Subsequent Rituximab Research Articles

#2154 Rituximab in the treatment of PLA2R-associated membranous nephropathy: insights from a hospital centre experience

Abstract Background and Aims Rituximab (RTX) is recommended as the first-line therapy for PLA2R-associated Membranous Nephropathy in patients with a moderate to high risk of progressive loss of kidney function, according to the KDIGO 2021 guidelines. This recommendation is based on the superior long-term efficacy and improved safety profile of RTX. This study aims to assess the use of RTX for the treatment of for PLA2R-associated Membranous Nephropathy at a hospital centre. Method A retrospective study was conducted on patients diagnosed with PLA2R-associated Membranous Nephropathy who underwent their first RTX administration between 2017 and 2022 at a tertiary hospital centre. Exclusion criteria involved patients with less than 6 months of follow-up post-RTX. The study evaluated the occurrence of immune remission, clinical remission, as well as instances of immune and proteinuria relapse, and recorded any adverse events. Results A total of 11 patients were included, with 54.5% being male. The mean age was 60.4 ± 14.7 years, and the median disease duration 69.0 [8.0-87.0] months. The mean follow-up time post-RTX was 36.7 ± 23.3 months. Regarding the risk of progressive loss of kidney function, 8 patients were classified as high risk, 1 as moderate risk, and 2 as low risk. RTX served as the initial immunosuppressive therapy for only 3 patients. Additional immunosuppressive therapies post-RTX, including further RTX doses, were administrated in 63.6% (n = 7) of patients. No response was observed in 18.2% (n = 2). Immune remission was achieved in 81.8% (n = 9), mean time of 3.8 ± 1.4 months. Within this group 55.5% (n = 5) patients achieved complete remission, 22.2% (n = 2) experienced partial remission, and 22.2% (n = 2) maintained nephrotic proteinuria, with immune remission consistently preceding clinical remission. Relapses occurred in 45.5% (n = 5), at a mean time of 20.8 ± 13.5 months. Patients with lower serum albumin at time of RTX administration were more likely to experience non-response or relapse (T (9) = 2.51, p = 0.03), with a Youden Index cut-off of 3.2 g/dL, demonstrating a sensitivity of 100% and a specificity of 85.7%. Patients with anti-PLA2R exceeding 150 RU/mL exhibited no response or relapsed. Four patients (36.4%) remained free of relapses throughout the entire follow-up period, mean time of 22.8 ± 10.0 months, with 1 keeping RTX maintenance therapy. During the 6 months post-RTX, 36.4% (n = 4) of patients experienced adverse events. Conclusion Rituximab demonstrated both efficacy and safety in treating PLA2R-associated Membranous Nephropathy. However, lower serum albumin levels and anti-PLA2R > 150 RU/mL at time of RTX administration were associated with worse response. Given the substantial need for additional immunosuppression, and considering lower albumin values and higher anti-PLA2R titres as risk markers, it is recommended to closely monitor these patients. Anti-PLA2R titres showed a meaningful association with disease activity, preceding changes in proteinuria levels. Therefore, tracking disease progression through the measurement of anti-PLA2R titres not only guides clinical decisions but also enables a judicious approach to subsequent RTX administrations.

Neuroleptic Intolerance and Residual Mutism in a Young Woman with Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis

We report a case of anti-NMDAR encephalitis and residual mutism in a 23-year-old woman who presented with neuroleptic intolerance. Admission to our department for investigation of her abnormal behavior revealed cerebrospinal fluid (CSF) positivity for anti-NMDAR antibodies, and the patient underwent immunotherapy. However, generalized tonic seizures developed, requiring mechanical ventilation in the intensive care unit. Antipsychotic drugs were also administered for involuntary movements and insomnia. Thereafter, a malignant syndrome of severe hyperCKemia (Max: 191,120 IU/L) and shock developed, requiring resuscitation and three sessions of hemodialysis. Subsequent rituximab therapy led to improvement, except for mutism, which had newly developed during resuscitation. Seven months after initial admission, the patient was discharged with independent gait. However, her mutism still persists. Temporary mutism has been reported to occur in this type of encephalitis, albeit rarely. The fact that remission was not observed in this case may have been due to cerebellar infarction occurring during resuscitation, but the true cause remains unclear. Malignant syndrome or rhabdomyolysis, as seen in this patient, has also sometimes been reported in this form of encephalitis when antipsychotic agents, especially dopamine receptor blockers, have been administered. Therefore, such agents should be administered with caution in patients with anti-NMDAR encephalitis. (Received August 17, 2023; Accepted October 24, 2023; Published March 1, 2024).

Response Duration and Relapse Free Survival Shorten after Each Episode of Immune Thrombotic Thrombocytopenic Purpura (iTTP) Treated in the Rituximab Era

INTRODUCTION: Immune thrombotic thrombocytopenic purpura (iTTP) is caused by an autoantibody mediated deficiency of ADAMTS13 and characterized by recurrent episodes of life-threatening thrombotic microangiopathy. Rituximab (anti-CD20 monoclonal antibody) reduces relapse rates in many cases. This multicenter observational aimed at comparing durability of rituximab response (measured as relapse free survival, RFS) in first versus subsequent episodes of iTTP based on the clinical observation that patients with multiply relapsing disease may have attenuated responses to rituximab. METHODS: We first evaluated clinical RFS (time from rituximab treatment to clinical relapse) in the United States Thrombotic Microangiopathy Consortium retrospective iTTP registry that includes data from 15 high volume academic centers. We performed a subsequent analysis from the well-phenotyped Johns Hopkins University (JHU) and University of Minnesota (UM) prospective iTTP cohorts, that additionally include serial assessments of ADAMTS13 activity in remission, to confirm our findings and to evaluate overall RFS [a composite of clinical relapse, ADAMTS13 relapse including ADAMTS13 relapse treated with preemptive rituximab) which is a clinically relevant endpoint in the era of ADAMTS13 monitoring and receiving preemptive rituximab. ADAMTS13 relapse was defined as ADAMTS13 <20% without thrombocytopenia or symptoms. In both analyses, we included only patients with > 1 year follow up after treatment with rituximab (either during iTTP episodes or preemptive) and excluded those who received immunosuppression other than rituximab or steroids. Patients who started maintenance rituximab (every 3 or 6 months) were censored at that point). We used Cox regression to examine factors associated with clinical RFS and overall RFS including first versus subsequent rituximab treatment episodes as a covariate, and Kaplan-Meier survival curves to visualize these relationships. RESULTS: In the USTMA registry, 310 unique patients had a total of 384 iTTP episodes treated with rituximab (310 first, 53 second, and 21 were 3rd to 5th courses of rituximab) between 2003-2019. Presenting in relapsed iTTP [HR 2.10 (95% CI 1.24 - 3.58)], Black race [HR 3.12 (95% CI 1.68-5.80)] and second or subsequent rituximab course [HR 2.80 (95% CI 1.53-5.10)] were associated with clinical relapse in a Cox regression model that also included age, sex, and exacerbations. Median RFS was higher after the first compared with subsequent (2nd-5th) rituximab courses (6.0 vs 2.1 years, P = 0.04). Since race was significantly associated with clinical RFS in the Cox regression model, we evaluated clinical RFS after first and subsequent rituximab courses separately for Black and White participants. Among White patients, clinical RFS after the second or subsequent rituximab courses was not significantly different compared to the first course [HR=1.86 (95% CI 0.22-15.80), P=0.57]. However, in Black patients, clinical RFS was shorter after the second and subsequent rituximab courses [HR=2.82 (95% CI 1.52-5.24), P=0.001]. The JHU and UM cohort included 97 patients with 266 episodes of rituximab treatment. Similar to the USTMA cohort, median clinical RFS was shortened with reach subsequent rituximab course. Median overall RFS (time to clinical or ADAMTS13 relapse) was also longest after the first rituximab course [2.8 (IQR 2.0-6.0) years] followed by the second course [2.0 (IQR 1.2-3.6) years], and third and subsequent episodes courses [1.0 (IQR 0.5-2.5) years] (P< 0.001). Overall RFS was shorter in White patients and the loss of response durability with later courses was most prominent in Black versus patients. For examples, median overall RFS from the first to the third or later courses reduced from 3.6 years to 1.5 years for White patients, and from 2.7 years and 0.9 years in Black patients (Figure 1). CONCLUSIONS: Despite's rituximab's known effect of prolonging RFS in iTTP, the time to clinical relapse or ADAMTS13 relapse (often a precursor of clinical relapse) shortens with multiple episodes/treatment courses with an earlier ‘wearing off’ effect in Black patients especially those being treated in relapse. Patients who have had ≥ 2 rituximab courses may need closer monitoring and and consideration of maintenance rituximab or other immunomodulators.

Comparing the Impact of Rituximab Dosing on Longitudinal ADAMTS13 Parameters in TTP

Introduction The use of rituximab to prevent clinical TTP relapse is widely accepted practice. However, the optimal dosing and regimen remains unclear with a variety used across treating centres. ‘Standard’ dosing is extrapolated from dosing for lymphoproliferative diseases: an equally efficacious lower dose would be time & cost-saving. We are investigating the impact of low dose (4 x 200mg weekly) vs standard dose rituximab (4 x 375mg/m 2 weekly) on ADAMTS13 response utilising prospectively collected samples from 69 ADAMTS13 relapse episodes from 4 UK sites who received elective treatment between 2017-2022 (REC: 17/LO/1055). A subset analysis of the cohort was performed, investigating open/closed ADAMTS13 conformation from time of elective rituximab treatment to subsequent rituximab retreatment. Method ADAMTS13 activity was measured at fixed timepoints from first day of elective rituximab on days 1, 8, 15 & 22, month 1, 3, 6 and then 6 monthly until retreatment. Open/closed ADAMTS13 conformation was analysed in a subset of 31 episodes with the 1C4 ELISA and ADAMTS13 antigen ELISA at 4 different timepoints (ADAMTS13 activity <15IU/dL or %; peak ADAMTS13 activity; interim follow-up sample after peak ADAMTS13 and at next ADAMTS13 relapse). Results Median time from one elective rituximab treatment to the next was 16 months (range: 2 - 64, IQR: 9 - 24) for the subset. Time to ADAMTS13 activity normalization was compared in 26 episodes: 5 episodes were excluded as they failed to achieve ADAMTS13 normalization. 17/31 had low dose and 14/31 standard dose. There was no significant difference in the rate of ADAMTS13 normalization in the low dose compared to standard dose rituximab regime, with median 34 days ( IQR: 18 - 99, range: 14 - 266) and 21 days (IQR: 15 - 65, range: 14 - 94) respectively. 13 patients remained in an open ADAMTS13 conformation at all four timepoints, of which 9 had received low dose rituximab. 5 of 13 patients did not achieve a normal ADAMTS13 activity (i.e. >60IU/dL) at any timepoint, with 3 having received low dose & 2 standard dose rituximab. These 13 patients had a slightly shorter time period between elective rituximab treatment episodes with a median of 8 months (range: 2 - 25, IQR: 6 - 15). In 3 patients, ADAMTS13 remained closed on the follow up sample 3 months after peak ADAMTS13 activity (mean 100IU/dL), despite subsequently relapsing 2, 8 & 12 months later. Two had received standard dose rituximab. 14 patients had a closed conformation at peak ADAMTS13 activity, but a subsequent open conformation on follow up sample testing, despite a normal ADAMTS13 activity (median: 82IU/dL, IQR: 72-86). The 7 patients receiving standard dose rituximab converted to an open conformation in 6 months (IQR: 3 - 12) compared to the 7 low dose patients who switched at 4 months (IQR: 3 - 12). Subsequent ADAMTS13 relapse after detection of an open conformation occurred at a median of 6 months later (range: 4 - 8) in the standard dose group and 8 months (range: 4 - 19) in the low dose group. Lastly, 1 patient had no follow up sample after peak ADAMTS13 activity (& closed confirmation), presented with ADAMTS13 relapse (<15IU/dL) and open conformation 7 months later. Of the 31 episodes, ADAMTS13 activity & antigen results were not significantly different between the two rituximab groups for both peak ADAMTS13 activity and follow up timepoints. At peak ADAMTS13 activity, approximately 31% of patients had an open conformation in the standard dose group compared to 69% in the low dose group. In the follow up samples, this increased to 85% open conformation in the standard dose group and 93% open in the low dose group. For two of the patients, with more than one episode of elective rituximab treatment during the study, a closed ADAMTS13 conformation was again achieved after subsequent rituximab treatment. Conclusion We studied the impact of low dose and standard dose rituximab on longitudinal parameters in ADAMTS13 relapse in TTP. Overall, there were no significant differences between open vs. closed conformation at peak ADAMTS13 activity and an interim follow up timepoint between low dose and standard dose rituximab. A higher proportion of patients on low dose rituximab failed to achieve closed conformation at any timepoint but numbers are small. Importantly, our data suggests that regardless of rituximab dose, the open conformation is not indicative of imminent ADAMTS13 relapse as patients required retreatment after a further 7 months on average.

Association of giant cell hepatitis and autoimmune hemolytic anemia in infancy

Giant cell hepatitis associated with autoimmune hemolytic anemia (GCH-AIHA) is a rare disorder with unfavorable prognosis, affecting infants and young children. The mortality rate is high, complications of acute liver failure, sepsis, or liver transplantation can be responsible for fatal outcomes. An 18-month-old child who was diagnosed previously with autoimmune hemolytic anemia, developed acute hepatitis and acute liver failure concomitant to the relapse of the disease. GCH-AIHA is characterized by Coombs positive hemolytic anemia and progressive liver injury, histologically defined by widespread giant cell transformation. Liver biopsy was performed to establish the diagnosis, histological examination confirmed the presence of multinuclear, giant cell hepatocytes. Corticosteroid and azathioprine treatment were started. As a result of subsequent rituximab treatment and intravenous immunoglobulin therapy, acute liver failure and anemia gradually resolved. The exact background of the association of the two entities is still unknown, an autoimmune mechanism is suspected. Conventional immunosuppressive treatment with corticosteroid and azathioprine seems to be ineffective in most cases, therefore second- and third-line therapies are required. Since the introduction of the anti-CD20 rituximab therapy, the prognosis of GCH-AIHA has improved significantly. Orv Hetil. 2023; 164(36): 1432-1436.

PHASE 1/2A CLINICAL TRIAL OF BI‐1206, A MONOCLONAL ANTIBODY TO CD32B (FCGRIIB), IN COMBINATION WITH RITUXIMAB IN SUBJECTS WITH INDOLENT B‐CELL LYMPHOMA

Introduction: Anti-CD20 antibodies, such as rituximab, are an essential therapy resource in patients with B-cell lymphomas. However, approximately 15% of patients are refractory to treatment, and 25% relapse within 3 years following treatment. Non-clinical and retrospective clinical data indicate that the inhibitory Fc receptor CD32b promotes resistance through mechanisms acting on tumor and immune effector cells. Expressed on tumor B cells, CD32b triggers rituximab internalization, and tumor CD32b expression correlates inversely with response to rituximab or rituximab-containing therapy in MCL, FL, and DLBCL. BI-1206 is a human recombinant anti-CD32b (FcγRIIB) antagonistic IgG1 antibody that blocks rituximab internalization and, in non-clinical experimental models, enhances efficacy and overcomes rituximab resistance. During early clinical development of BI-1206, frequent infusion-related reactions were observed after intravenous (IV) administration. The development of a novel pre-medication regimen using two doses (16–24 h and 1 h) of corticosteroids prior to IV administration, as well as of a subcutaneous (SC) administration, have been shown to improve the tolerability of BI-1206 significantly, and both methods of administration are evaluated in the current trial. Methods: The current phase 1/2a multicenter clinical trial includes relapsed or refractory B-cell lymphoma, including FL (except FL grade 3B), MZL, and MCL. This trial will evaluate the safety and tolerability of IV and SC BI-1206 administered in combination with rituximab. The ivRP2D has been established, and enrollment of patients to SC BI-1206 to establish scRP2D has started. Ph2a of the trial will consist of cohorts of at minimum 6 and maximum 12 subjects each, receiving ivRP2D, scRP2D, and potential additional dose levels of interest. During induction therapy, patients receive one dose of single-agent rituximab (375 mg/m2) followed by dosing of BI-1206 with subsequent rituximab on weeks 2, 3, and 4. Patients showing clinical benefit (complete response [CR], partial response [PR], or stable disease [SD]) at week 6 are eligible for continued maintenance therapy with dosing of BI-1206 and rituximab every 8 weeks for up to 7 cycles. The research was funded by: BioInvent Keywords: Combination Therapies, Immunotherapy, Ongoing Trials Conflicts of interests pertinent to the abstract. M. Jerkeman Honoraria: Gilead, Janssen, Roche, AstraZeneca, Abbvie, BMS Research funding: Gilead, Janssen, Roche, AstraZeneca, Abbvie, BMS P. Abrisqueta Costa Consultant or advisory role Janssen, Roche, Abbvie, BMS, Astrazeneca, Gilead, Beigene Honoraria: Janssen, Roche, Abbvie, BMS, Astrazeneca, Gilead Educational grants: Janssen, Abbvie J. M. Sancho Cia Consultant or advisory role Roche, Janssen, Novartis, BMS-Celgene, Kite-Gilead, Beigene, Lilly, Incyte, Miltenyi Biomedicine Honoraria: Roche, Janssen, Novartis, BMS-Celgene, Kite-Gilead, Takeda, Incyte M. Bastos-Oreiro Consultant or advisory role Roche, Kite, Novartis, Takeda, Janssen, Incyte Honoraria: Roche, Kite, Novartis, Takeda, Janssen, Incyte Research funding: Roche Educational grants: Roche, Kite, Novartis, Takeda, Janssen, Incyte J. B. Cohen Consultant or advisory role Janssen, Astra Zeneca, BeiGene, Loxo/Lilly, Gilead, ADCT Research funding: Genentech, Takeda, Novartis, Celgene, BioInvent, LAM Therapeutics, Loxo/Lilly, Astra Zeneca R. Cordoba Mascunano Consultant or advisory role Roche, Abbvie, Janssen, Astra Zeneca, Beigene, Lilly, Kite, Incyte, Takeda, Kiowa-Kirin E. Domingo Domenech Consultant or advisory role TAKEDA Honoraria: TAKEDA Educational grants: TAKEDA, BMS S. Novelli Canales Honoraria: Mundipharma Research funding: Novartis M. Borggren Employment or leadership position: BioInvent Stock ownership: BioInvent B. Frendeus Employment or leadership position: BioInvent Stock ownership: BioInvent I. Karlsson Employment or leadership position: BioInvent Stock ownership: BioInvent L. Mårtensson Employment or leadership position: BioInvent Stock ownership: BioInvent S. Patel Employment or leadership position: BioInvent Stock ownership: BioInvent I. Teige Employment or leadership position: BioInvent Stock ownership: BioInvent J. E. Wallin Employment or leadership position: BioInvent, Lilly Keywords: combination therapies, immunotherapy, ongoing trials Stock ownership: BioInvent, Lilly A. Mc Allister Employment or leadership position: BioInvent Stock ownership: BioInvent

Warm autoimmune hemolytic anemia and the best treatment strategies

Warm autoimmune hemolytic anemia (wAIHA) is characterized by evidence of red blood cell (RBC) hemolysis and a direct antiglobulin test positive for IgG and sometimes complement. While varying with the extent of the compensatory increase in RBC production, symptoms of anemia predominate, as does jaundice, the latter often exacerbated by concurrent Gilbert's syndrome. Initial treatment with corticosteroids is highly effective, with over 85% of patients responding but with less than one-third maintaining that response upon weaning. Subsequent rituximab administration in those failing corticosteroids provides complete remission in over 75% of patients and may be long-lasting. Over 50% of patients failing rituximab respond to erythropoiesis-stimulating agents or immunosuppressive agents. Splenectomy is best deferred if possible but does offer long-term remission in over two-thirds of patients. A number of new treatments for wAIHA (fostamatinib, rilzabrutinib, and FcRn inhibitors) show promise. A treatment algorithm for wAIHA is proposed to avoid the excessive use of corticosteroids.

Clinical manifestations and treatment outcomes of pyoderma gangrenosum following rituximab exposure: A systematic review

Clinical manifestations and treatment outcomes of pyoderma gangrenosum following rituximab exposure: A systematic review

Long-term Safety of Rituximab in Primary Sjögren Syndrome: The Experience of a Single Center.

This work aims to evaluate the long-term safety of rituximab (RTX) in primary Sjögren syndrome (pSS) and to determine the safety and the efficacy of long-term treatment with B cell depleting therapy in pSS patients with active systemic disease. A historical cohort study, enrolling 35 patients with pSS treated with RTX between 2008 and 2019 in a single rheumatologic unit, was performed. When patients experienced adverse events, the treatment was suspended and patients' data were recorded. The included patients were mainly female (91%), with a mean age of 54 years. During the time of observation, 13 patients (37.1%) suspended RTX treatment (10 cases per 100 patient-years, 95% CI 0.06-0.17). Baseline demographics, disease characteristics, European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) values, and treatment were comparable across RTX-suspended and nonsuspended groups. Patients exposed to RTX had been followed for 35.82 ± 32.56 months, and the time of observation varied from 6 to 96 months. All the patients except one experienced a significant and persisting meaningful improvement of their ESSDAI (≥ 3 points) during the long-term follow-up. For the duration of the follow-up, 13 (37%) patients discontinued RTX treatment. Four out of 13 (30.8%) discontinued the treatment after the first administration due to infusion-related reactions. During subsequent RTX courses, the main cause of withdrawal was hypogammaglobulinemia onset (7 patients). In 2 patients, hypogammaglobulinemia was associated with severe infections. Long-term RTX administration was shown to be a safe, well tolerated, and effective treatment in patients with active systemic disease, significantly reducing ESSDAI and controlling disease activity.

Rituximab maintenance improves outcomes of transformed diffuse large B-cell lymphoma: a retrospective study of 519 cases with de novo diffuse large B-cell lymphoma and 62 cases with concurrent diffuse large B-cell lymphoma and follicular lymphoma

Although outcomes of transformed diffuse large B-cell lymphoma (DLBCL) from follicular lymphoma (FL) were improved using rituximab-combined immunochemotherapy, the efficacy of subsequent rituximab maintenance (RM) remains unclear. We retrospectively analyzed the prognoses of 519 patients with de novo DLBCL and 62 patients with concurrent DLBCL and FL (concurrent-DLBCL/FL). Progression-free survival (PFS) was shorter in patients with concurrent-DLBCL/FL than in de novo DLBCL (p=.030). Twenty-four patients with concurrent-DLBCL/FL received RM after induction therapy, and they achieved better OS and PFS (p=.010 and p<.001, respectively) with lower risk of relapse (p<.001) than the non-RM group. Moreover, concurrent-DLBCL/FL showed better subsequent OS and PFS after recurrence than de novo DLBCL (p=.0083 and p=.0044, respectively). Our study indicates that in the face of a high relapse rate, concurrent-DLBCL/FL is manageable and benefits from RM.

Long-term outcomes of rituximab therapy in pemphigus.

Rituximab induces a rapid remission in most patients with pemphigus. Our aim was to assess the long-term efficacy of rituximab in this disease. We conducted a retrospective study of 59 patients with pemphigus treated with rituximab and observed over a median period of 104months. The rate of complete remission off therapy (CRoff) after the first rituximab cycle was 39%, increasing to 61% with additional rituximab courses. Long-term CRoff was achieved in 27% of patients. The recurrence rate after the first rituximab cycle was 63%, decreasing to approximately 40% with subsequent rituximab cycles. Median time to relapse after the first and subsequent rituximab cycles was 25months. Renewed rituximab therapy reinduced complete remission in 94% of cases. Baseline anti-desmoglein antibody levels of ≤250U/mL were significantly associated with the outcome of CRoff. In paired serum samples obtained before the first and six months after the last rituximab therapy, significant reductions of desmoglein-specific autoantibodies were observed. Patients relapsing after a complete remission induced by the first rituximab cycle were more likely to achieve CRoff than patients relapsing after a less favourable outcome and non-responders. There was no significant difference in age, sex, pemphigus subtype, rituximab dosing and disease duration between patients achieving CRoff and those not meeting this end point. Lower desmoglein-specific antibody levels at baseline were predictive of CRoff. In patients receiving multiple rituximab cycles, complete remission after the first cycle was associated with a favourable long-term outcome. Repeated rituximab courses were highly effective for relapsed disease and improved the overall outcome.

Unfavorable impact of anti-rituximab antibodies on clinical outcomes in children with complicated steroid-dependent nephrotic syndrome.

Anti-rituximab antibodies (ARA) are associated not only with adverse events, such as infusion reactions (IR) and serum sickness, but also with rituximab efficacy. However, the clinical relevance of ARA in children with steroid-dependent nephrotic syndrome (SDNS) remains unknown. We retrospectively reviewed clinical outcomes of 13 children with complicated SDNS receiving repeated single-dose rituximab treatments at 375 mg/m2 to assess whether ARA formation could impact toxicity and efficacy of additional rituximab. Pre-rituximab 22 samples collected from patients who developed IR during the second or subsequent rituximab doses were measured by electrochemiluminescence analysis. ARA were identified in 5 of 13 patients (9 of 22 samples). Median time to recovery of CD19+ B cells to > 1% of total lymphocytes and median relapse-free time after rituximab treatment were significantly shorter in the 9 ARA-positive samples than the 13 ARA-negative samples (41 vs. 100 days, p < 0.01 and 119 vs. 308 days, p < 0.05, respectively). Kaplan-Meier analysis showed that time to CD19+ B cell recovery after rituximab was significantly shorter in ARA-positive samples than in ARA-negative samples (p < 0.005). Severe IR developed in two ARA-positive patients and serum sickness in one ARA-positive patient. The incidence of ARA formation was high in the pre-rituximab samples of patients with complicated SDNS who developed IR during the second or subsequent rituximab doses, suggesting that ARA formation might have an unfavorable impact on the toxicity and efficacy of additional rituximab doses in these patients.

1476 Early Detection of Mantle Cell Lymphoma Recurrence With Colonoscopy

INTRODUCTION: Non-Hodgkin Lymphomas (NHL) are a group of malignancies that are derived from immature B cells, T cells and natural killer cells. The incidence of NHL is 19.6 per 100,000 per year in the United States. Mantle cell lymphoma (MCL) is a type of NHL which arises from mature B cells and has a more aggressive clinical course, accounting for 6% of all NHL cases. This amounts to approximately 4200 new cases in the US every year. MCL has a strong predilection for the gut with 92% of patients exhibiting gastrointestinal infiltration. CASE DESCRIPTION/METHODS: Our patient is a 68-year-old Caucasian male referred for a routine screening colonoscopy. History was notable for MCL involving the hard palate diagnosed in February 2013. This was initially treated with R-CHOP therapy with subsequent Rituximab maintenance. Patient relapsed in February 2015. His relapse was treated with FCR therapy which was completed in June 2015. Follow up bone marrow biopsy was negative. In June 2016 he had recurrence of the malignancy on his hard palate, requiring treatment with local radiation. After completion of radiation, surveillance imaging with integrated whole body PET/CT demonstrated no further activity. He was deemed to be in remission and maintained routine biannual oncologic follow up for three years. Routine screening colonoscopy performed in May 2019, revealed a polyp in the transverse colon, and an additional polypoid lesion in the rectum. Biopsy revealed atypical lymphoid infiltrate consisting of medium sized lymphocytes that were positive for CD5, CD20, CD10, PAX5, Bcl-2, and cyclin D1. Morphology, immunofluorescence, and FISH were positive for t11:14, with pathology being consistent with mantle cell lymphoma. Patient has been referred back to his oncologist to discuss further treatment options. DISCUSSION: Our case illustrates the importance of endoscopic surveillance in patients with MCL. While PET/CT is invaluable in the surveillance of multiple malignancies, it maybe inadequate in determining remission and recurrence of MCL. The National Comprehensive Cancer Network (NCCN) recommends that both upper endoscopy and colonoscopy be performed to assess treatment response and remission in this population. Given the high incidence of GI involvement in MCL, incorporating routine endoscopic surveillance as part of MCL management may be an important step for early detection of disease recurrence in this high-risk population.

Current approaches and future perspectives for advanced-stage follicular lymphoma with a low tumor burden.

The introduction of a chimeric anti-CD20 monoclonal antibody, rituximab, for the treatment of follicular lymphoma (FL) has dramatically improved the prognosis of this disease. Despite advances in therapy, the disease remains incurable with current standard therapeutic strategies. For advanced-stage and high-tumor-burden FL patients, a combination of rituximab with chemotherapy has improved the overall survival rates, and subsequent rituximab maintenance following successful rituximab-based chemotherapy induction also prolongs progression-free survival. Conversely, for advanced-stage low-tumor-burden FL patients, watchful waiting remains the appropriate approach, whereas rituximab monotherapy has also been suggested as a good alternative. However, the optimal timing of rituximab monotherapy in low-tumor-burden FL patients has not been clarified. It is important to address this issue for chemo-free treatment strategies. Furthermore, a predictive model for advanced low-tumor-burden patients is required to appropriately identify those patients who may benefit from immediate treatment. In this review, we address the current treatment approaches and present potential future management strategies for advanced-stage, low-tumor-burden patients.

Lenalidomide Maintenance after Autologous Transplantation Prolongs PFS in Young MCL Patients: Results of the Randomized Phase III MCL 0208 Trial from Fondazione Italiana Linfomi (FIL)

Lenalidomide Maintenance after Autologous Transplantation Prolongs PFS in Young MCL Patients: Results of the Randomized Phase III MCL 0208 Trial from Fondazione Italiana Linfomi (FIL)

Impact of Rituximab Infusion Reactions on Clinical Outcomes in Patients with Diffuse Large B-Cell Lymphoma

Introduction: Rituximab is a chimeric mouse/human monoclonal antibody that binds to CD20, which is expressed on both normal and neoplastic B-lymphocytes. The addition of rituximab to standard chemotherapy regimens has led to improvements in progression-free survival and overall survival for diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma (NHL). Despite the widespread clinical success of rituximab, its mechanism of action is not clear. However, evidence from pre-clinical models and clinical observations suggest complement-mediated cytotoxicity (CMC) and/or antibody-dependent cell mediated cytotoxicity (ADCC) may both play a role.Clinically, the most common complication of rituximab is mild infusion reactions (IR), characterized by fevers, rigors, flushing, dyspnea, and mild hypotension, which are typically limited to the first infusion. Complement activation has been suggested as an underlying mechanism for rituximab-related IR, though the exact nature or implications of such reactions are not known. Since complement activation is also a potential mechanism of rituximab-related anti-lymphoma activity, we aimed to determine whether an association exists between rituximab associated IR and outcomes in patients with DLBCL. These results would help guide future studies on the mechanism of monoclonal antibody therapy for NHL.Methods: We identified and analyzed a retrospective cohort of 229 patients with DLBCL. They were stratified into two cohorts, based on the presence or absence of an infusion reaction during the first cycle of rituximab. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was used to grade the severity of rituximab-associated IR. Univariate and multivariate analyses were performed to evaluate the prognostic significance of rituximab-related infusion reactions relative to DLBCL subtype, IPI score, c-Myc mutational status, chemotherapy regimen, and Ki-67 proliferative index.Results: Baseline characteristics did not differ significantly between the two groups. Rituximab was included as initial treatment in all patients studied. Among 226 patients, 68 (30.1%) had a grade 1-2 IR, all of whom were able to receive subsequent rituximab therapy. In comparing outcomes between the two cohorts, those with an IR had a significantly greater overall survival (HR 0.26, 95% CI 0.07-0.95) at five years (Figure 1). Multivariate analysis showed that patients with c-Myc alterations or higher IPI scores were more likely to experience a rituximab associated IR (Table 1). Furthermore, subgroup analysis showed that among patients with either c-Myc alterations or GCB subtype of DLBCL, those who experienced an IR had a statistically significant increase in progression-free survival (p-value of 0.01 and 0.03, respectively).Conclusion: Rituximab associated IR occurs commonly and is associated with better overall survival in patients with DLBCL. Subgroup analyses suggest that this benefit is largely restricted to patients with c-Myc alterations or the GCB subtype. While these data are limited by the small sample size and retrospective nature, they do generate some intriguing hypotheses related to underlying mechanism of action of rituximab in a subset of DLBCL patients. These data have potential implications in augmenting the efficacy of CD20-directed monoclonal antibody therapy in these patients that should be further validated in subsequent prospective studies. [Display omitted] DisclosuresBartlett:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Affimed: Research Funding; Forty Seven: Research Funding; ImaginAB: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Immune Design: Research Funding; Millennium: Research Funding; Merck & Co: Research Funding. Wagner-Johnston:JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Novartis: Research Funding; Celgene: Research Funding; ASTEX: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Infusion reactions associated with rituximab treatment for childhood-onset complicated nephrotic syndrome.

Infusion reaction (IR) is defined as an adverse event within 24h after monoclonal antibody infusion. In non-Hodgkin lymphoma, IR incidence following rituximab treatment is high (77-80%), but there are no data in complicated nephrotic syndrome. Records of rituximab infusions in patients with complicated nephrotic syndrome between February 2006 and December 2014 at the National Center for Child Health and Development were reviewed. Rituximab was administered at doses of 375mg/m2. The severity of IR was evaluated using the Common Terminology Criteria for Adverse Events ver. 4.0. For 309 rituximab infusions in 159 patients (male, 110; median age, 12years), IR was observed in 165 infusions (53.4%). Respiratory symptoms were most common (66% of all events). Ninety-five percent of the IR was observed within 3h after rituximab infusion initiation. Sixty-eight percent of the events were classified as grade 1 and others classified as grade 2. Only 18% required medical intervention. CD20 cell count in patients with IR was significantly higher than in patients without IR. Incidence of IR was similar in subsequent rituximab treatment after B-cell recovery. Patients who experienced IR at first rituximab treatment were more likely to experience recurrent IR with subsequent treatments compared to those not having IR at initial treatment (odds ratio 3.64; p < 0.001). In patients with complicated nephrotic syndrome, respiratory symptoms were the major type of IR, mostly observed within 3h of infusion. Incidence of IR was lower and its severity milder in patients with complicated nephrotic syndrome than those with lymphoma.

The incidence of biopsy-proven transformation in follicular lymphoma in the rituximab era. A retrospective analysis from the Czech Lymphoma Study Group (CLSG) database.

The aim of this study is to assess the incidence, risk factors, and outcome of biopsy-proven transformation in follicular lymphoma (FL) patients in the rituximab era. Transformation was analyzed in 1233 patients with initially diagnosed FL grades 1-3A, identified between 2002 and 2012 in the prospectively maintained Czech Lymphoma Study Group database. Only patients with histologically proven transformation (HT) were included. HT occurred in 58 cases at a median of 3.0years from the initial FL diagnosis; the HT rate was 4% at 5years. Transformation occurred most frequently at the first relapse (84% patients). Median OS from the HT was 2.5years (95% CI 0.4-4.6) and 6-year OS with HT was shorter compared to all FLs (60 vs. 83.9%; 95% CI). A bulky tumor (≥ 10cm), increased lactate dehydrogenase, age ≥ 60years, and International Prognostic Index (intermediate/high risk), but not Follicular Lymphoma International Prognostic Index, were associated with transformation (p < 0.05). In the first line, 70% of patients received rituximab (including 36% rituximab maintenance), 57% CHOP-like regimens, and 2.6% of patients were treated with fludarabine-based therapy, whereas 11% of patients were watched only. The patients treated with R-CHOP in the first line (n = 591) showed the transformation rate at 5years of 4.23% (95% CI 2.52-5.93); subsequent rituximab maintenance (n = 276) vs. observation (n = 153) was associated with a lower transformation rate (p.033; HR 3.29; CI 1.10-9.82). The transformation rate seems to be lower than in previous series, which may be influenced by broad use of rituximab, but prognosis of HT developed during therapy continues to be poor.

Sequential RCHOP, Radioimmunotherapy and Rituximab Maintenance Improves Early Outcomes in Advanced Stage Follicular Lymphoma: 5 Year Outcomes from SWOG 0801

Background:Despite an abundance of effective therapeutic options, advanced stage follicular lymphoma (FL) remains incurable. Further, prospective trials consistently demonstrate that 20% of patients relapse within 2 years and ultimately have an inferior survival (Casulo 2015). Maintenace rituximab following chemoimmunotherapy induction is able to delay disease progression but has not demonstrated a benefit in overall survival (Salles 2011). Additionally, radioimmunotherapy (RIT) is one of the most effective single agent options in FL but is not commonly utilized as part of upfront treatment. As such, the role of both remains unclear. Based on results demonstrated with RIT consolidation in SWOG 0016 and the efficacy of rituximab maintenance, SWOG 0801 was designed as a phase 2 single arm trial, conducted to evaluate the utility of consolidative RIT and sequential maintenance rituximab following chemoimmunotherapy induction.Methods:Eligible patients (pts) with treatment naïve stage III/IV or bulky stage II FL received RCHOP for 6 cycles (without rituximab for the last 2 cycles) followed by iodine-131 tositumomab and subsequent rituximab administered every 3 months for up to 4 years. The primary endpoint was progression-free survival (PFS) at 3 years. Secondary endpoints included 5-year overall survival (OS), overall response rate (ORR), and safety.Results:Of 87 pts registered to this study, 85 were deemed eligible following central pathologic review. One additional patient withdrew consent and received no treatment on protocol.Of the 84 evaluable patients, the median age was 52 years (range 29 - 80) ) and 18%, 40%, and 42%had low, intermediate and high risk FLIPI scores, respectively. Seventy-three pts completed RCHOP and I-131 tositumomab. Grade ≥3 AEs occurring ≥5% of pts included neutropenia (57%), leukopenia (40%), thrombocytopenia (20%), febrile neutropenia (17%), fatigue (10%), neuropathy (8%), anemia (7%) and hyperglycemia (5%). Reasons for discontinuation included refusal of tositumumab (6 pts), prolonged myelosuppression (2 pts), ascites (1pt), inability to provide tositumumab (1 pt), and an unrelated lower extremity wound (1 pt). Following induction and RIT, 59 complete responses and 23 partial responses were observed, for a ORR of 99% (95% CI: 93.5%, 99.9%)Sixty nine eligible patients registered to maintenance therapy with 42 completing the 4 year treatment plan. The only grade ≥3 AE that occurred in ≥5% of pts was leukopenia (5%). Twenty-seven pts discontinued maintenance therapy, including 11 in the first 2 years and 16 in the last 2 years, due to the following reasons: infection (8 pts), patient preference (8 pts), deaths (2 pts), treatment delay (2 pts), secondary solid tumors (2 pts), bowel perforation (1 pt), joint pain (1 pt), hepatic transaminase elevation (1 pt), insurance refusal (1 pt), and dose error (1 pt).Four additional secondary malignancies were reported following completion of therapy including solid tumors (3 pts) and AML (1 pt). To date, 9 deaths have occurred due to secondary malignancies (3 pts), unknown etiology (3 pts), cardiac arrest (2 pts) and non-alcoholic cirrhosis (1 pt).After median follow-up of 5.6 years (range 3-7 years), 17 events have occurred including 9 pts experiencing progressive FL resulting in a progression free survival of 90% (95% CI: 81.9%, 95.1%) at 3 years and 84%(95% CI: 74.5%, 90.6%) at 5 years (Figure). Three-year overall survival is 96% (95% CI: 89.3%, 98.8%) and 5-year overall survival is 94% (95% CI: 86.2%, 97.5%).Conclusions:SWOG 0801 demonstrates near universal responses following chemoimmunotherapy and RIT. This sequential therapeutic strategy appears to improve early outcomes as 94% of pts are without disease progression at 2 years, consistent with the best results ever demonstrated for FL in the National Clinical Trials Network. However, the majority of discontinuations occurred during maintenance suggesting that rituximab over a 4-year span is not feasible for many patients due to cumulative toxicity. Future studies investigating precision strategies in high-risk FL may consider an aggressive chemoimmunotherapy induction and RIT consolidation platform to overcome early FL progression given these promising outcomes.Support: NIH/NCI grants CA180888, CA180819, and in part by GlaxoSmithKline. [Display omitted] DisclosuresBarr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Smith:Amgen: Other: Educational lecture to sales force; Juno: Consultancy; Pharmacyclics: Consultancy; AbbVie: Consultancy; Portola: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; TGTX: Consultancy. Gopal:Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy. Persky:Merck: Research Funding; Gilead: Speakers Bureau. Press:Roche / Genentech: Consultancy, Research Funding. Fisher:Gilead: Consultancy; Seattle Genetics: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Other: Data Safety Monitoring Committee.

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up