A, Kameoka Y, Takahashi N. Ponatinib Improved the Prognosis of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Japanese Single-Center Cohort Study. Cureus 2023; 15:e50416. [PMID: 38222242 PMCID: PMC10784717 DOI: 10.7759/cureus.50416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2023] [Indexed: 01/16/2024] Open
Abstract
Introduction The overall survival (OS) of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has improved with the combination of tyrosine kinase inhibitor (TKI) with intensive chemotherapy. In recent years, there has been increased interest in the possibility of long-term survival without allogeneic hematopoietic stem cell transplantation (HSCT) or maintenance therapy. The aim of this study was to determine the effectiveness of treatment and the resultant outcomes in Ph+ALL patients using real-world data. Methods We performed a single-center retrospective analysis utilizing Akita University Hospital data (Akita, Japan) from November 2000 to June 2023 to evaluate the outcomes of TKI with intensive chemotherapy for Ph+ALL. Results Twenty-three patients with Ph+ALL were treated with intensive chemotherapy combined with TKI, including six imatinib, four dasatinib, and 13 ponatinib. The median patient age was 53 years (range; 28-67). Eighteen patients (78%) achieved complete molecular remission (CMR) within three months. HSCT was performed in 16 patients (70%), all of whom did not receive post-transplant TKI maintenance therapy. Six of the seven patients who did not undergo HSCT received maintenance therapy with ponatinib after intensive chemotherapy. The three-year OS was 81%. Ponatinib treatment resulted in a much higher OS rate than imatinib/dasatinib (100% vs. 60%; P=0.011). CMR within three months was identified as a prognostic factor for molecular relapse-free survival (hazard ratio (HR)=0.22; P=0.027). CD20 positivity was identified as a risk factor for hematological relapse (HR=5.2, P=0.032). Conclusion Even in a single-center cohort study, ponatinib, as a combination TKI with intensive chemotherapy or maintenance therapy, may improve the prognosis of Ph+ALL. Patients with CMR within three months might not necessarily need to receive HSCT, but a subsequent treatment-free status could have been achieved only by HSCT. Furthermore, CD20 positivity may be a useful biomarker for future treatment decisions in patients with Ph+ALL.
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Affiliation(s)
- Nagi Tozawa
- Department of Hematology, Akita University Hospital, Akita, JPN
| | | | - Miho Nara
- Department of Hematology, Akita University Hospital, Akita, JPN
| | - Yuki Fujioka
- Department of Hematology, Akita University Hospital, Akita, JPN
| | - Sho Ikeda
- Department of Hematology, Akita University Hospital, Akita, JPN
| | | | - Isuzu Kobayashi
- Department of Hematology, Akita University Hospital, Akita, JPN
| | | | | | - Naoto Takahashi
- Department of Hematology, Akita University Hospital, Akita, JPN
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19
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Rahman ZA, Kebriaei P. SOHO State of the Art Updates and Next Questions | Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in Adults: Therapeutic Options and Challenges in 2023. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2023; 23:779-785. [PMID: 37438208 DOI: 10.1016/j.clml.2023.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 06/23/2023] [Indexed: 07/14/2023]
Abstract
The therapeutic landscape of Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) for adults has dramatically changed over the past 2 decades; the emergence of newer generations of tyrosine kinase inhibitors and incorporation of targeted immunotherapies into front-line therapy have significantly improved outcomes to the point where an argument can be made that this entity may no longer be considered a high-risk ALL subgroup. In this review article, we discuss different front-line regimens (both intensive and deintensified regimens including chemotherapy-free regimens). We also review disease monitoring strategies, discuss the role of allogeneic hematopoietic stem cell transplantation, and discuss the rapidly changing therapeutic landscape for patients with relapsed disease.
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Affiliation(s)
- Zaid Abdel Rahman
- Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Partow Kebriaei
- Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
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20
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Prockop S, Wachter F. The current landscape: Allogeneic hematopoietic stem cell transplant for acute lymphoblastic leukemia. Best Pract Res Clin Haematol 2023; 36:101485. [PMID: 37611999 DOI: 10.1016/j.beha.2023.101485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 08/25/2023]
Abstract
One of the consistent features in development of hematopoietic stem cell transplant (HCT) for Acute Lymphoblastic Leukemia (ALL) is the rapidity with which discoveries in the laboratory are translated into innovations in clinical care. Just a few years after murine studies demonstrated that rescue from radiation induced marrow failure is mediated by cellular not humoral factors, E. Donnall Thomas reported on the transfer of bone marrow cells into irradiated leukemia patients. This was followed quickly by the first descriptions of Graft versus Leukemia (GvL) effect and Graft versus Host Disease (GvHD). Despite the pivotal nature of these findings, early human transplants were uniformly unsuccessful and identified the challenges that continue to thwart transplanters today - leukemic relapse, regimen related toxicity, and GvHD. While originally only an option for young, fit patients with a matched family donor, expansion of the donor pool to include unrelated donors, umbilical cord blood units, and more recently the growing use of haploidentical donors have all made transplant a more accessible therapy for patients with ALL. Novel agents for conditioning, prevention and treatment of GvHD have improved outcomes and investigators continue to develop novel treatment strategies that balance regimen related toxicity with disease control. Our evolving understanding of how to prevent and treat GvHD and how to prevent relapse are incorporated into novel clinical trials that are expected to further improve outcomes. Here we review current considerations and future directions for both adult and pediatric patients undergoing HCT for ALL, including indication for transplant, donor selection, cytoreductive regimens, and outcomes.
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Affiliation(s)
- Susan Prockop
- Pediatric Stem Cell Transplant Program, DFCI/BCH Center for Cancer and Blood Disorders, Pediatrics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States.
| | - Franziska Wachter
- Pediatric Stem Cell Transplant Program, DFCI/BCH Center for Cancer and Blood Disorders, Pediatrics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States.
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21
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Kako S. Prophylactic or pre-emptive therapies to prevent relapse after allogeneic hematopoietic stem cell transplantation. Int J Hematol 2023:10.1007/s12185-023-03631-w. [PMID: 37418118 DOI: 10.1007/s12185-023-03631-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 06/20/2023] [Accepted: 06/21/2023] [Indexed: 07/08/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation is a potent curative treatment for hematological malignancies, but relapse is still a major problem. Donor lymphocyte infusion (DLI) and maintenance therapies after transplantation are promising strategies to reduce the risk of relapse. DLI augments the graft-versus-tumor effect by directly adding allo-reactive donor lymphocytes, and has been used in relapsed patients. In this Progress in Hematology (PIH), we will focus on prophylactic or pre-emptive DLI, including DLI from a haploidentical donor. On the other hand, specific drugs, which are used in maintenance therapies for each disease, kill tumor cells directly and/or immunologically by stimulating immune cells. Maintenance therapies should be started early after transplantation without severe myelosuppression. Molecularly targeted drugs are therefore suitable for use in maintenance therapies, and are reviewed in this PIH. The optimal application of these strategies has not yet been established. However, important evidence regarding their efficacies, adverse events, and effects on immune systems is accumulating, and could help to improve outcomes in allogeneic transplantation.
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Affiliation(s)
- Shinichi Kako
- Division of Hematology, Department of Internal Medicine, Jichi Medical University Saitama Medical Center, 1-847 Amanuma, Omiya-Ku, Saitama-City, Saitama, 330-8503, Japan.
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22
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Ribera JM, Prawitz T, Freitag A, Sharma A, Dobi B, Rizzo F, Sabatelli L, Patos P. Ponatinib vs. Imatinib as Frontline Treatment for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Matching Adjusted Indirect Comparison. Adv Ther 2023; 40:3087-3103. [PMID: 37208556 PMCID: PMC10272268 DOI: 10.1007/s12325-023-02497-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 03/15/2023] [Indexed: 05/21/2023]
Abstract
INTRODUCTION Efficacy of ponatinib-based treatment for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) has not been compared to imatinib-based treatments in head-to-head clinical trials. We evaluated its efficacy versus imatinib-based regimens using a matching adjusted indirect comparison. METHODS Two ponatinib studies were used: the phase 2 MDACC study of ponatinib + hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in adult patients and the phase 2 GIMEMA LAL1811 study of ponatinib + steroids in patients > 60 years/unfit for intensive chemotherapy and stem cell transplant. Studies on imatinib as first-line treatment in adults with Ph + ALL were identified using a systematic literature search. Population adjustment was based on the prognostic factors and effect modifiers identified by clinical experts. Hazard ratios (HRs) were calculated for overall survival (OS) and odds ratios (ORs) for complete molecular response (CMR). RESULTS The systematic literature search identified two studies (GRAAPH-2005 and NCT00038610) reporting the efficacy of first-line imatinib + hyper-CVAD and one study reporting the efficacy of first-line imatinib monotherapy induction + imatinib-based consolidation (CSI57ADE10). Ponatinib + hyper-CVAD prolonged OS and gave a higher CMR rate than imatinib + hyper-CVAD. The adjusted HR [95% confidence interval (CI)] for OS was 0.35 (0.17-0.74) for MDACC vs. GRAAPH-2005 and 0.35 (0.18-0.70) for MDACC vs. NCT00038610; the adjusted OR (95% CI) for CMR was 12.11 (3.77-38.87) for MDACC vs. GRAAPH-2005 and 5.65 (2.02-15.76) for MDACC vs. NCT00038610. Ponatinib + steroids prolonged OS and gave a higher CMR rate than imatinib monotherapy induction + imatinib-containing consolidation. The adjusted HR (95% CI) for OS was 0.24 (0.09-0.64) and the adjusted OR (95% CI) for CMR was 6.20 (1.60-24.00) for GIMEMA LAL1811 vs. CSI57ADE10. CONCLUSION In adults with newly diagnosed Ph + ALL, first-line treatment with ponatinib was associated with better outcomes than first-line treatment with imatinib.
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Affiliation(s)
- Josep-Maria Ribera
- ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, c/ Canyet, s/n, 08916, Badalona, Spain.
| | | | | | | | | | - Federica Rizzo
- Incyte Biosciences International Sàrl, Morges, Switzerland
| | | | - Petros Patos
- Incyte Biosciences International Sàrl, Morges, Switzerland
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23
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Modi D, Alkassis S, Kim S, Kin A, Deol A, Ayash L, Ratanatharathorn V, Uberti JP. Allogeneic stem cell transplant outcomes between TBI-containing reduced intensity and myeloablative conditioning regimens for ALL in complete remission. Leuk Lymphoma 2023; 64:1285-1294. [PMID: 37154379 DOI: 10.1080/10428194.2023.2206181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 04/11/2023] [Accepted: 04/14/2023] [Indexed: 05/10/2023]
Abstract
Total-body irradiation (TBI)-based conditioning regimen is preferred in acute lymphoblastic leukemia (ALL). We retrospectively evaluated allogeneic stem cell transplant (alloSCT) outcomes of 86 adult ALL patients in complete remission (CR) who received TBI-containing reduced intensity (RIC) (Flu/Mel/TBI = 31) and myeloablative conditioning (MAC) (VP16/TBI = 47; CY/TBI = 8) between January 2005 and December 2019. All patients received peripheral blood allografts. Patients in the RIC group were older than the MAC group (61 years old versus 36 years, p < .001). Donor was 8/8 HLA-matched in 83% and unrelated in 65% of patients. Three-year survival was 56.04% for RIC and 69.9% for MAC (HR 0.64; p = .19). Propensity score-based multivariable Cox analyses (PSCA) did not demonstrate any difference in grade III-IV acute graft versus host disease (GVHD) (SHR 1.23, p = .91), chronic GVHD (SHR 0.92, p = .88), survival (HR 0.94, p = .92), and relapse-free survival (HR 0.66, p = .47) between both groups, while relapse rate was lower (SHR 0.21, p = .02) for MAC compared to RIC. Our study did not demonstrate any difference in survival for TBI-containing RIC and MAC alloSCT for adult ALL in CR.
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Affiliation(s)
- Dipenkumar Modi
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Samer Alkassis
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Seongho Kim
- Biostatistics Core, Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI, USA
| | - Andrew Kin
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Abhinav Deol
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Lois Ayash
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Voravit Ratanatharathorn
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Joseph P Uberti
- Department of Oncology, Blood & Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
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24
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Nishiwaki S, Sugiura I, Fujisawa S, Hatta Y, Atsuta Y, Doki N, Kurahashi S, Ueda Y, Dobashi N, Maeda T, Taniguchi Y, Tanaka M, Kako S, Ichinohe T, Fukuda T, Ohtake S, Ishikawa Y, Kiyoi H, Matsumura I, Miyazaki Y. High-risk Combinations of Additional Chromosomal Abnormalities in Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia: JALSG Ph+ALL TKI-SCT Study. Hemasphere 2023; 7:e899. [PMID: 37475881 PMCID: PMC10356120 DOI: 10.1097/hs9.0000000000000899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 04/21/2023] [Indexed: 07/22/2023] Open
Affiliation(s)
- Satoshi Nishiwaki
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Isamu Sugiura
- Division of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi, Japan
| | - Shin Fujisawa
- Department of Hematology, Yokohama City University Medical Center, Yokohama, Japan
| | - Yoshihiro Hatta
- Department of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
| | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan
- Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Shingo Kurahashi
- Division of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi, Japan
| | - Yasunori Ueda
- Department of Hematology/Oncology, Kurashiki Central Hospital, Kurashiki, Japan
| | - Nobuaki Dobashi
- Division of Clinical Oncology/Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomoya Maeda
- Department of Hemato-Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Yasuhiro Taniguchi
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Masatsugu Tanaka
- Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan
| | - Shinichi Kako
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Takahiro Fukuda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | | | - Yuichi Ishikawa
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hitoshi Kiyoi
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Itaru Matsumura
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Yasushi Miyazaki
- Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
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25
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Nishiwaki S, Sugiura I, Sato T, Kobayashi M, Osaki M, Sawa M, Adachi Y, Okabe M, Saito S, Morishita T, Kohno A, Nishiyama T, Iida H, Kurahashi S, Kuwatsuka Y, Sugiyama D, Ito S, Nishikawa H, Kiyoi H. Autologous peripheral blood stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia is safe but poses challenges for long-term maintenance of molecular remission: Results of the Auto-Ph17 study. EJHAEM 2023; 4:358-369. [PMID: 37206256 PMCID: PMC10188459 DOI: 10.1002/jha2.677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/01/2023] [Accepted: 03/07/2023] [Indexed: 05/21/2023]
Abstract
Autologous hematopoietic stem cell transplantation (SCT) is not a standard treatment option for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL); however, its position has been reassessed since the introduction of tyrosine kinase inhibitors (TKIs). We prospectively analyzed the efficacy and safety of autologous peripheral blood SCT (auto-PBSCT) for Ph+ALL patients aged between 55 and 70 years who had achieved complete molecular remission. Melphalan, cyclophosphamide, etoposide, and dexamethasone were used for conditioning. A total of 12 courses of maintenance therapy, including dasatinib, were performed. The required number of CD34+ cells was harvested in all five patients. No patient died within 100 days after auto-PBSCT, and no unexpected serious adverse events were observed. Although 1-year event-free survival was 100%, hematological relapse was observed in three patients at a median of 801 days (range, 389-1088 days) after auto-PBSCT. Molecular progressive disease was observed in the other two patients, although they maintained their first hematological remission at the last visit. Auto-PBSCT can be safely performed for Ph+ALL with TKIs. A limitation of auto-PBSCT was suggested, despite the increase in the intensity of a single treatment. The development of long-term therapeutic strategies by including new molecular targeted drugs is warranted to maintain long-term molecular remission.
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Affiliation(s)
- Satoshi Nishiwaki
- Department of Advanced MedicineNagoya University HospitalNagoyaJapan
| | - Isamu Sugiura
- Division of Hematology and OncologyToyohashi Municipal HospitalToyohashiJapan
| | - Takahiko Sato
- Department of ImmunologyNagoya University Graduate School of MedicineNagoyaJapan
- Department of Hematology and OncologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Miki Kobayashi
- Department of Hematology and OncologyJapanese Red Cross Aichi Medical Center Nagoya Daini HospitalNagoyaJapan
| | - Masahide Osaki
- Department of HematologyJapanese Red Cross Aichi Medical Center Nagoya Daiichi HospitalNagoyaJapan
| | - Masashi Sawa
- Department of Hematology and OncologyAnjo Kosei HospitalAnjoJapan
| | - Yoshitaka Adachi
- Department of Hematology and OncologyJA Aichi Konan Kosei HospitalKonanJapan
| | - Motohito Okabe
- Department of HematologyJapanese Red Cross Aichi Medical Center Nagoya Daiichi HospitalNagoyaJapan
| | - Shigeki Saito
- Department of Hematology and OncologyJapanese Red Cross Aichi Medical Center Nagoya Daini HospitalNagoyaJapan
| | - Takanobu Morishita
- Department of HematologyJapanese Red Cross Aichi Medical Center Nagoya Daiichi HospitalNagoyaJapan
| | - Akio Kohno
- Department of Hematology and OncologyJA Aichi Konan Kosei HospitalKonanJapan
| | | | - Hiroatsu Iida
- Department of HematologyNational Hospital Organization Nagoya Medical CenterNagoyaJapan
| | - Shingo Kurahashi
- Division of Hematology and OncologyToyohashi Municipal HospitalToyohashiJapan
| | - Yachiyo Kuwatsuka
- Department of Advanced MedicineNagoya University HospitalNagoyaJapan
| | - Daisuke Sugiyama
- Department of ImmunologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Sachiko Ito
- Department of ImmunologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Hiroyoshi Nishikawa
- Department of ImmunologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Hitoshi Kiyoi
- Department of Hematology and OncologyNagoya University Graduate School of MedicineNagoyaJapan
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26
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Badar T, Alkhateeb H, Aljurf M, Kharfan-Dabaja MA. Management of Philadelphia chromosome positive acute lymphoblastic leukemia in the current era. Curr Res Transl Med 2023; 71:103392. [PMID: 37121211 DOI: 10.1016/j.retram.2023.103392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 04/13/2023] [Accepted: 04/20/2023] [Indexed: 05/02/2023]
Abstract
Before the advent of tyrosine kinase inhibitors (TKI) the outcome of Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) was dismal. The TKI combination with induction regimens has greatly improved the long-term outcome of Ph+ ALL, specifically ponatinib a most potent TKI in combination with HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) chemotherapy has demonstrated 5 years overall survival up to 75%. Historically, allogeneic hematopoietic stem cell transplantation (allo-HSCT) used to be the only potential curative option, recent data suggest that patients who achieve complete molecular remission within 3 months of TKI based induction therapies can achieve comparable overall survival with or without allo-HSCT. Intensive cytotoxic chemotherapy may not be the desirable treatment option in elderly Ph+ ALL patients due to anticipated tolerance, recently in a phase II study, "chemotherapy free" combinations such as blinatumomab (bispecific anti-CD3 and anti-CD19 monoclonal antibody) with ponatinib in treatment naïve Ph+ ALL patients have shown a complete response rate of 95% and 2 years overall survival of 93%. In this review we have highlighted the evolving treatment landscape of Ph+ ALL and what to look for in future.
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Affiliation(s)
- Talha Badar
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, FL, USA.
| | - Hassan Alkhateeb
- Division of Hematology, Mayo Clinic, 200 First St SW., Rochester, MN, USA
| | - Mahmoud Aljurf
- Section of Adult Hematology/BMT Department of Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia
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Wan L, Ma J, Gong X, Li Q, Wang Y, Wei H, Wang J, Xiao Z, Mi Y. Droplet digital polymerase chain reaction improves the detection of BCR-ABL1 kinase domain mutation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Lab Hematol 2023. [PMID: 36990968 DOI: 10.1111/ijlh.14069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 03/15/2023] [Indexed: 03/31/2023]
Abstract
INTRODUCTION Sanger sequencing (SS) is the most frequently used method for detecting ABL1 kinase domain (KD) mutations in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, it cannot detect low levels of mutation. Recently, droplet digital polymerase chain reaction (ddPCR) has been developed as a sensitive technique for detecting mutations in hematological neoplasms. The aim of our study was to explore the value of ddPCR in detecting ABL1 KD mutations. METHODS We compared the results of SS and ddPCR in detecting ABL1 KD mutations in a consecutive cohort of 65 adolescent and adult patients with Ph+ ALL treated with intensive multiagent chemotherapy plus TKIs. RESULTS At diagnosis, SS and ddPCR identified 1 (1.5%) and 26 (40%) out of 65 patients with positive ABL1 KD mutations, respectively. Patients with T315I mutations detected by ddPCR at diagnosis all developed SS-detectable T315I mutations during treatment with first- or second-generation TKIs, and non-T315I mutations detected by ddPCR at diagnosis displayed a limited prognostic impact. CONCLUSION Our study demonstrates that ddPCR is a highly sensitive and accurate mutation detection method and the presence of T315I mutations before treatment shows prognostic significance in the context of first- or second-generation TKIs.
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Affiliation(s)
- Li Wan
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Jiao Ma
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Xiaoyuan Gong
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Qinghua Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Ying Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Hui Wei
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Jianxiang Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Zhijian Xiao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Yingchang Mi
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
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28
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Xie M, Shi T, Jiang Q, Jia Y, Zhou D, Tong H, Jin J, Zhu HH. Chemotherapy with the use of next-generation TKIs based on MRD has the potential to avoid hematopoietic stem cell transplantation in treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer 2023; 129:1523-1536. [PMID: 36882308 DOI: 10.1002/cncr.34710] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 03/09/2023]
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) as postremission treatment is recommended for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) in current guidelines. However, comparisons of later generation tyrosine kinase inhibitors (TKIs) plus chemotherapy with allo-HSCT have yielded similar outcomes. This meta-analysis was performed to evaluate allo-HSCT in first complete remission (CR1) versus chemotherapy for adult Ph+ ALL in the TKI era. METHODS Pooled assessment of the hematologic and molecular complete response rates was performed after 3-month TKI treatment. Hazard ratios (HRs) were determined for disease-free survival (DFS) and overall survival (OS) benefit with allo-HSCT. The effect of measurable residual disease status on survival benefit was also analyzed. RESULTS Thirty-nine retrospective and prospective single-arm cohort studies involving 5054 patients were included. Combined HRs indicated that in the general population, allo-HSCT favorably influenced DFS and OS. Achieving complete molecular remission (CMR) within 3 months after starting induction was a favorable survival prognostic factor regardless of whether the patient had undergone allo-HSCT. Among the patients with CMR, survival rates in the nontransplant subgroup were comparable with those in the transplant subgroup, with the estimated 5-year OS of 64% versus 58% and 5-year DFS of 58% versus 51%, respectively. The use of next-generation TKIs results in a higher proportion of patients achieving CMR (ponatinib 82% vs. imatinib 53%), while improving survival in nontransplant patients. CONCLUSION Our novel findings suggest that combination chemotherapy plus TKIs leads to a comparable survival benefit as with allo-HSCT for MRD-negative (CMR) patients. This study provides novel evidence for allo-HSCT indications for Ph+ ALL in CR1 in the TKI era.
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Affiliation(s)
- Mixue Xie
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ting Shi
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qi Jiang
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yunlu Jia
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - De Zhou
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Hongyan Tong
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hong-Hu Zhu
- Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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29
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Shahzad M, Hussain A, Tariq E, Anwar I, Faisal MS, Syed L, Karam A, Chaudhary SG, Ahmed N, Bansal R, Khurana S, Singh AK, Byrd KP, Hematti P, Abhyankar SH, McGuirk JP, Mushtaq MU. Outcomes of Tyrosine Kinase Inhibitors Maintenance Therapy with or without Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission: A Systematic Review and Meta-Analysis. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2023; 23:178-187. [PMID: 36682989 DOI: 10.1016/j.clml.2023.01.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/03/2023] [Accepted: 01/05/2023] [Indexed: 01/13/2023]
Abstract
We conducted a systematic review and meta-analysis to compare outcomes of tyrosine kinase inhibitor (TKI) maintenance therapy with or without allogeneic hematopoietic stem cell transplantation (HSCT) in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in first remission (CR1). A literature search was performed on PubMed, Cochrane, and Clinical trials.gov. After screening 1720 articles, 12 studies were included. Proportions and odds ratios (OR) with 95% confidence intervals (CI) were computed. I2 provides an estimate of the percentage of variability in results across studies that is due to real differences and not due to chance. Of 1039 patients, 635 (61%) had TKI alone and 404 (39%) patients had HSCT followed by TKI. At 3 years, a trend towards poor overall survival (OS; OR 0.67, 95% CI 0.39-1.15, I2 = 68%), (disease-free survival; OR 0.58, 95% CI 0.26-1.29, I2 = 76%), and higher relapse rate (RR; OR = 2.52, 95% CI = 1.66-3.83, I2 = 26%) was seen with TKI alone compared to HSCT-TKI. Although HSCT followed by TKI maintenance in Ph+ ALL has long been considered standard of care, the introduction of potent third-generation TKIs and bispecific T-cell engagers such as Blinatumomab has significantly improved outcomes while sparing the need for HSCT in newly diagnosed patients.
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Affiliation(s)
- Moazzam Shahzad
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS; Moffitt Cancer Center, University of South Florida, Tampa, FL
| | - Ali Hussain
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Ezza Tariq
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Iqra Anwar
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Muhammad S Faisal
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Leena Syed
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Alvina Karam
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Sibgha Gull Chaudhary
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Nausheen Ahmed
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Rajat Bansal
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Sharad Khurana
- Division of Hematology/Oncology, University of Arizona College of Medicine, Tucson, AZ
| | - Anurag K Singh
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Kenneth P Byrd
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Peiman Hematti
- Division of Hematology/Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Sunil H Abhyankar
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Joseph P McGuirk
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Muhammad Umair Mushtaq
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS.
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30
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Wieduwilt MJ. Ph+ ALL in 2022: is there an optimal approach? HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2022; 2022:206-212. [PMID: 36485090 PMCID: PMC9820632 DOI: 10.1182/hematology.2022000338] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) carried a very poor prognosis prior to the advent of tyrosine kinase inhibitors (TKIs) that block the activity of the BCR-ABL1 oncoprotein. With improvements in TKI efficacy and allogeneic hematopoietic cell transplantation (HCT), survival has improved over the past 3 decades, and the role of chemotherapy and allogeneic HCT is now changing. Better risk stratification, the application of the third-generation TKI ponatinib, and the use of immunotherapy with the CD19-CD3 bifunctional T-cell engaging antibody blinatumomab in place of chemotherapy has made therapy for Ph+ ALL more tolerable and arguably more efficacious, especially for older patients who comprise most patients with Ph+ ALL.
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Affiliation(s)
- Matthew J. Wieduwilt
- Correspondence Matthew J. Wieduwilt, 1 Medical Center Blvd #3rd, Winston- Salem, NC 27157, USA; e-mail:
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31
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Haddad FG, Short NJ. Evidence-Based Minireview: What is the optimal tyrosine kinase inhibitor for adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia? HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2022; 2022:213-217. [PMID: 36485089 PMCID: PMC9820762 DOI: 10.1182/hematology.2022000413] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
The incorporation of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy significantly improved the outcomes of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). This was first shown with the addition of the first-generation TKI imatinib, which allowed more patients to be bridged to an allogeneic stem cell transplant (SCT) and led to superior long-term outcomes compared with chemotherapy alone. The use of second-generation TKIs (eg, dasatinib and nilotinib) has led to further improvement in outcomes of patients with Ph- positive ALL, with a long-term survival of 40% to 60% in several studies. Ponatinib is a third-generation, more potent TKI that results in high rates of molecular response and promising long-term survival even when allogeneic SCT is not routinely performed. While randomized data to support the TKI selection in Ph-positive ALL are lacking, data from single-arm studies suggest deeper molecular responses and superior survival outcomes with each successive generation of TKI. More recently, chemotherapy-free regimens with blinatumomab and TKIs have shown excellent results in the frontline setting and may represent an emerging paradigm shift in the treatment of Ph-positive ALL.
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Affiliation(s)
- Fadi G Haddad
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Nicholas J Short
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
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32
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Chen H, Xu LP, Zhang XH, Wang Y, Chen YH, Yan CH, Cheng YF, Han W, Chen Y, Qin YZ, Liu Y, Chang YJ, Liu KY, Huang XJ. Safety and outcomes of maintenance therapy with third-generation tyrosine kinase inhibitor after allogeneic hematopoietic cell transplantation in Philadelphia chromosome positive acute lymphoblastic leukemia patients with T315I mutation. Leuk Res 2022; 121:106930. [PMID: 36007342 DOI: 10.1016/j.leukres.2022.106930] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 06/26/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022]
Abstract
Studies using third-generation tyrosine kinase inhibitor (TKI) as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) harboring the T315I mutation remain scarce. We conducted a cohort study to evaluate the safety and outcomes of ponatinib maintenance therapy after HCT in Ph+ALL patients with T315I mutation. BCR-ABL kinase domain mutations were assessed using direct sequencing. Twenty-six Ph+ALL patients with T315I mutation who received allogeneic HCT were enrolled. After HCT, ponatinib was administered as a prophylactic regimen (n = 12) or a preemptive therapy (n = 7). Seven patients did not receive maintenance therapy. Adverse events (AEs) occurred in 69.4 % of patients with ponatinib maintenance, but most presented with mild toxicities. Serious non-hematological AEs were not observed. The 5-year disease-free survival (DFS), overall survival (OS), and cumulative incidence of relapse in patients receiving prophylactic ponatinib were 81.5 %, 91.7 %, and 18.5 %, respectively, whereas they were 39.8 %, 46.0 %, and 48.4 % in the total cohort, respectively. The measurable BCR-ABL transcripts in the first three months after HCT was associated with poor DFS and OS, even with ponatinib therapy. We concluded that maintenance therapy with ponatinib is safe after HCT. Patients with T315I mutation who received prophylactic regimen showed promising results with an acceptable relapse rate and encouraging survival. However, patients with measurable BCR-ABL transcripts early post-transplant had poor outcomes.
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Affiliation(s)
- Huan Chen
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Lan-Ping Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Yu-Hong Chen
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Chen-Hua Yan
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Yi-Fei Cheng
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Wei Han
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Yao Chen
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Ya-Zhen Qin
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Yanrong Liu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Ying-Jun Chang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Kai-Yan Liu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11, Xizhimen South Street, Xicheng District, Beijing 100044, PR China.
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Jabbour E, Haddad FG, Short NJ, Kantarjian H. Treatment of Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia-From Intensive Chemotherapy Combinations to Chemotherapy-Free Regimens: A Review. JAMA Oncol 2022; 8:1340-1348. [PMID: 35834222 DOI: 10.1001/jamaoncol.2022.2398] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Importance With the advent of potent BCR::ABL1 tyrosine kinase inhibitors (TKIs), Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) is now a relatively favorable-risk acute leukemia. In this review, we discuss the current evidence for frontline therapies of Ph-positive ALL, the major principles that guide therapy, and the progress with chemotherapy-free regimens. Observations Incorporating TKIs into the chemotherapy regimens of patients with newly diagnosed Ph-positive ALL has led to improved remission rates, higher probability of reaching allogeneic stem cell transplantation (SCT), and longer survival compared with chemotherapy alone. Early achievement of a complete molecular remission (CMR) is an important end point in Ph-positive ALL and identifies patients who have excellent long-term survival and may not need allogeneic SCT. Second-generation TKIs combined with intensive or low-intensity chemotherapy resulted in higher CMR rates compared with imatinib-based regimens. This translated into better outcomes, with less reliance on allogeneic SCT. To further improve the outcomes, the potent third-generation TKI ponatinib was added to chemotherapy. The combination of hyper-CVAD and ponatinib resulted in an overall CMR rate of 84% and a 5-year survival rate of 73% and 86% among patients who did and did not undergo allogeneic SCT, respectively, suggesting that allogeneic SCT may not be needed with this regimen. The recent chemotherapy-free combination of dasatinib and blinatumomab was safe and effective in patients with newly diagnosed Ph-positive ALL and resulted in an estimated 3-year OS rate of 80%; 50% of patients underwent allogeneic SCT. The chemotherapy-free regimen of ponatinib and blinatumomab resulted in a CMR rate of 86% and a 2-year survival rate of 93%, with no relapses or leukemia-related deaths, and with only 1 patient proceeding to allogeneic SCT. Conclusions and Relevance The promising results obtained with the chemotherapy-free regimens of blinatumomab plus TKIs question the role of allogeneic SCT in first remission. Patients with Ph-positive ALL who achieve early and deep molecular responses have excellent long-term outcomes and may not benefit from allogeneic SCT.
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Affiliation(s)
- Elias Jabbour
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston
| | - Fadi G Haddad
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston
| | - Nicholas J Short
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston
| | - Hagop Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston
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Improvements in allogeneic hematopoietic cell transplantation outcomes for adults with ALL over the past 3 decades. Blood Adv 2022; 6:4558-4569. [PMID: 35737870 PMCID: PMC9636313 DOI: 10.1182/bloodadvances.2022008032] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 06/06/2022] [Indexed: 11/20/2022] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising treatment for adult acute lymphoblastic leukemia (ALL), an intractable hematological malignancy. The trends in allo-HCT outcomes over the past 30 years were examined to verify the efficacy of evolving treatment methods and to identify further challenges. We analyzed data from a registry database that included 8467 adult ALL patients who underwent their first allo-HCT between 1990 and 2019. The period was divided into three 10-year intervals for analysis. Five-year overall survival improved from 48.2% to 70.2% in the first complete remission (CR1), from 25.6% to 44.1% in subsequent CR, and from 10.0% to 22.7% in non-CR. Nonrelapse mortality improved over the 3 decades in each disease stage. However, the relapse rate only improved in CR1 every decade (26.3% to 15.9% in CR1, 33.4% to 32.8% in subsequent CR, and 53.6% to 54.8% in non-CR). Although there were continual improvements in adjusted survival for Philadelphia chromosome (Ph)-positive patients, the improvement was inadequate for Ph− patients with t(4;11), t(8;14), t(14;18), or hypodiploidy. Allo-HCT outcomes for adults with ALL have improved over the past 30 years. Improved outcomes in the future will require more effective prevention of relapse in patients with ALL not in CR1 and in those with high-risk chromosomal abnormalities.
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Affiliation(s)
- Robin Foà
- From Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome
| | - Sabina Chiaretti
- From Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome
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Harada K, Morita-Fujita M, Fukuda T, Ozawa Y, Doki N, Toyosaki M, Maruyama Y, Kanda Y, Ashida T, Eto T, Takada S, Uchida N, Ichinohe T, Kanda J, Onizuka M, Atsuta Y, Kako S, Arai Y. Overcoming minimal residual disease using intensified conditioning with medium-dose etoposide, cyclophosphamide and total body irradiation in allogeneic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia in adults. Cytotherapy 2022; 24:954-961. [DOI: 10.1016/j.jcyt.2022.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/28/2022] [Accepted: 03/10/2022] [Indexed: 11/03/2022]
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Nakagawa R, Iwamoto H, Makino T, Kadomoto S, Yaegashi H, Iijima M, Kawaguchi S, Nohara T, Shigehara K, Izumi K, Kadono Y, Mizokami A. Analysis of the Safety of Pegfilgrastim Addition in Bleomycin, Etoposide, and Cisplatin Treatment Patients With Germ Cell Tumors. Front Oncol 2022; 11:770067. [PMID: 35070973 PMCID: PMC8776647 DOI: 10.3389/fonc.2021.770067] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 12/16/2021] [Indexed: 12/16/2022] Open
Abstract
It has been reported that chemotherapy drugs and granulocyte colony-stimulating factor (G-CSF) administered on the same day can aggravate neutropenia. In the present study, we investigated the safety of pegfilgrastim during bleomycin, etoposide, and cisplatin (BEP) therapy. This single-center retrospective study, including 137 cycles of BEP therapy for germ cell tumors between January 2008 and April 2021, investigated safety. Short-acting G-CSF was used for 84 cycles and pegfilgrastim was used for 53 cycles. In the pegfilgrastim group, neutrophil count at nadir was significantly higher than in the G-CSF group (median 1,650/μl and 680/μl, respectively). The incidence of grade 3–4 neutropenia was significantly higher and the duration longer in the G-CSF group. Also, there was no significant difference in the incidence of febrile neutropenia. In conclusion, concomitant use of pegfilgrastim during BEP therapy did not increase neutropenia and was effective in terms of safety.
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Affiliation(s)
- Ryunosuke Nakagawa
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Hiroaki Iwamoto
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Tomoyuki Makino
- Department of Urology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
| | - Suguru Kadomoto
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Hiroshi Yaegashi
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Masashi Iijima
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Shohei Kawaguchi
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Takahiro Nohara
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Kazuyoshi Shigehara
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Kouji Izumi
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Yoshifumi Kadono
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Atsushi Mizokami
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
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Khader A, Bokhari R, Hakimelahi R, Scheirey C, Afnan J, Braschi-Amirfarzan M, Thomas R. A radiologist’s guide to novel anticancer therapies in the era of precision medicine. Eur J Radiol Open 2022; 9:100406. [PMID: 35265736 PMCID: PMC8899228 DOI: 10.1016/j.ejro.2022.100406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 12/13/2022] Open
Abstract
Novel anticancer agents have replaced conventional chemotherapy as first line agents for many cancers, with continued new and expanding indications. Small molecule inhibitors act on cell surface or intracellular targets and prevent the downstream signaling that would otherwise permit tumor growth and spread. Anticancer antibodies can be directed against growth factors or may be immunotherapeutic agents. The latter act by inhibiting mechanisms that cancer cells use to evade the immune system. Hormonal agents act by decreasing levels of hormones that are necessary for the growth of certain cancer cells. Cancer therapy protocols often include novel anticancer agents and conventional chemotherapy used successively or in combination, in order to maximize survival and minimize morbidity. A working knowledge of anti-cancer drug classification will aid the radiologist in assessing response on imaging.
Novel anticancer agents include small molecule inhibitors, antibodies and hormones. These agents are predominantly cytostatic and inhibit factors that provide a survival advantage to tumor cells. Modern cancer therapy employs a combination of novel anticancer agents and conventional chemotherapy. It is essential for radiologists to have a broad understanding of these agents and their mechanisms of action.
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Skhoun H, Khattab M, Belkhayat A, Takki Chebihi Z, Dakka N, El Baghdadi J. A prognostic approach on a case of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia with monosomy-7. Clin Case Rep 2021; 9:e05207. [PMID: 34963805 PMCID: PMC8710846 DOI: 10.1002/ccr3.5207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/04/2021] [Accepted: 11/14/2021] [Indexed: 11/21/2022] Open
Abstract
In this work, we present the first case of a Ph-positive ALL Moroccan girl with t(9;22)(q34;q11) and monosomy-7. She was diagnosed with Ph-positive ALL based on bone marrow examination, immunophenotyping, and cytogenetic analysis. She relapsed after treatment with the persistence of the Ph chromosome and the appearance of a monosomy-7.
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Affiliation(s)
- Hanaa Skhoun
- Genetics UnitMilitary Hospital Mohammed VRabatMorocco
- Laboratory of Human Pathologies BiologyGenomic Center of Human PathologiesFaculty of SciencesMohammed V University in RabatRabatMorocco
| | - Mohammed Khattab
- Department of Pediatric Hemato‐OncologyChildren's Hospital of RabatRabatMorocco
| | | | | | - Nadia Dakka
- Laboratory of Human Pathologies BiologyGenomic Center of Human PathologiesFaculty of SciencesMohammed V University in RabatRabatMorocco
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Guo Y, Wang FF, Xiang B, Ma HB, Gong YP. Tanshinone IIA potentiates the efficacy of imatinib by regulating the AKT-MDM2-P53 signaling pathway in Philadelphia chromosome-positive acute lymphoblastic leukemia. Oncol Lett 2021; 23:7. [PMID: 34820006 PMCID: PMC8607239 DOI: 10.3892/ol.2021.13125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 07/15/2021] [Indexed: 02/05/2023] Open
Abstract
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by breakpoint cluster region-abelson leukemia virus (BCR/ABL) kinase. Targeting BCR/ABL kinase with tyrosine kinase inhibitors combined with chemotherapy is the standard first-line therapy for Ph+ ALL. Imatinib and dasatinib are the preferred agents for the treatment of Ph+ ALL. Dasatinib treatment can induce a faster and deeper remission than imatinib treatment; however, the side effects of dasatinib, especially the cardiovascular side effects, are markedly greater than those of imatinib. Patients will benefit from treatments that improve the efficacy of imatinib without increasing its side effects. The present study revealed that tanshinone IIA markedly potentiated the cytotoxic and apoptotic induction effects of imatinib by regulating the AKT-MDM2-P53 signaling pathway and inhibiting the anti-apoptotic proteins BCL2 and MCL1 apoptosis regulator, BCL2 family member in Ph+ ALL cell lines. In vitro studies, MTT assay, flow cytometry, western blotting and reverse transcription-quantitative PCR were performed in the present study to detect cell viability, cell apoptosis, protein expression and gene expression, respectively. In a Ph+ ALL mouse model, imatinib combined with tanshinone IIA also exhibited a synergistic effect on the reduction in leukemia burden without increasing the toxic side effects of imatinib. These results demonstrated that imatinib combined with tanshinone IIA might be a promising treatment strategy for patients with Ph+ ALL.
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Affiliation(s)
- Yong Guo
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Fang-Fang Wang
- Hematology Research Laboratory, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bing Xiang
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hong-Bing Ma
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yu-Ping Gong
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
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41
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Dasatinib and dexamethasone followed by hematopoietic cell transplantation for adults with Ph-positive ALL. Blood Adv 2021; 5:4691-4700. [PMID: 34492682 PMCID: PMC8759134 DOI: 10.1182/bloodadvances.2021004813] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/24/2021] [Indexed: 11/20/2022] Open
Abstract
Dasatinib and dexamethasone induction then allogeneic hematopoietic cell transplantation was feasible and effective for untreated Ph+ ALL. Treatment failure was associated with BCR-ABL1 T315I mutation, the p210 BCR-ABL1 isoform, or isolated CNS relapse. Post-remission strategies after dasatinib-corticosteroid induction in adult Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) are not well studied. We evaluated dasatinib and dexamethasone induction then protocol-defined post-remission therapies, including hematopoietic cell transplantation (HCT). Adults (N = 65) with Ph-positive ALL received dasatinib-dexamethasone induction, methotrexate-based central nervous system (CNS) prophylaxis, reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or chemotherapy alone, and dasatinib-based maintenance. Key end points were disease-free survival (DFS) and overall survival (OS). The median age was 60 years (range, 22-87 years). The complete remission rate was 98.5%. With a median follow-up of 59 months, 5-year DFS and OS were 37% (median, 30 months) and 48% (median, 56 months), respectively. For patients receiving RIC allogeneic HCT, autologous HCT, or chemotherapy, 5-year DFS were 49%, 29%, and 34%, and 5-year OS were 62%, 57%, and 46%, respectively. Complete molecular response rate after CNS prophylaxis was 40%. Relative to the p190 isoform, p210 had shorter DFS (median 10 vs 34 months, P = .002) and OS (median 16 months vs not reached, P = .05). Relapse occurred in 25% of allogeneic HCT, 57% of autologous HCT, and 36% of chemotherapy patients. T315I mutation was detected in 6 of 8 marrow relapses. Dasatinib CNS concentrations were low. Dasatinib-dexamethasone followed by RIC allogeneic HCT, autologous HCT, or chemotherapy was feasible and efficacious, especially with RIC allogeneic HCT. Future studies should address the major causes of failure: T315I mutation, the p210 BCR-ABL1 isoform, and CNS relapse. This study was registered at www.clinicaltrials.gov as #NCT01256398.
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42
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Posttransplant blockade of CXCR4 improves leukemia complete remission rates and donor stem cell engraftment without aggravating GVHD. Cell Mol Immunol 2021; 18:2541-2553. [PMID: 34635806 PMCID: PMC8545944 DOI: 10.1038/s41423-021-00775-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 09/04/2021] [Indexed: 02/08/2023] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematological malignancies, but relapse resulting predominantly from residual disease in the bone marrow (BM) remains the major cause of treatment failure. Using immunodeficient mice grafted with laboratory-generated human B-ALL, our previous study suggested that leukemia cells within the BM are resistant to graft-versus-leukemia (GVL) effects and that mobilization with CXCR4 antagonists may dislodge leukemia cells from the BM, enabling them to be destroyed by GVL effects. In this study, we extended this approach to patient-derived xenograft (PDX) and murine T-ALL and AML models to determine its clinical relevance and effects on GVHD and donor hematopoietic engraftment. We found that posttransplant treatment with the CXCR4 antagonist AMD3100 significantly improved the eradication of leukemia cells in the BM in PDX mice grafted with B-ALL cells from multiple patients. AMD3100 also significantly improved GVL effects in murine T-ALL and AML models and promoted donor hematopoietic engraftment in mice following nonmyeloablative allo-HCT. Furthermore, posttransplant treatment with AMD3100 had no detectable deleterious effect related to acute or chronic GVHD. These findings provide important preclinical data supporting the initiation of clinical trials exploring combination therapy with CXCR4 antagonists and allo-HCT.
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Brown PA, Shah B, Advani A, Aoun P, Boyer MW, Burke PW, DeAngelo DJ, Dinner S, Fathi AT, Gauthier J, Jain N, Kirby S, Liedtke M, Litzow M, Logan A, Luger S, Maness LJ, Massaro S, Mattison RJ, May W, Oluwole O, Park J, Przespolewski A, Rangaraju S, Rubnitz JE, Uy GL, Vusirikala M, Wieduwilt M, Lynn B, Berardi RA, Freedman-Cass DA, Campbell M. Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19:1079-1109. [PMID: 34551384 DOI: 10.6004/jnccn.2021.0042] [Citation(s) in RCA: 139] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.
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Affiliation(s)
- Patrick A Brown
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | - Anjali Advani
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | | | | | | | - Shira Dinner
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | - Jordan Gauthier
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | - Nitin Jain
- The University of Texas MD Anderson Cancer Center
| | | | | | | | - Aaron Logan
- UCSF Helen Diller Family Comprehensive Cancer Center
| | - Selina Luger
- Abramson Cancer Center at the University of Pennsylvania
| | | | | | | | | | | | - Jae Park
- Memorial Sloan Kettering Cancer Center
| | | | | | - Jeffrey E Rubnitz
- St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
| | - Geoffrey L Uy
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | - Beth Lynn
- National Comprehensive Cancer Network
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Dasatinib-based Two-step Induction for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Blood Adv 2021; 6:624-636. [PMID: 34516628 PMCID: PMC8791587 DOI: 10.1182/bloodadvances.2021004607] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 06/17/2021] [Indexed: 12/04/2022] Open
Abstract
Dasatinib-based 2-step induction resulted in a 100% CR rate with minimal toxicities and 53% MRD negativity. This protocol treatment increased the number of HSCTs in CR1, thereby improving 3-year EFS. The standard treatment for adults with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.
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Short NJ, Kantarjian H, Jabbour E. SOHO State of the Art Updates & Next Questions: Intensive and Non-Intensive Approaches for Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 22:61-66. [PMID: 34561201 DOI: 10.1016/j.clml.2021.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/09/2021] [Accepted: 08/16/2021] [Indexed: 10/20/2022]
Abstract
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) was historically considered to be a very poor-risk subtype of ALL. However, with the introduction of highly potent BCR-ABL tyrosine kinase inhibitors (TKIs), Ph+ ALL can now be considered relatively favorable-risk acute leukemia. Considering the high rates of measurable residual disease negativity and excellent long-term survival that has been achieved with regimens incorporating later-generation TKIs and particularly with ponatinib, lower-intensity and even chemotherapy-free regimens are now being evaluated for patients of all ages with Ph+ ALL. The very encouraging early results observed with blinatumomab-based, chemotherapy-free regimens challenge previous notions that all patients with Ph+ ALL should undergo allogeneic stem cell transplantation in first remission, as these regimens are capable of achieving deep and durable remissions without need for transplant in the vast majority of patients, particularly when combined with ponatinib. In this review, we discuss the evolving approach to the treatment of adults with newly diagnosed Ph+ ALL and the major principles that should guide therapy in this disease. We also review the rationale and data supporting the use of novel, chemotherapy-free regimens in Ph+ ALL, and how these approaches may soon become new standards of care.
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Affiliation(s)
- Nicholas J Short
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
| | - Hagop Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Elias Jabbour
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
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46
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Ansuinelli M, Della Starza I, Lauretti A, Elia L, Siravo V, Messina M, De Novi LA, Taherinasab A, Canichella M, Guarini A, Foà R, Chiaretti S. Applicability of droplet digital polymerase chain reaction for minimal residual disease monitoring in Philadelphia-positive acute lymphoblastic leukaemia. Hematol Oncol 2021; 39:680-686. [PMID: 34402088 PMCID: PMC9292453 DOI: 10.1002/hon.2913] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/30/2021] [Accepted: 08/01/2021] [Indexed: 12/18/2022]
Abstract
In Ph+ acute lymphoblastic leukaemia (Ph+ ALL), minimal residual disease (MRD) is the most relevant prognostic factor. Currently, its evaluation is based on quantitative real‐time polymerase chain reaction (Q‐RT‐PCR). Digital droplet PCR (ddPCR) was successfully applied to several haematological malignancies. We analyzed 98 samples from 40 Ph+ ALL cases, the majority enrolled in the GIMEMA LAL2116 trial: 10 diagnostic samples and 88 follow‐up samples, mostly focusing on positive non‐quantifiable (PNQ) or negative samples by Q‐RT‐PCR to investigate the value of ddPCR for MRD monitoring. DdPCR BCR/ABL1 assay showed good sensitivity and accuracy to detect low levels of transcripts, with a high rate of reproducibility. The analysis of PNQ or negative cases by Q‐RT‐PCR revealed that ddPCR increased the proportion of quantifiable samples (p < 0.0001). Indeed, 29/54 PNQ samples (53.7%) proved positive and quantifiable by ddPCR, whereas 13 (24.1%) were confirmed as PNQ by ddPCR and 12 (22.2%) proved negative. Among 24 Q‐RT‐PCR‐negative samples, 13 (54.1%) were confirmed negative, four (16.7%) resulted PNQ and seven (29.2%) proved positive and quantifiable by ddPCR. Four of 5 patients, evaluated at different time points, who were negative by Q‐RT‐PCR and positive by ddPCR experienced a relapse. DdPCR appears useful for MRD monitoring in adult Ph+ ALL.
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Affiliation(s)
- Michela Ansuinelli
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Irene Della Starza
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy.,GIMEMA Foundation, Rome, Italy
| | - Alessia Lauretti
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Loredana Elia
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Veronica Siravo
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Monica Messina
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Lucia Anna De Novi
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Akram Taherinasab
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Martina Canichella
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Anna Guarini
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Robin Foà
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Sabina Chiaretti
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
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Ansuinelli M, Cesini L, Chiaretti S, Foà R. Emerging tyrosine kinase inhibitors for the treatment of adult acute lymphoblastic leukemia. Expert Opin Emerg Drugs 2021; 26:281-294. [PMID: 34259120 DOI: 10.1080/14728214.2021.1956462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Introduction: The broadening of targeted and immunotherapeutic strategies markedly impacted on the management of acute lymphoblastic leukemia (ALL). The advent of tyrosine kinase inhibitors (TKIs) changed the history of Philadelphia-chromosome positive (Ph+) ALL. Nowadays, almost all Ph+ ALL patients treated with TKIs achieve a complete hematologic response, and most become minimal residual disease negative. In Ph- ALL, genomic profiling studies have identified a subtype associated with a high relapse risk and a transcriptional profile similar to that of Ph+ ALL, the so-called Ph-like ALL. Given the high prevalence of kinase-activating lesions in this subset, there is compelling evidence from experimental models and clinical observations favoring TKI administration.Areas covered: We discuss the main findings exploring the efficacy of TKIs in ALL.Expert opinion: The use of more potent TKIs will further enhance the inhibitory activity on leukemia cells and increase the possibility of eradicating the disease at a molecular level. In the future, 'combined' approaches of different inhibitors may be considered to prevent/avoid resistance and/or mutations. A rapid identification of Ph-like ALL patients is needed to propose early TKI-based intervention. Several questions remain open, including the initial TKI choice in Ph+ ALL and whether Ph-like ALL patients might benefit from immunotherapy.
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Affiliation(s)
- Michela Ansuinelli
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Laura Cesini
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Sabina Chiaretti
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Robin Foà
- Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
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Salvaris R, Fedele PL. Targeted Therapy in Acute Lymphoblastic Leukaemia. J Pers Med 2021; 11:715. [PMID: 34442359 PMCID: PMC8398498 DOI: 10.3390/jpm11080715] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 07/21/2021] [Indexed: 11/26/2022] Open
Abstract
The last decade has seen a significant leap in our understanding of the wide range of genetic lesions underpinning acute lymphoblastic leukaemia (ALL). Next generation sequencing has led to the identification of driver mutations with significant implications on prognosis and has defined entities such as BCR-ABL-like ALL, where targeted therapies such as tyrosine kinase inhibitors (TKIs) and JAK inhibitors may play a role in its treatment. In Philadelphia positive ALL, the introduction of TKIs into frontline treatment regimens has already transformed patient outcomes. In B-ALL, agents targeting surface receptors CD19, CD20 and CD22, including monoclonal antibodies, bispecific T cell engagers, antibody drug conjugates and chimeric antigen receptor (CAR) T cells, have shown significant activity but come with unique toxicities and have implications for how treatment is sequenced. Advances in T-ALL have lagged behind those seen in B-ALL. However, agents such as nelarabine, bortezomib and CAR T cell therapy targeting T cell antigens have been examined with promising results seen. As our understanding of disease biology in ALL grows, as does our ability to target pathways such as apoptosis, through BH3 mimetics, chemokines and epigenetic regulators. This review aims to highlight a range of available and emerging targeted therapeutics in ALL, to explore their mechanisms of action and to discuss the current evidence for their use.
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Affiliation(s)
- Ross Salvaris
- Department of Clinical Haematology, Monash Health, Clayton 3168, Australia;
- School of Clinical Sciences at Monash Health, Monash University, Clayton 3168, Australia
| | - Pasquale Luke Fedele
- Department of Clinical Haematology, Monash Health, Clayton 3168, Australia;
- School of Clinical Sciences at Monash Health, Monash University, Clayton 3168, Australia
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Chiaretti S, Ansuinelli M, Vitale A, Elia L, Matarazzo M, Piciocchi A, Fazi P, Di Raimondo F, Santoro L, Fabbiano F, Califano C, Martinelli G, Ronco F, Ferrara F, Cascavilla N, Bigazzi C, Tedeschi A, Sica S, Di Renzo N, Melpignano A, Beltrami G, Vignetti M, Foa R. A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia patients: final results of the GIMEMA LAL1509 protocol. Haematologica 2021; 106:1828-1838. [PMID: 33538150 PMCID: PMC8252956 DOI: 10.3324/haematol.2020.260935] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Indexed: 12/18/2022] Open
Abstract
The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) patients, was based on dasatinib plus steroids induction - with central nervous system prophylaxis - followed by dasatinib alone in patients in complete molecular response or by chemotherapy and/or allogeneic transplant in patients not reaching complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and nine p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained complete molecular response. Among the incomplete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months; range, 3-40.1): 13 during consolidation and four post-transplant. ABL1 mutations (five T315I, three V299L, one E281K and one G254E) were found in ten of 13 relapsed cases. With a median follow-up of 57.4 months (range, 4.2-75.6), overall survival and disease-free survival were 56.3% and 47.2%. A better disease-free survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (P=0.005 and P=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemotherapyfree induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up (clinicatrial gov. Identifier: EudraCT 2010-019119-39).
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Affiliation(s)
- Sabina Chiaretti
- Hematology, Department of Translational and Precision Medicine, Sapienza University.
| | - Michela Ansuinelli
- Hematology, Department of Translational and Precision Medicine, Sapienza University
| | - Antonella Vitale
- Hematology, Department of Translational and Precision Medicine, Sapienza University
| | - Loredana Elia
- Hematology, Department of Translational and Precision Medicine, Sapienza University
| | - Mabel Matarazzo
- Hematology, Department of Translational and Precision Medicine, Sapienza University
| | | | | | - Francesco Di Raimondo
- Section of Haematology, Department of General Surgery and Medical-Surgical Specialties, University of Catania
| | - Lidia Santoro
- Struttura Complessa di Ematologia e Trapianto Emopoietico-A.O. S.G.Moscati, Avellino
| | - Francesco Fabbiano
- Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia-Cervello, Palermo
| | | | - Giovanni Martinelli
- Seragnoli Institute of Hematology, Bologna University School of Medicine, Bologna
| | - Francesca Ronco
- Operative Unit of Hematology, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli", Reggio Calabria
| | - Felicetto Ferrara
- Division of Hematology and Stem Cell Transplantation Program, AORN Cardarelli Hospital, Naples
| | | | - Catia Bigazzi
- Department of Hematology and Stem Cell Transplantation Unit, C.G. Mazzoni Hospital, Ascoli Piceno
| | | | - Simona Sica
- Fondazione Policlinico Universitario A. Gemelli, Rome; Universita Cattolica del Sacro Cuore
| | - Nicola Di Renzo
- Department of Hematology and Stem Cell Transplant, Presidio Ospedaliero Vito Fazzi, Lecce
| | | | | | | | - Robin Foa
- Hematology, Department of Translational and Precision Medicine, Sapienza University.
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Harama D, Yahata T, Kagami K, Abe M, Ando N, Kasai S, Tamai M, Akahane K, Inukai T, Kiyokawa N, Ibrahim AA, Ando K, Sugita K. IMiDs uniquely synergize with TKIs to upregulate apoptosis of Philadelphia chromosome-positive acute lymphoblastic leukemia cells expressing a dominant-negative IKZF1 isoform. Cell Death Discov 2021; 7:139. [PMID: 34117218 PMCID: PMC8195985 DOI: 10.1038/s41420-021-00523-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 05/01/2021] [Indexed: 11/24/2022] Open
Abstract
The long-term prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is still unsatisfactory even after the emergence of tyrosine kinase inhibitors (TKIs) against chimeric BCR-ABL, and this is associated with the high incidence of genetic alterations of Ikaros family zinc finger 1 (IKZF1), most frequently the hemi-allelic loss of exons 4–7 expressing a dominant-negative isoform Ik6. We found that lenalidomide (LEN), a representative of immunomodulatory drugs (IMiDs), which have been long used for the treatment of multiple myeloma, specifically induced accumulation of Ik6 with the disappearance of functional isoforms within 24 h (i.e., abrupt and complete shut-down of the IKZF1 activity) in Ik6-positive Ph+ALL cells in a neddylation-dependent manner. The functional IKZF3 isoforms expression was also abruptly and markedly downregulated. The LEN treatment specifically suppressed proliferation of Ik6-positive-Ph+ALL cells by inducing cell cycle arrest via downregulation of cyclins D3 and E and CDK2, and of importance, markedly upregulated their apoptosis in synergy with the TKI imatinib (IM). Apoptosis of IM-resistant Ph+ALL cells with T315I mutation of BCR-ABL was also upregulated by LEN in the presence of the newly developed TKI ponatinib. Analyses of flow cytometry, western blot, and oligonucleotide array revealed that apoptosis was caspase-/p53-dependent and associated with upregulation of pro-apoptotic Bax/Bim, enhanced dephosphorylation of BCR-ABL/Akt, and downregulation of oncogenic helicase genes HILLS, CDC6, and MCMs4 and 8. Further, the synergism of LEN with IM was clearly documented as a significant prolongation of survival in the xenograft mice model. Because this synergism was further potentiated in vitro by dexamethasone, a key drug for ALL treatment, the strategy of repositioning IMiDs for the treatment of Ik6-positive Ph+ALL patients certainly shed new light on an outpatient-based treatment option for achieving their long-term durable remission and higher QOL, particularly for those who are not tolerable to intensified therapeutic approaches.
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Affiliation(s)
- Daisuke Harama
- Department of Pediatrics, Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Takashi Yahata
- Department of Innovative Medical Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Keiko Kagami
- Department of Pediatrics, Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Masako Abe
- Department of Pediatrics, Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Norie Ando
- Department of Pediatrics, Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Shin Kasai
- Department of Pediatrics, Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Minori Tamai
- Department of Pediatrics, Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Koshi Akahane
- Department of Pediatrics, Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Takeshi Inukai
- Department of Pediatrics, Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Nobutaka Kiyokawa
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Abd Aziz Ibrahim
- Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Kiyoshi Ando
- Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Kanji Sugita
- Department of Pediatrics, Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
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