Rituximab in neuromyelitis optica: A review of literature

Table 1 Case series of rituximab in neuromyelitis optica

Ref.	Country; Type of study	No. of patients (n = 209)	Mean age at RTX; % Female	% Anti-AQP4 Ab seropositive	RTX Protocol /treatment duration	ARR before RTX	ARR after RTX	% Relapse-free	EDSS (median) before --> after RTX
Cree et al[20]	United States; Retrospective	8	371; 88%	N/A	A- treatment B- retreatment	2.6 (median)	0 (median)	75% (6/8 pts at 12 mo f/u)	7.5--> 5.5
Jacob et al[23]	United States/England; Retrospective	25	431; 88%	70%	A or B; median interval between cycles-8 mo 19 mo follow up	1.7 (median)	0 (median)	72% (17/25 at 12 mo estimated)	7--> 5 2 patients deceased
Bomprezzi et al[31]	United States; Retrospective	18	46 (+/-12); 83%	67%	B	15 pts-RTX tx and 7 had relapses. 42% (5/12) showed “positive treatment effects”, the other 7 continued to relapse despite RTX therapy		53% (8/15)	Severe disability from NMO’ - 10 patients
Bedi et al[24]	United States; Retrospective	23	461; 91%	72%	A or B; 32.5 mo	1.87 (median)	0 (median)	74 % (17/23 pts)	7--> 5.5
Pellkofer et al[30]	Germany; Prospective	10	471; 90%	100%	B; number of cycles of RTX 1-5	Ever before RTX: 1.3 mo, 12 m before RTX: 2.4 mo, 24 m before RTX: 1.72 mo, With RTX: 0.93 mo		50% (5/10 at 12 mo estimated)	6--> 6.51 1 patient deceased
Javed et al[22]	United States; Retrospective	15	34; N/A	N/A	B; patients were given RTX 1g x1 usually 6-9 mo after the initial dose	2/10 had 2 relapses in 6 mo post RX. 5 non-responders had mean of 1.45 (median 1) relapses in mean 12.2 (median 10) mo		67% (RTX delayed further relapses for 9 mo or more)	N/A
Gredler et al[26]	Austria; Retrospective	6	38; 83%	66%	375 mg/m2; no of infusions 3-16 (mean = 6.67), interval between infusions 3.3-11 mo	2.5 (mean)1	0.4 (mean)1	67% (4/6)	5.25--> 2.251
Ip et al[25]	China; Prospective	7	52; 85%	66%	A or B: Mean # trx courses: 2.85. median 2	Mean ARR = 2.4 median ARR = 21 5 became relapse free. 2 had 50% reduction over median 24 mo		71 % (5/7)	8--> 7
Lindsey et al[32]	United States; Retrospective	9	N/A; 89%	60%	A or B: Mean duration: 74.2 mo	3 pts with early relapses in first month after RTX, 4 pts (including 1 pt with early relapse) with later relapses		33% (3/9)	3.5--> 4.31
Kim et al[27]	South Korea; Retrospective	30	38.4 (± 10.5); 90%	77%	A or B; mean 61 mo (range 49-82 mo), median 60 mo	2.4 (mean)	0.3 (mean)	70% (21/30 at 2 yr f/u)	4--> 3
Yang et al[28]	China; Prospective	5	421; N/A	80%	100 mg (50-59 mg/m2) RTX IV 1 dose/wk for 3 cons wk; mean duration: 12.2 mo	1.161 (mean)	01 (mean)	100%	4.5--> 4
Mealy et al[29]	United States; Retrospective	30	451; 83%	50%	B; median of 20 mo (range 5-83 mo)	Total pretreatment ARR- 2.89	Total post-treatment ARR- 0.33	67% (20/30)	N/A
Farber et al[21]	United States; Retrospective	23	38; 100%	74%	Mean of 22 mo (range 2-96 mo)		Median ARR was 0.24; mean was 1.02 (SD = 1.36)	48% (11/23)	N/A

¹Estimated based on results table or manuscript when possible. A or B (in RTX protocol column): There were two treatment protocols used- Protocol A with 4 doses RTX 375 mg/m² IV wk for 4 wk; Protocol B with 2 doses of RTX 1000 mg IV 2 wk apart. NMO: Neuromyelitis optica; ARR: Annual relapse rate; EDSS: Expanded disability status scale; RTX: Rituximab; AQP4: Ab - aquaporin 4 antibody; N/A: Not available.

Table 2 Monitoring parameters in Neuromyelitis optica patients treated with rituximab

Ref.	Monitoring parameter/comments
Cree et al[20]	CD19 levels- when detectable, patients were re-treated. CD 19 followed bimonthly. 2 protocols-planned infusions every 6 mo or 12 mo
Jacob et al[23]	CD19 not routinely monitored. Some RTX given when B-cell counts detectable either 6 or 12 mo in intervals or when CD19+ became detectable
Bomprezzi et al[31]	Flow cytometry used to test circulating B cells. Suggest clinical relapses occurring while on RTX therapy correlate with reconstitution of circulating B cells. Correlated that even early rise in CD20+ cells correlated with radiologically proven relapses. B cells had re-sent between 2% and 12% at time of new attack. Total of 7 patients relapsed after RTX-5 had acute event when B cell counts just returned to greater than 1%, whereas 2 patients continued to relapse despite B cells being undetectable. Detected significant variability in timing of reconstitution of normal values, which implies that scheduling of doses of RTX can be adjusted accordingly
Bedi et al[24]	CD19 cell counts planned every 2-3 mo, but not collected systematically for report
Pellkofer et al[30]	Measured lymphocyte subsets by flow cytometry; B cell depletion defined as counts below 0.01 × 109 /L. B cells became undetectable in 9 out of 10 patients within 14 d after 1st dose. Time of B-cell repopulation varied. After 3 patients experienced a relapse shortly after reappearance of B cells, RTX given at fixed interval every 6 to 9 mo, which this led to improved outcomes
Javed et al[22]	“Non-responders” were defined as clinical attack < 6 mo post rituximab treatment, when B cell count was still undetectable
Gredler et al[26]	Flow cytometry used; B cells quantified using following combinations of monoclonal antibodies: CD3/19/45, 19/27/45, 19/38/45. Two patients out of 6 had relapses while B-cells were absent
Lindsey et al[32]	4 patients had relapses after more than 1 mo when peripheral B cell count “very low”. Case 1: CD19 increased to 250 cells/µL had sensory relapse, no further symptoms for 18 mo; Case 2: Had relapses with CD19 count of 0; Case 3, 4, 6 no further relapses; Case 5: CD19 1 cells/µL at 10 mo, 12 cells/µL at 13 mo and subsequent relapses; Case 7--continued to have relapses with 1 cell/µL at 7 mo, 4 cells/µL at 12 mo. Case 8: CD19 count 3 cells/µL, with continued relapses; Case 9: continued relapses with CD19 1 cells/µL
Kim et al[27]	Blood samples obtained every 6 wk in 1st year, every 8 wk in second year. Therapeutic target for CD 27+ memory B cell depletion was less than 0.05% of PBMCs. Patients received additional infusion of 375 mg/m2 if frequency of re-emerging memory CD27+ B cells in PBMCs exceeded 0.1% by flow cytometry. CD 19 B cells counts measure- less than 0.01 × 109 /L or less than 0.5% of PBMCs (considered B cell depletion in prior studies. 60%-65% relapses occurred when CD19 were depleted. Authors argue CD27+ more informative biomarker than CD19
Yang et al[28]	Goal of CD19+ B cells to less than or equal to 1%, as well as CD19 CD27 B cells to less than or equal to 0.05% of PBMCs. All with no relapses despite low doses of RTX (100 mg single infusion and follow up infusion at mean of 35 wk)
Mealy et al[29]	CD19 cell counts tested monthly, repeated dosing scheduled on detection of CD19 greater than 1% of total lymphocyte population or at regular 6 mo intervals
Farber et al[21]	Total of 23 relapses, of which 70% occurred when B cells < 1% of lymphocytes. 7 relapses (30%) occurred when B cells greater or equal to 1% of lymphocytes. CD19 > 1% was associated with higher rate of relapses

RTX: Rituximab.