scholarly journals P231 B-cell depletion therapy with rituximab in RA: UCLH/UCL 20 years of experience

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Caitlin M Norris-Grey ◽  
Samantha Moore ◽  
Geraldine Cambridge ◽  
Venkat Reedy ◽  
Maria Leandro
Keyword(s):  
B Cell ◽  
Service Evaluation ◽  
Cell Depletion ◽  
Phase Iii ◽  
Tender Joint Count ◽  
B Cell Depletion ◽  
Concomitant Therapy ◽  
Open Label ◽  
Tender Joint

Abstract Background B-cell depletion therapy based on rituximab in patients with seropositive rheumatoid arthritis (RA) was pioneered at UCLH/UCL in 1998. The positive results of the initial open-label UCLH/UCL trials led to the Phase IIa proof of concept trial confirming efficacy and safety for rituximab in the treatment of patients with RA. A Phase III trial followed and licensing in 2006. We report a service evaluation of the UCLH/UCL cohort of RA patients treated with rituximab over the last 20 years. Methods A retrospective review of electronic records from all patients with RA treated with rituximab followed up in a dedicated clinic at UCLH/UCL (1998-2019) were included. Data on gender, age at first treatment, previous DMARDs, concomitant therapy at the time of the first rituximab cycle, total number of rituximab cycles and length of follow-up while on rituximab were collected. For patients currently on rituximab, further information was collected at last follow-up, including concomitant therapy, swollen and tender joint count, global VAS, CRP and ESR. DAS28ESR was calculated. Results 296 patients had received rituximab therapy since November 1998, with 105 remaining on rituximab at final data collection (14/10/2019). Median follow-up was 77.5 months. Clinical data is shown in Table 1. Information for previous DMARDs was only available for 196 patients in the whole cohort, and for 70 patients currently on rituximab. The most common concomitant DMARD at first cycle was methotrexate with a similar percentage receiving methotrexate at last follow-up. The median number of previous DMARDs were 4 and 3 respectively. Within both cohorts approximately 31% of patients received rituximab as their first biologic. Conclusion This retrospective service evaluation of 296 patients with RA who had undergone rituximab therapy since 1998 showed that more than one third remained on rituximab at last follow-up. Of these, 70.2% of patients were in clinical remission or with low disease activity. Most patients (94%) remaining on rituximab were receiving only 1 or no concomitant therapies. Multiple cycles of treatment with rituximab have thus proved to be an effective therapeutic strategy for patients with RA resulting in long-term and highly favourable control of their disease. Disclosures C.M. Norris-Grey None. S. Moore None. G. Cambridge None. V. Reedy None. M. Leandro Consultancies; Genentech: consultancy fees for attending meeting on obinutuzumab trial in lupus nephritis.

Low doses of humanized anti-CD20 antibody, IMMU-106 (hA20), in refractory or recurrent NHL: Phase I/II results

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8032-8032 ◽  
Author(s):  
F. Morschhauser ◽  
J. P. Leonard ◽  
L. Fayad ◽  
B. Coiffier ◽  
M. Petillon ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Serum Levels ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Open Label ◽  
Clear Cut ◽  
Cd20 Antibody ◽  
Anti Cd20

8032 Background: An open-label, multicenter study has shown that the humanized anti-CD20 antibody, IMMU-106 (hA20), which has framework regions of epratuzumab, has a good safety and efficacy profile in NHL pts when administered once-weekly × 4 at different doses. The trial is now focused on confirming the efficacy of lower doses (80–120 mg/m2/wk × 4). Methods: A total of 68 pts (35 male, 33 female; age 34–84) received hA20 at 750 (N=3), 375 (N=27), 200 (N=11), 120 (N=21), or 80 mg/m2 (N=6). They had follicular (FL, N=47) or other (N=21) B-cell NHL, were predominantly stage III/IV (N=47) at study entry, and had received 1–8 prior treatments (median, 2), including 1 (N=40) or more (N=21) rituximab regimens (without progression within 6 months). Results: Sixty- six pts completed all 4 infusions; 1 pt progressed during treatment and withdrew, while another pt with hives and chills after prior rituximab discontinued treatment after a similar episode at 1st infusion. hA20 was generally well tolerated, with shorter infusion times (typically 2 h initially and 1 h subsequently) at lower doses. Drug-related adverse events were transient, Grade 1–2, most occurring only at 1st infusion, and there was no evidence of HAHA in 54 pts now evaluated. Mean antibody serum levels increased with dose and infusions; serum clearance at 375 mg/m2 appears similar to rituximab. Currently, 48 pts with at least 12 wks follow-up were evaluated by Cheson criteria: 32 FL pts had 15 (47%) OR's with 7 (22%) CR/CRu's, even after 2–4 prior rituximab-regimens, and 17 non-FL pts had 6 (38%) OR's, with 1 CRu in a marginal zone NHL pt. At a median follow-up of 11 mo., 9/21 pts with ORs are continuing responses, including 4 long-lived responses (15–20 mo). The evaluated pts include 17 pts at 120 mg/m2 who had 5 (29%) ORs with 3 (17%) CR/CRu's. Responses at 80 mg/m2 remain to be evaluated, but B-cell depletion occurs after the 1st infusion even at this low dose. Conclusions: hA20 appears well-tolerated, with no evidence of significant adverse events other than minor infusion reactions, even at short infusion times. B-cell depletion and responses have occurred at all doses evaluated, with no clear-cut evidence of a dose-response. As such, the study is continuing to confirm the efficacy of lower doses. No significant financial relationships to disclose.

Rituximab-Relapsing Patients with Non-Hodgkins Lymphoma Respond Even at Lower Doses of Humanized Anti-CD20 Antibody, IMMU-106 (hA20): Phase I/II Results.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2719-2719 ◽  
Author(s):  
Franck Morschhauser ◽  
John P. Leonard ◽  
Luis Fayad ◽  
Bertrand Coiffier ◽  
STephen J. Schuster ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Post Treatment ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Open Label ◽  
Dose Escalation Study ◽  
Cd20 Antibody ◽  
Anti Cd20

Abstract Background: An open-label, multicenter, dose-escalation study in patients with recurrent NHL was initially undertaken to establish the safety, tolerance, PK, and immunogenicity (HAHA) of humanized anti-CD20 antibody, IMMU-106 (hA20), administered once-weekly for 4 weeks at different doses. Additional patients have now been entered to confirm the efficacy of 120 and 375 mg/m2 dosing, and to determine the feasibility of using even lower hA20 doses. Methods: A total of 55 patients (23 male, 32 female; 51 Caucasian; 40–84 years old) received hA20 at 120 (N=21), 200 (N=6), 375 (N=25) or 750 mg/m2 (N=3). They had follicular (FL, N=37) or other (N=18) B-cell lymphomas, were predominantly stage III/IV (N=44) at study entry, and had received 1–7 prior treatments (median, 2), including 1 (N=34) or more (N=14) rituximab regimens (without progression within 6 months). Results: Fifty-two patients completed all 4 infusions, 2 are currently being treated, and one patient with hives and chills after prior rituximab discontinued treatment after similar NCI CTC v.3 grade 1–2 reactions at 1st hA20 infusion. hA20 was generally well tolerated with a median infusion time at the lowest dose of 120 mg/m2 of 2.2 h for 1st infusion and 1.2 h for subsequent infusions. Twenty-one patients had drug-related adverse events; these were all transient, mild-to-moderate (Grade 1–2) events, most occurring only at first infusion. No consistent pattern of abnormal laboratory changes occurred, and there was no evidence of immunogenicity in 29 patients now evaluated for HAHA. Mean antibody serum levels increased with dose and with repeated infusions, and limited post-treatment data indicate the serum clearance at 375 mg/m2 dosing is similar to rituximab. Even at 120 mg/m2, peripheral blood B-cell depletion occurred after the first infusion and persists after 4th infusion, with analysis continuing > 6 mo. Thirty-nine patients with at least 12 wks follow-up had one or more responses evaluated by Cheson criteria (Table), with all CR/CRu occurring in follicular lymphoma except for one patient with marginal zone lymphoma; 6 pts progressed by week 4. Of 18 pts with OR’s, 9 have continuing responses (median follow-up, 9 mos post-treatment), including 4 with long-lived responses (12–18 mos). Conclusions: hA20 is well tolerated, with no evidence of significant toxicity or pattern of adverse events other than minor infusion reactions, even at short infusion times. All dose levels studied so far, including the lowest dose of 120 mg/m2, resulted in B-cell depletion and objective responses (including CR/CRu), with no clear-cut evidence of dose response in efficacy. As such, further dose de-escalation is ongoing. Treatment Response hA20 Dose OR CR/CRu All patients (n = 39) 46% (18/39) 21% (8/39) 120 mg/m2 (n = 11) 36% (4/11) 27% (3/11) 200 mg/m2 (n = 6) 67% (4/6) 33% (2/6) 375 mg/m2 (n =19) 42% (8/19) 11% (2/19) 750 mg/m2 (n = 3) 67% (2/3) 33% (1/3)

B-Cell Depletion and Prevention of Hemolysis in Allogeneic Peripheral Blood Stem Cell Transplantation with Minor ABO Incompatibility.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5151-5151
Author(s):  
Emmanuelle Tavernier ◽  
Anne Thiebaut ◽  
Franck Nicolini ◽  
Quoc Hung Le ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Peripheral Blood Stem Cell ◽  
Ex Vivo ◽  
Median Number ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Abo Incompatibility ◽  
Allogeneic Pbsct

Abstract Immune hemolysis is a severe complication of allogeneic peripheral blood stem cell (PBSC) transplantation with minor ABO-incompatibility, principally observed after conventional allogeneic PBSCT. The B-cell depletion of the PBSC graft is a prophylactic intervention which may decrease incidence and severity of this event. Eight patients who underwent allogeneic PBSCT in our institution between August 1999 and April 2004 were analysed. They all received a B-cell depleted transplantation performed because of minor ABO-incompatibility. There were 5 males and 3 females and the median age was 42.5 years (19–65). The pre-transplant diagnosis were solid tumours for 2 patients and haematological malignancies for 6. All received allogeneic PBSC recruited by G-CSF from 3 HLA identical unrelated and 5 HLA identical sibling donors. The median number of nucleated cells and CD34+ cells harvested were 7.75x108 /Kg (3.9–11) and 6x106/kg (4.3–8.7) and the median number of infused cells were 5.5x108 /Kg (3.4–8.71) and 5x 106/kg (3.1–8.33) respectively. Two patients received myeloablative and 6 patients reduced intensity conditioning regimens (RIC). As graft-versus-host-disease (GVHD) prophylaxis, cyclosporin with methotrexate was given after myeloablative conditioning. After RIC, cyclosporin alone (n=4) or cyclosporin associated to methotrexate (n=1) or cyclosporin associated to mycophenolate mofetil (n=1) were given. The ex-vivo manipulation consisted of a negative CD19 immuno-selection using the Isolex 300 I Baxter procedure. The median number of CD19+ cells (x106/kg) before and after ex-vivo manipulation was respectively 73 and 0.05, which represented a B-cell log depletion of 3.16. The ex-vivo manipulation nevertheless induced a nucleated cell depletion of 20% (from 7.75 x108 cells/kg to 5.52x108 cells/kg after B-cell depletion) and a CD34+ cell loss of 18.5% (from 6x106 cells/kg to 5x106 cells/kg). Engrafment was observed for all patients and median time to neutrophiles (>0.5 G/l) and platelets (>50 G/l) recovery were respectively 19 and 12 days. Acute GVHD occurred for 5 patients whereas 3 patients developed chronic GVHD. At last follow-up, 4 patients died, 3 due to progressive disease, one due to hepatic GVHD. None of these 8 patients developed any clinical severe hemolysis, except one patient who presented a biological hemolysis with the development of a positive antiglobulin test 3 weeks after transplantation, without any consequences. Three months after transplant and at the last follow-up, the 4 long-term alive patients showed a stable erythropoietic reconstitution with an ABO-RhD donor determination. These data indicate that B-cell depletion is an efficient and safe method which could be used in case of minor ABO incompatibility.

Id/KLH Vaccine (FavId™) Following Treatment with Rituximab: An Analysis of Response Rate Improvement (RRI) and Time-to-Progression (TTP) in Follicular Lymphoma (FL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 587-587 ◽  
Author(s):  
Omer N. Koc ◽  
Charles Redfern ◽  
Peter H. Wiernik ◽  
Fred Rosenfelt ◽  
Jane N. Winter ◽  
...  
Keyword(s):  
T Cell ◽  
Injection Site ◽  
B Cell ◽  
Single Agent ◽  
Injection Site Reaction ◽  
T Cell Response ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Gm Csf

Abstract Background: Id/KLH vaccine (FavId) administered as a single agent has been associated with tumor regressions in patients with relapsed/refractory (RR) FL. B-cell depletion has been demonstrated to augment the T-cell immune response to subsequent vaccine administration in mice (Qin 1998 Nat Med 4:627). Objective: To evaluate the efficacy and safety of Id-KLH administered during the period of rituximab induced B-cell depletion. Eligibility: FL pts who were: treatment naïve (TN); RR following chemotherapy; or relapsed following rituximab. Treatment: Following rituximab (375mg/m2 i.v. weekly x 4) pts received Id-KLH (1 mg s.q. monthly x 6) starting on week 12. GM-CSF, 250 mcg, was administered s.q. at the Id-KLH injection site on days 1–4. Pts could continue Id-KLH until progression. Results: 103 pts received rituximab. Response to rituximab at month 3 was 35% (3-CR; 33-PR). Eleven (11) pts were PD following rituximab (11%). Id/KLH could not be made for 4 pts (4%). Eighty-eight (88) pts were begun on Id-KLH. Among the 45 RR pts, 32 (72%) have not progressed at a median follow-up of 12 months compared with 40% of historical control pts treated with rituximab alone (Witzig 2002 JCO 20:2453). Among the 43 TN pts, 82% have not progressed after a median follow-up of 9 months. RRI (SD to PR, PR to CR after month 3) was observed in 21 pts (12-SD to PR; 9-PR to CR). Robust T-cell responses to both Id and KLH were observed (3 of 3 pts tested). Anti-KLH antibody responses were generally not seen until B-cell recovery. The most frequent adverse event was an injection site reaction. A flu-like syndrome was also observed consistent with GM-CSF administration. Conclusion: Id/KLH vaccine (FavId), administered to pts with FL during a period of B-cell depletion induced by rituximab, can result in an anti-Id T-cell response, and appears to result in an RRI and an increased TTP compared to historical controls. A randomized, double-blind, placebo-controlled, Phase 3 trial of rituximab + FavId has been initiated.

scholarly journals B cell depletion therapy in systemic lupus erythematosus: long-term follow-up and predictors of response

2007 ◽  
Vol 66 (9) ◽  
pp. 1259-1262 ◽  
Author(s):  
K. P Ng ◽  
G. Cambridge ◽  
M. J Leandro ◽  
J. C W Edwards ◽  
M. Ehrenstein ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Systemic Lupus ◽  
Predictors Of Response ◽  
Long Term Follow Up

25 Year Old Female Conceiving 6 Months After Last Dose of Rituximab: a Case Report

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4924-4924 ◽  
Author(s):  
Lydia Y Cheung ◽  
Caroline Hamm ◽  
Michelle Suga ◽  
Mohammed Adie
Keyword(s):  
B Cell ◽  
Case Reports ◽  
Post Treatment ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Antibody Titres ◽  
Cd20 Antibody ◽  
Trimester Exposure ◽  
Anti Cd20

Abstract Abstract 4924 For female patients treated with rituximab, a monoclonal anti-CD20 antibody, it is recommended to wait 12 months post-treatment before pregnancy to avoid fetal B cell depletion. We report a case of a 25 year old female with a history of Grade II follicular lymphoma, Stage III who was treated with CHOP/R and maintenance rituximab therapy which was stopped when she expressed intentions for pregnancy. However, she conceives within only 6 months after her last dose of rituximab. This prompts questions of risks to the fetus. Rituximab is a monoclonal anti-CD20 antibody which targets and destroys normal and malignant CD20 positive B cells. As an IgG molecule, rituximab can cross the placenta, and has been documented to cause B cell depletion and immunosuppression in the fetus (McKeever et al, 2003). During treatment, high drug levels are detectable in the umbilical cord blood, and remains in the patient's blood between 3–6 months post-treatment (Pereg et al, 2007). The half life of rituximab varies with tumour burden and ranges from 3 – 19 days. B cell levels start to recover at 6 months post-treatment and are normal by 12 months. Hence, it is recommended by the manufacturer that pregnancies should be separated from rituximab use by a minimum of 12 months. Current literature regarding rituximab's safety in pregnancy is limited to animal studies and 10 case reports. When pregnant macaque cynomolgus females were exposed in 1st trimester, no teratogenic or embryotoxic effects were shown. There was a decrease in B cell levels but these were reversible by 179 days (McKeever et al., 2003). Among case reports, six involved women treated for hematological conditions. Of these cases, one was inadvertently exposed in 1st trimester and the fetus had B cell depletion that recovered to normal levels by 16 days (Kimby, 2004). All other cases were exposed in 2nd trimester of which two had transient B cell depletion that recovered by 4 months. All babies were healthy at birth, had normal antibody titres after their first vaccinations and normal childhood development at follow-up (Friedrich, 2006; Decker 2006). Four case reports involved rituximab use for non-hematological conditions; two cases of 1st trimester and two cases of 3rd trimester exposure. Only one 3rd trimester case reported transient fetal B cell depletion that recovered by 6 months (Klink, 2008). Again, all babies were healthy at birth and at follow-up, including normal antibody titres after vaccinations. From the cases reported, regardless of trimester exposure, the B cell depletion effect was only transient with no documented short-term or long-term effects on the baby's immune function and overall development. In this case, the patient stopped rituximab therapy 6 months prior to conception. There were no complications during pregnancy or delivery. Furthermore, a healthy baby boy was born at 42 weeks gestation with normal apgar scores, length at 75th percentile, and normal weight of 8 lbs 16 oz. Since the baby was clinically stable after delivery, B cell levels were not drawn. At 3 months old, the baby was healthy and had no difficulties with vaccinations to date. This is yet another case to add to the small literature base, and we hope it can help further inform the usage of rituximab during pregnancy. Disclosures: No relevant conflicts of interest to declare.

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