Thalidomide for refractory gastrointestinal bleeding from vascular malformations in patients with significant comorbidities

Table 1 Studies evaluating the effect of thalidomide on treating gastrointestinal vascular malformations

Ref.	No. patients	Patient population	Treatment	Follow-up	Results
Heidt et al[18], 2006	1	von-Willebrand's disease type II-a	100 mg daily	11 mo	Case report. Recurrent bleed within 2 wk of starting, at 11 months no further bleeding episodes. No side effects. Rebleeding upon cessation and with decreased dose
Dabak et al[15], 2007	3	Excluded: HIV positive on treatment. History of seizure disorder. Pregnant or lactating females. Patient with nonmalignant disease (congestive heart failure, uncontrolled infection, etc.). History of noncompliance	Thalidomide 100 mg daily and increased every 2 wk by 100 mg up to 400 mg daily	250 d	Prospective study. 2/3 patients had responded to thalidomide with decrease transfusion requirements starting at 12 wk of study drug initiation. 1/3 stopped due to lack of response. 1/3 had side effects and dose reduced to 50 mg daily
Kamalaporn et al[19], 2009	7	Excluded: Severe medical conditions, such as heart or liver disease	50 mg daily, increased by 50 mg weekly up to 200 mg daily for 6 mo	12 mo	Case series. Response to treatment in 3/6 with no blood transfusions at 6 months. 4/7 discontinued thalidomide because of side effects. Upon cessation of thalidomide, of the response group: 1 maintained response with no transfusion for 2 mo, then 1 unit every 4 wk. 1 required 2 u every 3-4 wk, 1 passed from diabetes complications
Ge et al[10], 2011	55	Excluded: Cirrhotic or portal gastropathy. Severe comorbidities of cardiac, pulmonary, renal, liver, hematological, rheumatologic, or uncontrollable diabetes mellitus or hypertension. History of severe bilateral peripheral neuropathy or seizure activity, thromboembolic disease, known thalidomide or iron allergy. Treatment with ASA, NSAID, antiplatelet, anticoagulant, or Chinese medications, gingko, echinacea, or immunomodulators. Pregnant or lactating. Undergoing cancer therapy via chemotherapy or radiation	Thalidomide 25 mg four times daily vs ferrous succinate 100 mg four times daily. Both for 4 mo	39 mo (8-52)	Prospective, randomized, parallel control trial. Effective response rate of decrease bleed > 50% first year of follow-up period in thalidomide 71.4% vs iron supplementation response 3.7% (P < 0.001). Secondary endpoints of rates of bleeding cessation, blood transfusion, overall hospitalization, and hospitalization for bleeding demonstrated thalidomide was more effective. Level of VEGF significantly reduced in thalidomide group (P < 0.001). Minor side effects reported in thalidomide group
Garrido Serrano et al[17], 2012	19	Cirrhosis	Thalidomide 200 mg daily for 4 mo	4 mo	Prospective study. Mean hemoglobin before thalidomide 7 g/dL, after 2 mo 9 g/dL and at end of 4 mo 10 g/dL. Side effects included HE (2/19), sensitive axonal polyneuropathy (1/19) which resolved after withdrawal of thalidomide
Ray et al[20], 2014	1	LVAD	50 mg twice daily	12 mo	Case report. No further bleeding after starting thalidomide and remained on warfarin. No reported side effects
Bond et al[12], 2015	1	Cutaneous T-cell lymphoma	100 mg daily	6 mo	Case report. No further bleeding episodes at 6 mo. Side effects of dizziness and unsteadiness
Draper et al[23], 2015	8	LVAD	50 mg twice daily increased by 50 mg weekly up to 200 mg daily	Not included	Case series. No recurrence of bleeding 5/8, reduced bleeding 2/8. Death 1/8 within 1 wk of starting due to sepsis. Side effects in 2/8
Chen et al[14], 2016	80	Excluded: Cirrhotic or portal hypertension gastropathy. Severe cardiac, pulmonary, renal, liver, pancreas, hematological, or rheumatologic comorbidities, uncontrolled diabetes mellitus or hypertension, or renal insufficiency without hemodialysis or peritoneal dialysis. Severe bilateral peripheral neuropathy or seizure, thromboembolic disease. Known thalidomide allergy, treatment with any systemic or oral topical corticosteroids, NSAID, any putative immunomodulators, or antiangiogenic agents. Pregnant or lactating. Alcohol and/or drug abuse. Poor compliance	Thalidomide 25 mg four times a day for 4 mo	42.6 mo (12-120)	Retrospective study. In first year of follow-up, overall response rate was 77.5% (62/80) with 41.3% (33/80) achieving complete cessation. Overall response rate of 79.5% (62/78). Adverse effects in 60% with serious effects in 31.3% (25/80)
Chan et al[13], 2017	4	LVAD	50 mg daily	11.4 mo (7-24)	Case series. No further bleeding. When medications stopped, recurrence of bleeding, with restart of medication and cessation of bleeding
Duarte et al[16], 2017	1	Glanzmann's thrombasthenia	50 mg daily, after 15 d increased to 100 mg daily	6 mo	Case report. Recurrent bleeding at 5 mo, requiring transfusions. Thalidomide suspended at 5 mo. Death due to sepsis and hemorrhage
Seng et al[21], 2017	11	LVAD	Thalidomide 50 mg daily	186 d (3-512 d)	Retrospective study. Resolution of bleeding in 90.9% (10/11). Discontinued in 6 (63.6%) due to resolution of bleeding (n = 4) or side effects (n = 2), with GIB recurring in 4 of these patients. Adverse effects in 5/11 patients including pump thrombosis (n = 2) leading to death. 4/11 died during the study with 1 from continued bleeding and 1 from septic shock

NSAID: Non-steroidal anti-inflammatory; ASA: Aspirin; HE: Hepatic encephalopathy; LVAD: Left ventricular assist device; GIB: Gastrointestinal bleeding.

Table 2 Patient characteristics

Patient	Age	Sex	Comorbidities	Cause of GIB	Prior failed treatments	Iron supplementation	Comments
1	58	M	LVAD	GIAD	Octreotide
2	67	F	ESRD	GIAD		Sodium ferric gluconate	Aspirin
3	70	M	LVAD	GIAD	Octreotide	Ferrous sulfate	Warfarin
4	61	F	Cirrhosis	GIAD		Ferrous sulfate
5	81	M	LVAD	GIAD	Octreotide	Ferrous sulfate	Aspirin, warfarin
6	83	M	CAD, AS, AAA, CVA	GIAD	Octreotide, estrogen	Polysaccharide iron	Aspirin, cilostazol, plavix
7	72	M	Hepatoportal sclerosis	GAVE
8	69	F	Polyclonal gammopathy	GIAD
9	70	F	ESRD, HHT	GIAD	Octreotide	Ferrous sulfate
10	62	M	Cirrhosis	GAVE		Ferrous fumarate
11	58	M	Cirrhosis, CHF, ESRD	GAVE	Octreotide	Ferrous sulfate
12	64	F	Cirrhosis, MDS, NHL	GAVE
13	80	F	AS	GIAD
14	74	M	NSCLC, AFIB, MDS	GIAD			Lost to follow-up
15	68	M	AFIB, CHF, Cirrhosis	GAVE			Aspirin, warfarin, lost to follow-up

LVAD: Left ventricular assist device; ESRD: End stage renal disease; CAD: Coronary artery disease; AS: Aortic stenosis; AAA: Abdominal aortic aneurysm; CVA: Cerebrovascular accident; HHT: Hereditary hemorrhagic telangiectasia; CHF: Congestive heart failure; MDS: Myelodysplastic syndrome; NHL: Non-Hodgkin lymphoma; NSCLC: Non-small cell lung cancer; AFIB: Atrial fibrillation; GIAD: Gastrointestinal angiodysplasia; GAVE: Gastric antral vascular ectasia.

Table 3 The effect of thalidomide treatment on refractory gastrointestinal bleeding due to vascular malformation

Patient	Duration of treatment (mo)	Recurrence of bleeding after 6 mo	Number of hospitalizations due to GIB		Units RBC transfused		Number of endoscopic treatments (APC)		Comments
			1 yr before thalidomide	After starting thalidomide	1 yr before thalidomide	After starting thalidomide	1 yr before thalidomide	After starting thalidomide
1	6	No	2	0	21	0	2	0
2	19	Yes	4	1	8	12	3	1	Side effect of fatigue and dizziness
3	45	No	2	0	20	0	1	0	Side effect of neuropathy
4	14	No	1	0	Weekly transfusion	0	6	0	Side effect of fatigue and constipation. Death
5	44	Yes	5	1	14	4	4	1	Side effect of neuropathy. Death, Sepsis
6	17	Yes	6	5	Biweekly transfusion	4	3	2	Stopped due to cost. Death
7	24	Yes	9	3	33	9	4	10	Death
8	30	Yes	1	2	2	8	2	1	Side effect of fatigue
9	28	Yes	17	8	48	32	12	1	Death
10	3	NA	1	0	3	0	1	0	Stopped due to drug interaction
11	25	No	20	1	65	3	12	1	Death, Sepsis
12	6	No	2	0	99	0	9	4	Side effect of neutropenia
13	3	NA	1	1	12	16	1	1

GIB: Gastrointestinal bleeding; APC: Argon plasma coagulation; RBC: Red blood cell; NA: Not available.