Combination Of Rituximab Research Articles

Real-World Efficacy and Safety of Rituximab, Lenalidomide and İbrutinib Combination in Patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma

Background: Relapsed or refractory (R/R) Non-Hodgkin Lymphoma (NHL) is associated with poor outcomes and the therapic options are limited. Recently, the combination of rituximab, lenalidomide, and ibrutinib (RLI) suggest promising efficacy in some clinical studies. Consequently, we report outcome of patients with R/R HL treated with RLI in this retrospective study aiming at evaluating efficacy and safety of RLI in a real-life setting. Methods: This retrospective, single-center study analyzed the outcomes of RLI as an off label salvage theraphy in patients with R/R NHL between June 2020 and April 2022. All patients received Lenalidomide 10-25 mg po daily on days 1-21 every 28 days and Ibrutinib 560 mg po daily on days 1-28. Patients with diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), marginal zone lymphoma (MZL) received Rituximab at a dose of 375 mg/m2 iv on day 1 of cycles 1-6 every 28 days, patients with mantle cell lymphoma (MCL) received the same dose of Rituximab once a week for 4 weeks during cycle 1, then on day 1 of cycles 2-12 every 8 weeks. Ibrutinib and/or lenalidomide was administered until progression or unacceptable toxicity. The response was assessed with according to the Lugano criteria. The primary end point was overall response rate (ORR). Secondary endpoints were complete response (CR), partial response (PR), time to response (TTR), duration of response (DoR), overall survival (OS), progression free survival (PFS) and safety. Results: We analyzed 21 patients including DLBCL (n = 16), PCNSL (n = 2), MCL (n = 2), MZL (n = 1). The median age was 60 years (range, 24-84). The majority of patients had advanced disease stage (53%) and were refractory to their last therapy (57%). The non-GCB type was more common (67%) in patients with DLBCL and PCNSL. Nine patients (56%) with DLBCL had MYC and BCL2 and/or BCL6 rearrangements. Median number of prior therapies was 3 (range, 2-6). Eleven patients had prior auto and/or allo stem cell transplantation. Median follow-up time was 6.6 months (range, 0.4-22.3). Eleven patients (52%), 6 patients (29%) and 2 patients (10%) received RLI for ≥ 3, 6 and 12 months respectively. Patients had received a median of 3 (range, 1-19) cycles of RLI. Progressive disease (PD) was the most common reason for treatment discontinuation (53%). All of the patients were evaluable for response. The median TTR was 2 months (range, 1.7-3.8). The ORR was 38% (95% CI 15%-61%) with 29% CR and 9% PR. At the time of the analysis, the median DoR was 12.8 monts (range, 4.4-19.5+). Deaths were reported for 13 (62%) patients [n = 10 PD, n = 3 adverse events (AEs)]. The median OS was 7.9 months (95% CI 2.2-13.5) and median PFS was 3.5 months (95% CI 0.0- 8.3). The most common non-hematologic AEs were fatigue (48%), infection (38%), diarrhea (29%). AEs were frequently reported at the 25 mg lenalidomise dose, but the majority (77%) of patients experienced a grade 1-2 AE. The hematologic AEs were neutropenia (48%) [grade 3-4 (100%)], thrombocytopenia (19%) and anaemia (19%). AEs led to discontinuation in 5% (n = 1) of patients (sepsis). Conclusions: Our results suggest that RLI is a viable therapeutic option with promising activity and favorable toxicity profile in patients with R/R NHL patients.

Evaluating Effective Therapeutic Options for Inhibitor Eradication in Patients with Acquired Hemophilia a: A 10-Year Single Center Experience

Background Acquired hemophilia A (AHA) is a rare disorder characterized by emergence of neutralizing antibodies or inhibitors to factor VIII. The main treatment strategy for AHA involves control of bleeding with factor VIII bypassing agents and eradicating the autoantibodies using immunosuppressive therapy (IST) for restoration of normal hemostasis. Previous studies have demonstrated the effectiveness of both cyclophosphamide and rituximab in combination with steroids for treating AHA, however, clear guidelines for choosing between these agents for rapid inhibitor eradication are lacking. This retrospective study aimed to compare the effectiveness of cyclophosphamide and rituximab as first-line therapies for rapid antibody elimination and relapse prevention. Methods We queried our hospital electronic health record system using ICD 9/10 code to identify patients >18 years that had at least 2 inpatient or outpatient encounters for the diagnosis of AHA between 1 st July 2013 and 30 th June 2023. Variables collected included initial aPTT value, serial factor VIII activity & Bethesda inhibitor titer and immunosuppressive therapies used. Time to remission was defined when inhibitor titer was <1% along with improving factor VIII activity. At our institute, all patients received 1mg/kg of steroids initially, then either six cycles of 400mg/kg IV Cyclophosphamide every 28 days on day 1 along with 100mg of oral Prednisone days 1-5 or four cycles of IV Rituximab at a weekly dose of 375mg/m2 was used as 1 stline IST for patients with inhibitor titer >10%. Patients that did not achieve remission or those with persistently high inhibitor titers after 3 cycles of Cyclophosphamide were switched to 2 nd line therapy. In few patients oral Cyclophosphamide or Mycophenolate mofetil was used as maintenance therapy after 1 st or 2 nd line therapy. Bleeding control was achieved with use of rpFVIII or rFVII, FEIBA or emicizumab depending on product availability. Descriptive statistics (mean, SD) & openAI.ChatGPT-4 generated correlation coefficient was used for data analysis. Results A total of 11 male and 5 female patients were identified. The mean age at diagnosis was 69 years and the average length of follow up was 672 days. The mean aPTT value at diagnosis was 84.3 seconds. Inhibitor titer ranged from 1.5 to 329% with an average of 63.62%. Patients with low inhibitor titer of <10% received only steroids and all of them achieved remission without relapse. Rituximab as first-line therapy led to remission in 100% of cases, while only 28.5% of patients treated with cyclophosphamide achieved remission without needing second-line therapy. The time to remission was significantly shorter in patients treated with rituximab compared to cyclophosphamide (43.4vs148.7days). Additionally, none of the patients treated with rituximab experienced a relapse after 1 st remission, while 57% of patients treated with cyclophosphamide did and majority needed 2 nd line & maintenance therapy (Figure-1). Initial inhibitor titer had a moderate to strong positive correlation with the time to remission, the incidence of relapse, and the need for second line and maintenance therapy (Figure- 2). Conclusions Rituximab as first line IST appeared to be more effective than cyclophosphamide in achieving rapid remission and reducing incidence of relapse. Our analysis also revealed that initial inhibitor titer may serve as a useful predictor of disease course, potentially guiding therapeutic decision-making and eliminating need for cytotoxic medication or maintenance therapy. Future large prospective studies are needed to confirm these findings and further investigate other factors influencing therapeutic outcomes in patients with AHA.

36-Month Follow-up Results of the Gimema ‘Veritas’ Trial of Front-Line Venetoclax and Rituximab (VenR) in Young and Fit Patients with Chronic Lymphocytic Leukemia and an Adverse Biologic Profile

Introduction: Based on the efficacy of the fixed-duration venetoclax and rituximab combination (VenR) in the setting of relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL), we investigated the efficacy and safety of the front-line VenR regimen in young (≤65 years) and fit patients with CLL and an unfavorable biologic profile in the GIMEMA LLC1518 VERITAS trial. Here, we report the 36-month updated results of this phase II, single-arm, multicenter, front-line study for young patients with CLL carrying an unmutated IGHV profile and/or a TP53 disruption. Methods: Seventy-five CLL patients requiring treatment, according to the International Workshop on CLL (iwCLL) criteria, were enrolled between October 2018 and May 2020. Treatment consisted of the five-week Ven ramp-up, six-monthly courses of the VenR combination, followed by six monthly courses of Ven single agent. Patients received tumor lysis syndrome (TLS) prophylaxis with urate-reducing agents and oral or iv hydration. The primary endpoint of this study was the complete remission (CR) rate assessed at the end of treatment (EOT, month 15) according to the iwCLL criteria. Measurable/minimal residual disease (MRD) was assessed on the peripheral blood (PB) and bone marrow (BM) by ASO-PCR at baseline, EOT and during the follow-up. MRD was categorized as undetectable (uMRD) with a cut-off of <1 cell in 10,000 leukocytes. Results: The median age of patients was 54 years (range 38-65); 96% had unmutated IGHV, 9 (12%) had TP53 disruption, and 4% showed mutated IGHV with TP53 disruption. At the EOT, the overall response rate (ORR) was 94.7%, with a CR rate of 76%. On an intention-to-treat basis, 52 (69.3%) patients showed a response with uMRD in the PB and 44 (58.7%) in the BM. At 33 months from the EOT, uMRD was maintained by 50% of patients who had achieved an uMRD in the PB and by 57% of those with a prior uMRD in the BM. The 33-month PB MRD-free survival was 50% (Figure 1). In multivariate analysis, factors associated with a significantly shorter MRD-free survival were the presence of an unmutated IGHV associated with a TP53 disruption (HR: 3.43 [95%CI: 1.13-10.4]; p=0.029), Binet B stage (HR: 0.16 [95%CI: 0.06-0.43]; <0.001) or, Binet C stage (HR: 0.19 [95%CI: 0.07-0.52]; p=0.001), while the clinical response, CR, or PR, did not show a significant impact. Three patients have died due to COVID-19. Despite iv hydratation, the administration of anti-uric acids, fatal TLS occurred in a patient who used self-administered fentanyl patches for analgesis purposes during the ramp-up phase. The 36-month OS was 96%. A further lymphoproliferative disorder was diagnosed in 2 patients (follicular lymphoma, 1; large granular cell leukemia, 1) and a second malignancy in 1 (prostate cancer), while no cases of Richter transformation were recorded. No unexpected adverse events were observed during the follow-up. Conclusions: The updated data from the VERITAS trial show that in young and fit patients with adverse genetic characteristics the front-line VenR combination was an effective regimen with high rates of deep responses with uMRD. Furthermore, at 33 months from the EOT, uMRD was maintained in the PB and BM in about half of the patients.

Verlen, “Very Elderly Rituximab Associated to Lenalidomide - Tafasitamab Combination in Frontline DLBCL Patients”, a Phase II Open-Label Study Evaluating Efficacy of Lenalinomide and Tafasitamab Combination Associated to Rituximab in Frontline Diffuse Large B-Cell Lymphoma Patients of 80 y/o or Older from the Lysa Group

The reduced intensity CHOP (so-called miniCHOP) associated with CD20-directed antibody has become a standard of care for elderly patients above 80 years old, with newly diagnosed Diffuse Large B Cell Lymphomas (DLBCL)(Peyrade Lancet Hematol 2017 and Lancet Oncol 2011). While the results are consistent along with time and in several clinical trials, 40% of patients will die in the first 2 years of follow-up. Increased dose-intensity would be not achievable for most of this population, paving the way for innovative strategies. In the Relapse/Refractory setting of DLBCL, lenalidomide associated to anti-CD20 immunotherapy has demonstrated encouraging rates in both young (Houot et al. Leukemia 2019), and elderly populations (Zinzani et al. Clin Lymphoma Myeloma Leuk. 2011; Gini et al. ASH 2015) with manageable toxicities. Furthermore, the Tafasitamab combination with Lenalidomide has yeldied high and sustained response rates, with a favorable profile of tolerance (Salles et al. Lancet 2020). It is to note that frontline lenalidomide associated with Rituximab has recently been reported in a very frail population (FIL_ReRi trial, Gini et al Blood 2023), yelding an ORR of 51%. VERLen is an open-label, international and multi-centric phase II trial designed to assess the efficacy of tafasitamab, lenalidomide and rituximab combination in very elderly patients who have a newly diagnosed DLBCL. VERLen is an Investigator Initiated study, funded by Morphosys/Incyte. Patients must be ≥80y.o. and have a CD20+ DLBCL, with a stage I-IV PET-avid disease and a Performans status ≤2. Importantly, to achieve comparison with miniCHOP based regimens, patients should have a LVEF≥50% and no severe renal impairment (Cockroft clearance ≥30mL/min/m²). A prephase treatment with vincristine (1mg total dose) at D-7 and prednisone (60 mg/m2/d) from D-7 to D-4 is delivered prior study treatment. The treatment duration is fixed to 12 cycles (1 year). Patients receive monthly rituximab, up to 6 cycles, that can be delivered subcutaneously after 1st dose. Lendalidomide is delivered at a starting dose of 20mg/d (21d/28d per cycle) for 6 months, and tapered to 15mg/d from Cycle 7 to C12. Tafasitamab is delivered at D1,D8,D15,D22 of cycles 1-3, then D1,D15 of cycles 4-6, then monthly up to cycle 12, at a fixed dose of 12mg/kg. Principal objective is the efficacy (overall response rate) after 3 cycles, assessed by PET-CT. We expect an increase of 15% (60->75%) of the disease control rate for the patients treated with VERLen, with a power of 90%. Seventy-one patients will be enrolled to obtain 67 evaluable patients (5% drop-out estimate). Patients with progressive/stable disease after 3 cycles should start a conventional chemotherapy (R-miniCHOP) at investigator's discretion and will remain monitored for survival. A particular attention will be given to patients that would not receive R-miniCHOP despite trial recommendation. Enrolments started in January-22, 40 patients have enrolled and Last Patient-In is awaited for Q4-2023/Q1-2024. Secondary objectives include safety analyses, 2-y PFS/OS rates, Complete Metabolic rate at 3months ; and response/safety after R-miniCHOP for patients who switched after cycle 3. From a translational perspective, ctDNA, analysis of the microenvironnment and patients' genomics will be analysed. CONCLUSION VERLen trial is an innovative frontline trial for very elderly patients (≥80y.o) with newly diagnosed DLBCL, associating Tafasitamab; Lenalidomide and Rituximab, with a fixed duration of 12 cycles. Considering enrolling rates, we should provide the audience with results for ASH meeting 2024 (N+1).

Acrue: A Phase 2, Open-Label Study of Acalabrutinib in Combination with Rituximab in Elderly and/or Frail Patients with Treatment-Naive Diffuse Large B-Cell Lymphoma

Background and Significance: Patients aged ≥80 years with diffuse large B-cell lymphoma (DLBCL) account for approximately 18% of DLBCL cases in the United States (Morrison et al. Future Oncol. 2018). Standard-of-care chemoimmunotherapy (CIT) regimens such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), including reduced doses of CHOP (R-miniCHOP), are not well tolerated in elderly and/or frail patients, leading to high treatment-related mortality rates (Boslooper et al. Leuk Lymphoma. 2014; Freudenberger et al. Ann Hematol. 2021; Peyrade et al. Lancet Oncol. 2011). Therefore, safe, effective, and convenient treatment alternatives to CIT are needed. Acalabrutinib is a highly selective, second-generation Bruton tyrosine kinase inhibitor approved for the treatment of patients with relapsed/refractory mantle cell lymphoma and in patients with chronic lymphocytic leukemia. Acalabrutinib monotherapy has demonstrated encouraging activity in patients with DLBCL in phase 1b (NCT02112526) and phase 2 (NCT04002947) studies (Strati et al. Haematologica. 2021; Roschewski et al. Blood. 2021). However, neither of these studies were conducted specifically in a population of elderly and/or frail patients. Study Design and Methods: ACRUE (NCT05952024) is a phase 2, open-label, single-arm, global, multicenter study of acalabrutinib plus rituximab in elderly and/or frail patients with treatment-naive (TN) DLBCL who are unable to tolerate standard CIT ( Figure). Eligible patients are aged ≥80 years or aged 65-79 years with impairment in ≥1 activity of daily living (ADL) or instrumental ADL (IADL), or with cardiac/renal/liver function impairment or other comorbidities that render them unable to tolerate CIT. Furthermore, patients must have histologically confirmed CD20-positiveDLBCL (not otherwise specified), according to WHO 2016 classification, an Ann Arbor classification of stage II, III, or IV disease, an Eastern Cooperative Oncology Group performance status of 0-2, and ≥1 measurable lesion. Patients with active central nervous system involvement by lymphoma, leptomeningeal disease, or spinal cord compression, or significant cardiovascular disease within 6 months of screening are excluded. Target enrollment is 80 patients. Patients will receive acalabrutinib plus rituximab combination for 8 cycles (acalabrutinib 100 mg orally twice daily beginning on day 1 of cycles 1-8; rituximab 375 mg/m 2 intravenously on C1D15, then 1400 mg subcutaneously, on day 1 of cycles 2-8; cycles 1-8 are 21 days/cycle), followed by acalabrutinib monotherapy until disease progression, unacceptable toxicity, or 24 months (cycles 9-28 are 28 days/cycle). The primary endpoint is the percentage of patients with grade 3-4 treatment-emergent adverse events. The key secondary endpoint is investigator-assessed objective response rate per Lugano 2014 criteria. Other secondary endpoints include progression-free survival, event-free survival, overall survival, duration of response, and Timed Up and Go test. Exploratory biomarker analyses may include genomic characterization of baseline samples to evaluate predictors of survival, and of progression samples to evaluate genomic resistance mechanisms. Descriptive safety and efficacy data will be summarized. If patients discontinue treatment prior to completing 28 cycles of therapy, they will be followed every 12 weeks after their last treatment dose for up to 2 years. Patients who are still on treatment at the end of the study and are deriving clinical benefit may receive continued treatment, with assessments reverting to standard of care. Enrollment is planned to begin Q4 of 2023 in approximately 40 sites from North and South America and Asia. Summary: This study will help determine if acalabrutinib plus rituximab combination therapy is tolerable and effective in elderly and/or frail patients with TN DLBCL who are unable to tolerate CIT.

Predictors of Response to Rituximab in Chronic Immune Thrombocytopenia: Do Race, Gender and ABO Blood Type Matter?

Introduction: Immune thrombocytopenia (ITP)is characterized by immune mediated destruction of platelets causing isolated thrombocytopenia with a peripheral blood platelet count <100,000/microL in the absence of other causes that may be associated with thrombocytopenia. It remains a diagnosis of exclusion. Corticosteroids are the first-line treatment for ITP and more than 75% of adults with ITP will respond to them. However, approximately 70-80% of adult patients with ITP will experience treatment failure with corticosteroids or become dependent on them and require second-line therapy. Various options in the second line setting include thrombopoietin receptor agonists, rituximab, and splenectomy. In one study rituximab was noted to result in an overall platelet count response in 62.5% of adults. However not all patients remain in remission and clinical factors that are predictive of response are lacking. Racial disparities are known to predict response to rituximab in other hematologic disorders such as immune mediated thrombotic thrombocytopenic purpura (Mezapa et al, 2022). Herein, we are examining the effect of race, gender and ABO blood type on response to rituximab in patients diagnosed with ITP. Methods: This retrospective cohort study included adult patients, aged 18 and above, with a diagnosis of ITP who had received single agent rituximab within a multihospital academic healthcare system between January 2015 and December 2022. Initially 196 patients were identified but only 127 of those were included in the study. We excluded patients with missing response data, and those with combined rituximab and other therapies (stable or decreasing doses of steroids were allowed). Our primary end point was any response to rituximab by day 180 after starting rituximab. Any response was defined as complete response or partial response. Complete response was defined as platelet count ≥ 100,000 /microL and absence of bleeding. Partial response was defined as platelet count of at least 30,000/microL after week 4 from rituximab administration or doubling of platelet count from baseline without administration of any platelet increasing therapy. Our secondary end point was relapse rate which was defined as platelet count below 100,000/microL if complete response had been attained or below 30,000/microL or less than 2 fold increase of baseline platelet count. We also investigated clinical and socioeconomic predictors of response. Exploratory analysis was performed. Summary statistics are presented as percentages for categorical data and median with interquartile range for quantitative data. Chi square test was used to compare percentages and t-test was used to compare means. Univariate and multivariate regression models were used to analyze the predictors of any response to rituximab. Kaplan-Meier method was used to calculate estimates of relapse-free survival, and log-rank test was used to compare these estimates. Result: We identified 127 patients diagnosed with ITP who received rituximab. The median age was 64 years (IQR 48-74), there were 46.5% females. The majority of the patients were Caucasians (95.3%), and rituximab was most commonly received as a second line therapy (73.2%). Median initial platelet count was 28,000/microL. Complete response was observed in 50% of African American patients compared with 43.0% in Caucasian patients (p-value 0.63). No predictors for any response on univariate or multivariate analyses were found. Race (OR 0.30, 95CI 0.03-3.25, p-value 0.32) and female gender (OR 0.76, 95CI 0.33-1.76, p-value 0.51) did not affect response to rituximab in our patient cohort. Relapse rate was 60% in African American patients versus 67.5% in Caucasians (p-value 0.72), and 68.7% in males versus 64.9% in females (p-value 0.71). ABO blood type also did not predict a response to Rituximab in our patient population (Table 1) Conclusion: In our study, race and gender did not affect response or relapse rates after rituximab treatment in chronic ITP. Patient's ABO blood type also did not predict a difference in response to Rituximab. However, our study was limited by a small sample size and further multi-institutional analysis is warranted to confirm the findings of our study.

Six Years Follow up of Ibrutinib Plus Rituximab (IR) Followed By Short Course R-Hyper CVAD/MTX in Patients (age ≤ 65 years) with Previously Untreated Mantle Cell Lymphoma - Phase-II Window-1 Clinical Trial

Background - We reported the efficacy and safety of using a combination of ibrutinib plus rituximab (IR) induction followed by short course (4 cycles) of R-HCVAD/MTX-ara-C as consolidation in previously untreated young (age ≤ 65 years)patients (pts) with mantle cell lymphoma (MCL), Wang M et al Lancet Oncology 2022. Here we report the long term follow up of this study. Methods - We enrolled 131 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT02427620. Pts received IR induction (part-A), until they achieved complete remission (CR) for up to a maximum of 12 cycles, followed by a maximum of 4 cycles of R-HCVAD/R-MTX-ara-C (part-B) as consolidation. The primary objective was to assess overall response rate (ORR), [defined as either a partial response (PR) or a complete response (CR)] after part A. Adverse events were coded as per CTCAE version 4. High risk pts received ibrutinib for 1 year and rituximab once every 2 months for 24 months after completion of part B. Results - Among the 131 pts, the median age was 56 yrs (range - 35-65). High Ki-67 (≥30%) in 58/117 (49.5%) pts, 10 pts (8%) had high risk simplified MIPI score, 15 pts (11%) had aggressive MCL (blastoid/pleomorphic) and 114 pts (87%) had initial bone marrow involvement. Fifty percent of the patients had Ki-67 (≥30%). ORR in part-A was 98% (87% CR). After completion of part A and part B, ORR was 90% (89% CR). After a median follow up of 71 months, 43 patients progressed/died. The median progression free survival (PFS) and overall survival (OS) were not reached. Overall, 30 pts (23%) relapsed after treatment, including 5 who transformed to aggressive MCL. PFS among pts with high and low Ki-67% was 42 months vs not reached (P=0.01) while no difference was observed in OS. PFS was significantly shorter in pts with aggressive histology (p=0.001) but not the OS. PFS was similar in pts who received maintenance vs no maintenance therapy. Overall, 8 pts died (4 with progression, 2 due to disease transformation, one on study due to multiple complications including splenic hematoma, cardio-pulmonary arrest and progression and the last one expired outside and came off study due to encephalitis). 50 pts came off study for various reasons [30 disease progression (including 5 transformation), 10 pt choice, 8 intolerance, 1 second cancer and 1 lost to follow up]. Long term, grade 3-4 toxicities on part A were 6% myelosuppression and 10% each with fatigue, myalgia and rashes and 2% mucositis. Maintenance therapy did not show high toxicities. Conclusions -Long term follow up of chemo-free induction with IR induced durable and deep responses in young MCL pts in the frontline setting. Short course R-HCVAD chemotherapy minimized toxicities and consolidated responses. IR maintenance improved survival outcomes. This combined modality treatment approach may significantly improve young MCL pts outcomes across all risk groups.

Australasian Leukaemia & Lymphoma Group NHL35-Pacific: An Open Label Phase II Study of Pembrolizumab and Chemo-Immunotherapy As First-Line Therapy for Primary Mediastinal B-Cell Lymphoma - Trial in Progress

Background: Primary Mediastinal B-cell Lymphoma (PMBL) comprises 10% of Diffuse large B-cell lymphoma (DLBCL), primarily affecting young adults. Combination chemoimmunotherapy with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) is effective, however up to 10-20% of patients may have either refractory disease or experience relapse within 12 months of completing treatment. Consolidative radiotherapy has often been used following R-CHOP, with retrospective data suggesting a survival benefit compared with R-CHOP alone. However, mediastinal radiotherapy increases risk of breast cancer and cardiovascular disease and the recently reported randomised IELSG37 study demonstrated no improvement in progression free survival (PFS) with the use of consolidative radiotherapy following chemoimmunotherapy. Dose-adjusted Etoposide, Prednisolone, Vincristine, Cyclophosphamide, Doxorubicin and Rituximab (DA-EPOCH-R) without radiotherapy has demonstrated excellent activity in a small phase II study but with increased chemotherapy toxicity. In IELSG37, PFS was inferior for patients treated with R-CHOP-21 compared with other chemoimmunotherapy regimens, supporting intensification of therapy beyond R-CHOP-21 in this entity. The outcome for patients with relapsed/refractory PMBL is poor, with response rates of around 25% to second line therapy, and a 2-year overall survival of 15%. Therefore, there remains a need to improve initial therapy for patients with PMBL. Programmed-Death-1 (PD-1) ligands PD-L1/PD-L2 are commonly upregulated in PMBL. The PD-1 inhibitor Pembrolizumab blocks the interaction of PD-1 and PD-L1/2, and subsequent signalling, and has encouraging activity in relapsed/refractory PMBL, with an overall response rate of 43% (complete response 23%) and modest toxicity in a phase II study. ‘Window’ induction treatment involving delivery of checkpoint inhibitor therapy to patients with lymphoma, prior to initiation of chemotherapy has been investigated in phase II studies, showing encouraging efficacy and no safety concerns with this ‘chemotherapy-free’ initial treatment approach. The combination of Pembrolizumab and Rituximab is predicted to be synergistic, and in non-randomised trials in other B-cell lymphoma histologies, has demonstrated superior response rates to those expected with Rituximab monotherapy, suggesting synergism of the combination. There is therefore compelling rationale for combining R-CHOP and Pembrolizumab as first-line therapy for PMBL. This study investigates the efficacy and safety of this novel, time-limited, radiotherapy sparing regimen. Methods ALLG-PACIFIC (ANZCTR- ACTRN12621001529831) is a phase II, single arm, open-label study of R-CHOP in combination with Pembrolizumab. The trial is open to recruitment across Australia. Approximately 35 patients with newly diagnosed PMBL, will be enrolled to receive two cycles of Rituximab (375mg/m 2) plus Pembrolizumab (200mg) once every 21 days ('window phase') followed by six cycles of R-CHOP plus Pembrolizumab once every 21 days ('induction phase') followed by five cycles of Pembrolizumab 400mg once every 42 days ('consolidation phase') (Figure 1). Adults (≥18 years) with treatment naïve histologically confirmed PMBL and adequate organ function are eligible. Key exclusion criteria are the presence of active autoimmune disease, requiring recent immunosuppressive therapy, life-threatening or organ-compromising lymphoma symptoms requiring urgent cytoreductive therapy, and other medically significant conditions that preclude eligibility to receive R-CHOP. Patients who require urgent cytoreductive therapy following initiation of window phase treatment may proceed immediately to induction phase chemotherapy. The primary endpoint is 18-month event free survival. Key secondary endpoints include response to window phase treatment, overall survival, requirement for radiotherapy and safety of treatment including rates of early discontinuation due to treatment toxicity. Several biomarkers are also being investigated for their predictive value for treatment response including minimal residual disease status (measured by Adaptive Immunoseq and CAPP-Seq), PET-CT parameters (e.g., Metabolic tumour volume), and PD-1/PD-L1 expression and 9q24 alterations.

The Final Results of a Phase I Study Using Bortezomib (Velcade), Cladribine, and Rituximab (VCR) in Treating Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is a moderately aggressive and incurable small to medium sized B cell lymphoma. No standardized treatment exists for this disease. Cladribine is a hypomethylating agent that indirectly down-regulate DNA methylation to suppress tumorigenesis. Combination of Cladribine and Rituximab showed a synergetic effect in treating B cell lymphomas. Bortezomib (Velcade) is an FDA approved proteasome inhibitor to treat relapsed/refractory MCL. In this study, we evaluated the safety and efficacy of Valcade, Cladribine, and Rituximab (VCR) combination treatment in newly diagnosed and relapsed/refractory MCL. Patients and Methods: This is a single arm open label phase I trial. This study employed a standard 3+3 dose escalation scheme designed to determine the maximum tolerated dose (MTD) of Cladribine in VCR regimen. Briefly, the treatment scheme was consisted of 6 28-day cycles. At first cycle of the treatment, Rituximab 375 mg/m 2 infusion started on day 5 of the first week and then given weekly for 3 weeks; in the next 5 cycles Rituximab was given on day 5 of each cycle, and then every 2 months as the maintenance therapy. Cladribine 3 to 5 mg/m 2 (3 mg/m 2 for level 1, 4 mg/m 2 for level 2, and 5 mg/m 2 for level 3) infusion was given on days 1 to 5 for 6 cycles. For patient older than 70 years old, Cladribine was only given on days 1 to 3 of each cycle. Velcade 1.6 mg/m 2 subcutaneous injection was given on days 12, 19 and 26 for cycles 1 to 3, Days 5 and 19 for Cycles 4 to 6, then once per month as maintenance therapy. The primary endpoint of this study was the dose limiting toxicity (DLT), safety, and efficacy of this regimen in patients with MCL. The secondary endpoints included remission rate (RR), progression free survival (PFS) and overall survival (OS) (Figure 1). The analysis was done by intent to treat. Differentially methylated region (DMR) analysis and cytokine assay were performed to explore biomarkers differentiating good-responders from poor-responders. Results: This study recruited 13 patients, with a median age of 64 years old (range from 55 to 83) and including 11 males and 2 females. Ten patients were never previously treated, other 3 either relapsed or failed from previous treatments. Most patients tolerated this regimen well. No patient experienced DLT at either level 1 or 2, one possible DLT (infectious colitis) was observed during 2nd cycle at level 3. Two relapsed patients experienced disease progression after received two cycles of treatment and died in 5 and 7 months. Another patient died in 15 months after receiving treatment. The overall remission (OR) rate was 85% (11/13) and complete remission (CR) rate was 77% (10/13). In newly diagnosed patient cohort, CR rate was 100% (10/10), OS rates were 90% (9/10), and PFS was 80% (8/10), of which 3 patients have been followed for more than 4 years, 3 other patients for more than 3 years, and 3 others for over 2 years (Fig.1). In relapsed/refractory patient cohort, 1 achieved CR for 7 months but then relapsed, 2 had no response. There were 2 blastoid patients, 1 of these 2 patients was newly diagnosed and achieved CR. Bone marrow suppression caused prolonged anemia and thrombocytopenia were the most common toxicity (3/13 with ≤grade 2). Low grade peripheral neuropathies (≤grade 2) were observed in 15% (2/13). Mild fatigue was a frequent complaint. Cytokine assay showed decreased CXCL12 level in the good responders. Though global methylation pattern showed no difference, DMRs were identified in the good responders and the poor responders. DMRs-related genes involved in CXCL2 pathways were further extracted and enriched biological process analysis revealed the pathway profile difference between good responders and poor responders. Good responders exhibited alternation of apoptotic and Wnt signaling pathways (Fig.2). Conclusions: The VCR combination is a well-tolerated, low toxicity and effective regimen for MCL, especially for untreated MCL. Cladribine 5 mg/m 2 is a tolerable dose with manageable toxicity. Individual patient methylation profile may affect response to VCR therapy.

Copanlisib in Combination with Rituximab and Bendamustine for Transplant-Ineligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients: Results from the Phase II Multicenter Fil_Copa-Rb Trial from Fondazione Italiana Linfomi (FIL)

Background: 60% of Diffuse large B-cell lymphoma (DLBCL) are cured with R-CHOP. Treatment options for relapsed/refractory (R/R) patients (pts) not eligible to high-dose chemotherapy and autologous stem cell transpntation (ASCT) or CAR-T are limited with short-lasting efficacy. The PI3-K inhibitor copanlisib showed activity in B-cell lymphomas including DLBCL. We reported the results of the phase II single arm multicenter FIL Copa-RB trial which investigated the combination copanlisib plus rituximab and bendamustine (copa-RB) in transplant-ineligible R/R DLBCL. Methods: Patients with R/R DLBCL previously treated with 1-3 prior lines, not eligible to ASCT and CAR-T were enrolled to receive 6 cycles of copa-RB q28 days (induction treatment schedule: copanlisib 60 mg i.v. days 1,8,15. Rituximab 375 mg/m2 i.v. day 1, Bendamustine 90 mg/m2 i.v. days 1,2). Patients with at least stable disease continued with a maintenance phase up to 12 q28 day cycles of Copanlisib (60 mg i.v. days 1,15). The primary end point was 12-month progression free survival (PFS) with an expected improvement from 20% to 35% and a calculated sample size of 81 pts. Results: From 11/2019 to 7/2022, 37 pts were enrolled. Median age was 76 years (68-87), 23 (62%) were at IPI ≥3, 25 (68%) had stage IV, 23 (62%) and 14 (38%) received 1 and 2 prior lines and 35% were refractory to the last treatment. The best overall response rate (ORR) was 51%, with 22% CR. With a median follow-up of 12 months, the 12-mo PFS was 25.2% (95%CI:13.6-38.5%) and median PFS 5.5 months (95%CI:3.7-10.0). The 12-mo overall survival (OS) was 49.4% (95%CI:30.7-65.7%) (fig. 1). Nine patients were alive and in continuous response at time of the data cut-off. 91% of the patients experienced grade > 2 adverse events (AE): neutropenia (58%), infections (28%), gastrointestinal (19%), skin (16%) and thrombocytopenia (13%). SARS-COV-2 infection occurred in 19% with 5 deaths. CMV reactivation occurred in 47%, but without infection. Febrile neutropenia was recorded in 2.8%. AEs led to dose interruptions in 19%. Since the slow recruitment, the unfavorable safety profile and the emerging of potentially more effective new treatment options in this setting of patient, the study was interrupted prematurely by steering committee decision. Conclusions: Copa-RB study was conducted in a difficult-to treat R/R DLBCL cohort (elderly, advanced stage) during COVID pandemic that affected its management. Copa-RB induced a good ORR, but it was short lasting with unfavorable safety profile, so the overall activity was modest and did not support further the development of this combination in this setting of patients. A subset of patients had a long-lasting response. A mutational study is ongoing to identify molecular pathways potentially predictive of response to the combination

Novel Chemotherapy-Free Initial Treatment of Rituximab Biosimilar Plus Pegylated Interferon α-2b in Pts with Untreated Advanced Indolent B-Cell Non-Hodgkin's Lymphoma: Results of the Ripple 3-Year Follow-up Study

Background: Indolent B-cell lymphoma (iBCL) are clinically heterogeneous and accounts for 10-15% of all kinds of subtypes in NHL in China. Although iBCL have a relatively good survival, majority of these lymphomas is considered incurable. The favorable activity and safety profile of rituximab monotherapy in the initial treatment of iBCL has been proven. Interferon alpha (IFN-α) was effective in modulating immune responses and may enhance the clinical efficacy of rituximab in vitro and in vivo studies. Clinical combination of rituximab and conventional IFN-α was associated with fewer early treatment failures compared to single agent rituximab. Peginterferon-α-2(peg-IFN-α2) has a longer half-life with less toxicity. It is also recommended as one of the therapeutic options for chronic hepatitis B virus (CHB) infection. The RIPPLE study (ClinicalTrials. gov identifier: NCT04246359) was initiated to evaluate the efficacy and safety of rituximab plus pegylated interferon α-2b for treatment-naive patients with iBCL. This publication provides long-term follow-up data. Methods: This trial enrolled pts aged 18-80 years with newly diagnosed iBCL including follicular lymphoma (FL, grade 1-2,3a), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), small lymphocytic lymphoma (SLL). Pts were eligible if they had ECOG ≤ 2, adequate organ function and bone marrow function, and at least one measurable or evaluable lesion. Further eligibility criteria were HBsAg positivity with HBV DNA load <3000 IU/mL prior to study; serum ALT level of <5 times the upper limit of normal. During induction phase, pts received rituximab biosimilar (Henliritux ® Shanghai Henlius Biotech) 375 mg/m 2 intravenous infusion on d1. Peg-IFN-α2b (Pegberon ®, Xiamen Amoytop Biotech) was given at a dose of 135ug, subcutaneously, on d1,8. The combination repeated every 21 days for 6 cycles. Responded pts receive rituximab (every 2 months) plus peg-IFN-α2b (every month) maintenance at the dose described above, for up to 2 years until disease progression and intolerance. Simultaneously, CHB pts orally treated with entecavir continuously. The primary endpoint is ORR assessed by investigators per Lugano 2014 criteria. Key secondary endpoints included TTR, DOR, PFS, OS, HBV DNA load clearance, and safety. Adverse events (AEs) were summarized according to NCI CTCAE v5.0. Results: From September 2018 to July 2021, 57 eligible pts with median age of 54 (range, 29-75) years were enrolled from 6 institutions in China. Thirty (56.1%) are female, 21(36.8%) pts were symptomatic and 22(38.6%) pts with FLIPI score≥3, 6(10.5%) pts suffer from hepatitis B with HBV DNA load <3000 IU/mL at study entry. At cutoff date, there were 26(45.6%) FL (grade 1-2), 21(36.8%) MALT, 7(12.3%) FL (grade 3a) , 2(3.5%) SLL, 1(1.8) LPL pts enrolled. Of 57 response evaluable pts, 38(66.7%) pts achieved an objective response including 29(50.9%) pts with CR based on investigators. ORR were 69.2% (18/26), 71.4% (5/7), 61.9% (13/21), 0, 100% (2/2) and the CR rates were 46.2% (12/26), 71.4% (5/7), 52.4% (11/21), 0, 50% (1/2) for FL (grade 1-2), FL (grade3a), MALT, LPL, SLL, respectively (Figure 1-2). Median HBV DNA load clearance time was 1.8 months (1.3-2.1months), no hepatitis B virus reactivation reported. With median follow-up time was 34.2 months (IQR:26.5-42.3 months), median OS, PFS and DoR was not reached; 3-years OS and PFS rate of whole cohort was 92.5%, 70.4%, respectively (Figure 3 C-D). Median TTR was 3.0months (1.5-5.2months). The most common treatment-emergent adverse events (TEAEs) were hematological relevance toxicities. The most common hematological TEAEs (>30%) were neutropenia 63.2% (36/57), anemia 36.5% (19/57), thrombocytopenia 29.8% (17/57). Non-hematological TEAEs (>10%) were fever (28.1%, 16/57), transaminase elevated (26.3%, 15/57), fatigue (26.3%, 15/57), infusion reaction (21.7%, 10/46). No treatment-related death occurred. Conclusion: Rituximab biosimilar plus pegylated interferon α-2b provided favorable response in newly diagnosed advanced iBCL with mild toxicity. No hepatitis B virus reactivation was observed.

Multicenter, Prospective Study to Investigate the Efficacy and Safety of Intravenous-Immunoglobulin Therapy in Elderly Patients with Diffuse Large B Cell Lymphoma Treated with R-Mini-CHOP

Background The median age at initial diagnosis of DLBCL is estimated to be between the ages of 60 and 70. The number of elderly patients with DLBCL is gradually increasing. But, treatment outcomes of elderly patients were not significantly improved compared to younger patients. Infection is an independent predictor of treatment outcome in patients with DLBCL, and the risk of infection increases with age. The incidence of hypogammaglobulinemia in patients with malignant lymphoma increased from 15% to 39% after rituximab therapy. There was a significant decrease in the occurrence of major infections after intravenous immunoglobulins (IVIG) prophylaxis in hypogammaglobulinemia patients with lymphoproliferative. disorders. In this multicenter prospective study, infection prevention effect and treatment outcomes were identified using IVIG in elderly DLBCL patients with hypogammaglobulinemia who received rituximab combination chemotherapy. Methods In the current study, newly diagnosed DLBCL patients aged 70 years or older who were planning to receive R-mini-CHOP therapy were included. Patients with hypogammaglobulinemia at diagnosis were assigned to the IVIG group. Patients received R-mini-CHOP (rituximab: 375mg/m 2 D1; cyclophosphamide: 400mg/m 2 D1; doxorubicin: 25mg/m 2 D1; vincristine: 1.0mg D1, and prednisolone 40mg/m 2 from D1 to D5), and pegylated G-CSF. After the first cycle of R-mini-CHOP, 400mg/kg of IVIG was administered on D3 and D11. After the second cycle to sixth cycle of chemotherapy, patients received 400mg/kg of IVIG on D11. The primary objective was to evaluate the efficacy of IVIG in reducing severe infections. Grade 3 or 4 infections were defined as severe infections. Results A total of 118 elderly patients were newly diagnosed with DLBCL and were scheduled to receive R-mini-CHOP therapy. Hypogammaglobulinemia was identified in 85 (72.0%) patients. Decreased immunoglobulin D (n=42) and immunoglobulin M (n=39) level were most common, and 18 patients had two or more types of hypogammaglobulinemia at the same time. Fifty-six patients were assigned to the group receiving IVIG. Median age was 77 years (range, 70-90), and 31 (55.4%) were male. In patients who completed R-mini-CHOP and IVIG treatment, complete remission rate was 79.4%. Severe infections of grade 3 or 4 occurred in 3 of 56 (5.4%) patients, and only five (8.9%) patients had COVID-19 infection during the study period. Adverse effects associated with IVIG include fever/chilling, nausea/vomiting which were generally manageable. Only one patient discontinued the study because of chest pain that occurred during IVIG administration. In patients with hypogammaglobulinemia who did not receive IVIG, severe infections occurred in 8 of 29 (27.6%) patients, and COVID-19 infection was developed in 7 of 29 (24.1%). In patients without hypogammaglobulinemia, severe infection occurred in 5 of 33 (15.2%), and COVID-19 infection was developed in 8 of 33 (24.2%) patients. Patients receiving IVIG had a significantly reduced incidence of severe infection compared to patients not receiving IVIG (p=0.028). Furthermore, COVID-19 infection rate during R-mini-CHOP therapy was lower in IVIG receiving patients (p=0.050). Long-term outcomes with relapse rate and survival will be followed up and updated. Conclusion In elderly patients with DLBCL, the combination of R-mini-CHOP and IVIG was safe and effective in preventing infection. In the COVID-19 era, the combination of chemotherapy and IVIG should be considered in elderly DLBCL patients to reduce infection rate and improve treatment outcomes.

Efficacy and Safety of Golcadomide, a Novel Cereblon E3 Ligase Modulator (CELMoD) Agent, Combined with Rituximab in a Phase 1/2 Open-Label Study of Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Introduction: Golcadomide is a novel, oral, small-molecule CELMoD ® agent that co-opts cereblon to induce targeted degradation of the transcription factors Ikaros/Aiolos, which are crucial to B-cell malignancy development. We previously reported promising efficacy with a predictable and manageable safety profile of golcadomide in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (Michot et al. ICML 2023, presentation #90). Methods: CC-99282-NHL-001 (NCT03930953) is a 2-part, multicenter, first-in-human study with dose escalation (Part A) of golcadomide monotherapy and expansion (Part B) ± combination partners. Patients with R/R diffuse large B-cell lymphoma (DLBCL) or R/R follicular lymphoma and disease progression after ≥ 2 lines of therapy or transplant-ineligible patients with R/R DLBCL after ≥ 1 line of therapy were included. Following dose exploration in Part A, golcadomide was administered at 0.2 or 0.4 mg alone or with rituximab on 2 intermittent schedules in Part B. Total duration of treatment is up to 2 years. Here, we report efficacy and safety results for golcadomide + rituximab in patients with DLBCL treated in Part B expansion on a 14 days on/14 days off schedule. The efficacy-evaluable population consisted of patients completing ≥ 1 cycle of golcadomide (taking ≥ 75% of assigned doses) and having baseline and ≥ 1 post-baseline tumor assessment. Results: As of May 10, 2023, 35 patients with DLBCL were enrolled and 34 received ≥ 1 dose of golcadomide or rituximab (safety population); 17 (49%) patients were ongoing and 17 (49%) had discontinued treatment, mostly due to progressive disease (n = 10, 29%). The median age was 60 years (range, 35-80). The median number of prior anticancer therapies was 4.5 (range, 1-11); 68% (n/N = 23/34) of patients had prior CAR T-cell therapy and 49% (n/N = 17/35) were refractory to their last regimen. Golcadomide median treatment duration was 8 weeks (range, 4-48) and median follow up was 15 weeks (range, 2-55). In the efficacy-evaluable population (n = 16), overall response rate (complete response [CR] + partial response) was 50% (n = 8), with CR occurring in 13% (n = 2) of patients. Median duration of response was 17.4 weeks (range, 7.4-45.9). Response data in the 0.2-mg and 0.4-mg golcadomide-treated groups are shown in the table. In the safety population (n = 34), neutropenia was the most common any-grade treatment-emergent adverse event (TEAE), occurring in 15 (44%) patients, all of which were grade 3/4. No febrile neutropenia occurred. The most common treatment-related adverse event (TRAE) for golcadomide was neutropenia (all grade 3/4), occurring in 14 (41%) patients, comprising 5/19 (26%) patients treated at the 0.2-mg and 9/15 (60%) patients treated at the 0.4-mg dose level. Granulocyte colony-stimulating factors were used in 14 (41%) patients. Six serious TRAEs related to golcadomide were reported (n = 1 each), all in the 0.4-mg group. One grade 5 TEAE occurred (tubulo-interstitial nephritis in the 0.2-mg group), which was reported to be due to progressive disease and considered unrelated to study treatment. TEAEs led to golcadomide discontinuation in 2 (6%) patients (1 at each dose level) and rituximab discontinuation in 5 (15%) patients. Similar pharmacokinetic (PK) exposures of golcadomide were observed when golcadomide was dosed alone and in combination with rituximab, indicating no apparent impact of rituximab on golcadomide PK. Analysis of circulating tumor DNA data is underway and will be presented. Conclusions: Golcadomide oral therapy combined with rituximab showed promising efficacy in heavily pretreated patients with R/R DLBCL, including 1 durable response over 300 days. Golcadomide can be safely combined with rituximab, and the combination showed a safety profile similar to that previously reported for golcadomide monotherapy. This study is ongoing, with continued enrolment in the monotherapy and golcadomide + rituximab combination expansion cohorts.

IgG4-related uveitis. A French cohort and literature review

IntroductionIgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder that can affect almost any organ. IgG4-related ophthalmic disease is a protean condition involving the orbit and ocular adnexa. Although a few cases of uveitis have been reported, the exact pattern of IgG4-related intraocular manifestations remains unclear. Here, we report on a nationwide French multicenter cohort of patients with IgG4-RD and uveitis and conducted a literature review. MethodsPatients with uveitis and a concomitant definite diagnosis of IgG4-RD (Revised Comprehensive Diagnostic criteria, American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD, International Consensus Diagnostic Criteria for auto-immune pancreatitis, or diagnostic criteria for IgG4-related hypophysitis), were screened from our national IgG4-RD and systemic fibrosis database. Concomitantly, we conducted a PubMed literature review and selected cases of definite IgG4-RD with uveitis. ResultsWe reported on 16 patients (8 from our database and 8 from the literature) and a total of 30 episodes of uveitis. Uveitis cases represented 3 % of total IgG4-RD patients in the national database on IgG4-RD and systemic fibrosis. Uveitis was inaugural in IgG4-RD in 4/16 cases (25 %) (appearing before any other IgG4-related symptom, at a median of 9 months), occurred concurrently to other IgG4-related symptoms in 9/16 cases (56 %) (at a median of 15 months before IgG4-RD diagnosis), and appeared during follow up in 3/16 patients (19 %) (at a median of 57 months after first IgG4-related symptoms). When uveitis occurred during follow up, it was associated with IgG4-RD manifestations in other organs in 6/9 patients (67 %). Uveitis was bilateral in 8/16 cases (50 %) and granulomatous in 5/10 cases (50 %). It was anterior in 8/13 (62 %), intermediate in 3/13 (23 %), and global (panuveitis) in 4/13 patients (31 %). Median serum IgG4 at diagnosis was 3.2 g/L. Median follow up time was of 6 years, during which 8/16 patients (50 %) experienced at least one relapse of uveitis. Treatment data was available for 29/30 uveitis flares. Steroids were used in 28/29 episodes of uveitis (97 %), leading to remission of uveitis in 16/28 cases (57 %). Methotrexate and rituximab (in combination with systemic steroids) were administered as second- or third-line therapy in 6/29 (21 %) and 5/29 (17 %) episodes of uveitis, respectively, and led to remission of uveitis in 4/6 cases (67 %) and 4/5 cases (80 %), respectively. One third of uveitides required at least two different lines of treatment for remission induction (mainly a combination of both systemic steroids and methotrexate or rituximab). Discussion and conclusionsUveitis may be one of the initial symptoms of IgG4-RD, and IgG4-RD should be considered in the diagnostic workup of uveitis. Its early onset in IgG4-RD may help with early diagnosis and treatment of the disease. Steroid monotherapy may be sufficient to treat IgG4-related uveitis, yet relapses were frequent (50 %) and ultimately a third of patients required at least two lines of treatment. Hence, steroid-sparing agents can be considered at early stages of the disease, particularly for patients with a high risk of relapse or steroid-related complications.

INNV-40. DURABLE 10-YEAR RESPONSE TO VEMURAFENIB IN A PATIENT WITH CNS HAIRY CELL LEUKEMIA

Abstract Hairy cell leukemia (HCL) is an uncommon form of chronic B-cell lymphoproliferative disease, accounting for approximately 2% of all cases of leukemias. Although there have been rare instances of HCL affecting the central nervous system (CNS), these cases usually involve highly fatal leptomeningeal disease or direct leukemic infiltration into the brain. The BRAF V600E mutation, leading to the constitutive activation of the MAPK/ERK signaling pathway, is recognized as a key activating mutation in HCL and is present in almost all HCL patients. First-line treatment for HCL remains purine analogs; however, up to 20% of patients only achieve a partial response. Vemurafenib, an oral inhibitor of BRAF V600E, has demonstrated strong anti-tumor activity in patients with systemic relapsed/refractory HCL and has good CNS penetration. In this case study, we present a 67-year-old patient with HCL who initially presented with multifocal cranial neuropathies In August of 2013. His brain MRIs demonstrated multiple enhancing leptomeningeal foci. While a combination of cytarabine, methotrexate, and rituximab initially prevented disease progression, he experienced multiple relapses over the course of 2 years and eventually became refractory to treatment. Subsequently, the patient was started on vemurafenib, which resulted in the complete resolution of all lesions observed on MRIs. This response has persisted for 10 years since starting the medication. We suggest that besides its high response rate in systemic relapsed/refractory HCL, vemurafenib may offer benefits for patients with CNS involvement who are refractory to conventional chemotherapies and can achieve a durable response. Further investigation is needed to potentially establish vemurafenib as a first-line treatment option for HCL patients with CNS involvement.

CTIM-39. A PHASE 1B STUDY OF PEMBROLIZUMAB, IBRUTINIB AND RITUXIMAB IN RECURRENT/REFRACTORY (RR) PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL)

Abstract BACKGROUND PCNSL exhibit B-cell receptor (BCR) pathway activation due to CD79B and MYD88 mutations, concurrently with 9p24.1/PD-L1/PD-L2 copy number alterations. These genetic features suggest complementary approaches of targeting PD1, BCR/BTK (Bruton’s tyrosine kinase) and CD20. Pembrolizumab, ibrutinib and rituximab have each been used as monotherapy in RR PCNSL. We investigate these agents in combination to determine tolerability and synergistic efficacy. METHODS This is a phase 1b/2 study of pembrolizumab, ibrutinib and rituximab in RR PCNSL patients. In phase 1b, patients were accrued using a 3 + 3 design to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D). Patients were treated with pembrolizumab 200mg IV every 3 weeks, ibrutinib oral daily and rituximab 375mg/m2 IV weekly (for 4 doses). Two dose levels (DL) of ibrutinib (DL1: 560 mg, DL2: 840 mg) were evaluated. Primary endpoint is progression-free survival at six months (PFS6); secondary endpoints include safety, tolerability, objective response rate (ORR), duration of response (DOR), progression-free and overall survival. RESULTS We completed accrual on the phase 1b part and report results of 10 evaluable patients (50% women). The median age was 74 years (38-82) and median ECOG 1 (0-1). There was 1 DLT at DL1 (grade 4 transaminases) and 2 DLTs at DL2 (hypertension, flu-like symptoms); the MTD/R2PD of ibrutinib with pembrolizumab and rituximab is 560mg. The most common grade 3/4 adverse events were elevated transaminases and decrease in lymphocyte counts. There were 13 dermatologic events, all < grade 3. Reasons for discontinuing treatment include progression (6), consent withdrawal (1), toxicity (2). The ORR is 80% (6 complete responses, 2 partial responses). As of June 2023, the median DOR is 177 days (49-619); PFS6 is 50%. CONCLUSIONS The combination of pembrolizumab, ibrutinib and rituximab is well-tolerated with manageable side effects and encouraging efficacy. The phase 2 portion of the study is open.

BIOM-64. A PROGNOSTIC SCORING SYSTEM FOR IMMUNODEFICIENCY-ASSOCIATED PRIMARY CNS LYMPHOMAS: AN INTERNATIONAL MULTI-CENTER STUDY

Abstract BACKGROUND Immunodeficiency-associated (ID-) primary CNS lymphomas (PCNSL) were introduced as a distinct entity in the 2021 World Health Organization classification of brain tumors. Given their rarity, larger clinical studies and prognostic models to guide management are lacking. METHODS PCNSL, newly diagnosed between 2004-2023 at six centers in the USA and in Germany, were retrospectively analyzed for concurrent immunodeficiency. Clinical, radiological, and pathological data were collected and assessed for prognostic significance using univariate and multivariate analyses. RESULTS Among 1112 patients with newly diagnosed PCNSL, 93 (8.4%) were identified as ID-PCNSL. Median age at diagnosis was 57 years and most tumors (66%) stained positive for Epstein-Barr virus (EBV). In addition to immune reconstitution, tumor-directed treatments were administered in 91/93 patients. These included chemotherapy (87%), radiation (25%), and autologous stem cell transplantation (14%). Outcome varied with a median overall survival (OS) of 46 months (range: 1-206 months). Age ≥ 60 years, Karnofsky performance status (KPS) < 70, EBV positivity, and non-rituximab or -methotrexate-based chemotherapy were associated with shorter OS on multivariate analysis adjusting for clinical and demographic factors. A prognostic scoring system was designed based on the sum of treatment-unrelated (age, KPS, EBV) unfavorable factors. The resulting score was highly prognostic and stratified ID-PCNSL into four subgroups: median OS was not reached, 90, 26, and 1 months (p < 0.0001) in cases with zero, one, two, or three unfavorable factors, respectively. Prognostic value was retained when limiting analysis to patients (n = 53), who had received HD-MTX and rituximab combination chemotherapy, with median OS of 98, 90, 46 and 4 months (p < 0.0001). CONCLUSIONS EBV was associated with inferior outcome in ID-PNCSL, which may reflect peculiar genetic alterations. An easily-applicable prognostic score based on three variables (age, KPS, EBV) allowed ID-PCNSL stratification into four risk groups. Prospective validation and therapeutic relevance warrant further investigation.

Efficacy of Chemo-Free Combination Therapy with BRAF Inhibitor and Rituximab in Classic Hairy Cell Leukemia: Insights from the French Experience

Background: Hairy cell leukemia (HCL) is a rare form of leukemia. The introduction of purine analogs has revolutionized its prognosis, leading to a life expectancy closer to that of the general population. However, patients experience relapses and require other treatment options. The BRAF V600E mutation is present in 80-100% of patients with HCL, which has prompted the use of BRAF inhibitors (vemurafenib or dabrafenib) in this condition. Recently, the combination of vemurafenib with rituximab has shown efficacy with durable responses in relapsed patients. Here, we present, for the first time, real-life data on the combination of a BRAF inhibitor with rituximab through a retrospective study involving 9 French centers. Data collection was completed by July 1, 2023. Results: We collected data from 17 patients with a male-to-female ratio of 13:4; the median age was 69 years (38-90), and 6 patients were aged over 75. The median number of previous treatments was 4 (0-7), and 3 patients were treatment-naive because they were deemed ineligible for purine analogs based on age or performance status. All 14 relapsed patients had previously received purine analogs once or multiple times (1-3). The median progression-free survival (PFS) after purine analogs was 48 months, and the median PFS after the last line of therapy was 24 months. Five patients were exposed to moxetumumab pasudotox, and 3 patients received single-agent vemurafenib previously. The BRAF V600E mutation was tested and positive for 16 patients. In our cohort, 13 patients received a combination of vemurafenib with rituximab (V+R), and 4 patients received a combination of dabrafenib with rituximab (D+R). All patients received the same regimen (Tiacci, NEMJ 2021), which included an induction phase (V+R or D+R for 8 weeks) followed by rituximab consolidation (4 injections every 15 days), except for one patient who received a rituximab sequence followed by vemurafenib. At the time of analysis, 15 out of 17 patients had completed the treatment, and the remaining 2 had completed the induction phase. Fourteen patients initiated treatment at the standard dose (960 mg bid for vemurafenib and 150 mg bid for dabrafenib), and 3 patients at a reduced dose (240-480 mg bid for vemurafenib). Toxicity of any grade was reported in 15 out of 17 patients, with 3 of them experiencing grade 3-4 toxicity. Skin toxicity was the most frequent, recorded in 12 patients (grade 1-2), leading to temporary treatment interruption in 2 patients and dose reduction in 6 patients. Other toxicities included musculoskeletal, hepatic, hematological, and cardiac, with only one patient experiencing a grade 2 infection during treatment. No secondary cancers were reported during or after treatment. Treatment was discontinued due to toxicity in 5 patients, with 4 of them resuming treatment later. Eight patients required a dosage reduction, with a median final vemurafenib dosage of 480 mg bid. At the end of treatment, 14 patients achieved a complete hematological response, and 1 patient achieved a partial response. Among the 9 patients with early response data, the median time for platelet recovery was 15 days, and for neutrophil recovery, it was 14 days. End-of-treatment bone marrow aspiration and/or biopsy was performed for 8 patients, showing a complete response in 7 patients. With a median follow-up of 12 months (4-56), only 2 patients had progressed, and as of the last update, no patients had died, and the 2 relapsed patients achieved a complete response after a new line of therapy. Conclusion: Despite a limited median follow-up of 12 months, the combination of a BRAF inhibitor with rituximab proves to be an effective regimen in heavily treated patients with HCL, achieving a 100% overall response rate. Our study confirms a rapid hematological response and an acceptable toxicity profile, even in elderly patients. The most frequent toxicity observed was cutaneous toxicity, mainly grade 1-2, and it never led to a definitive treatment discontinuation. A comparison of the two BRAF inhibitors in terms of efficacy or toxicity cannot be established due to the small sample size of patients treated with dabrafenib. Lastly, the combination of rituximab with vemurafenib or dabrafenib appears to be an interesting option in frontline treatment for patients ineligible for purine analogs.

A Rare Case of Unilateral Lymphadenopathy: Unicentric Castleman Disease

Background Castleman Disease (CD) involves a group of disorders characterized by an enlargement of lymphoid follicles with capillary proliferation. The disorders are largely separated into unicentric (UCD) or multicentric (MCD) depending on the number of involved lymph nodes. MCD has been linked to HHV8 or immunosuppression secondary to HIV, while UCD has been thought to be driven by a clonal neoplastic process, likely from the follicular dendritic cell. Case Presentation A 14-year-old female with ADHD, OCD, and autism spectrum disorder (ASD) presents to clinic with a 2-year history of a right-sided neck mass. There was no history of trauma or illness around the time of the mass being noted and the mass has not changed significantly in size for the past two years. An excisional biopsy was attempted but, due to excessive vascularity around the mass, was ultimately deferred. Following subsequent MRI and CT scans, a core needle biopsy was performed, revealing lymphoid tissue with regressed follicles and focal hyalinization without signs of malignancy. PET/CT scans at this time showed increased metabolic activity confined to the right-sided neck mass without any increased metabolic activity in the other lymph nodes of the head and neck. Eventually, the 7 cm diameter mass was excised; pathology studies revealed distorted architecture with hyaline deposits in the germinal centers and sclerotic blood vessels penetrating the germinal centers consistent with the hypervascular variant of Castleman Disease. Pre- and post-operative labs such as the C-reactive protein, immunoglobulin counts, and protein electrophoresis panels were all within normal limits. Furthermore, post-operative PET/CT scans showed no metabolically active foci indicating that the lesion was indeed unicentric Castleman Disease. After the excision of the mass, the patient continues to do well without any further surgeries or complications. Discussion Differentiation between UCD and MCD requires imaging, often with a CT scan, to establish the number and locality of the affected lymph nodes. UCD often presents with one bulky lymph node or multiple enlarged lymph nodes within the same region, whereas MCD tends to be smaller lymph nodes spread over multiple regions. MCD is also more often associated with B symptoms and abnormal lab values such as elevated CRP or ESR along with abnormal protein levels. Other subtypes exist, thought to be driven primarily by cytokines like VEGF and IL-12 similar to other neoplasms. The hypervascular type, more commonly associated with UCD, consists of fibrous bands running through lymphoid follicles with regressed germinal centers while the plasmacytic type, found more often in MCD, consists of sheets of plasma cells and hyperplastic germinal centers. Lastly, mixed type has features of both the main types. Preferred treatment for resectable UCD is surgery with treatments for unresectable UCD involving observation (if asymptomatic) or a combination of rituximab and steroids with anti-IL6 monoclonal antibody treatment (such as tocilizumab) followed by surgery or radiation therapy. Similarly, MCD is often treated with rituximab, steroids, and tocilizumab. Conclusion Due to the presence or absence of other signs and symptoms, Castleman Disease is often difficult to diagnose without a biopsy. Further studies into the etiologies of CD, including possible associations with other neoplastic or immunosuppressed states, are needed to develop better criteria for diagnosing the disease. Developing standardized patient registries with information on disease progression as well as proper follow-up for patients after treatment are vital to diagnosing, treating, and providing surveillance for patients with Castleman Disease.

Rituximab Plus Bortezomib for Refractory and Relapsed Warm Autoimmune Hemolytic Anemia：a Prospective, Single-Arm, Phase Ⅱ Trial

Background Treatment of refractory and relapsed warm autoimmune hemolytic anemia （RR wAIHA） is challenging, especially for those who are in emergency with severe anemia and crossmatching incompatibility. Rituximab is now the preferred second-line treatment for RR wAIHA with unsatisfactory onset speed and sustained efficacy. Bortezomib induces apoptosis of plasma cells that produce autoantibodies and has multiple immunoregulatory functions. In this study, we report the results of rituximab plus bortezomib for the treatment of RR wAIHA in a prospective phase 2 trial. Methods A prospective single arm trial to investigate the activity and safety of the combination of rituximab and bortezomib (RB regimen) in RR wAIHA patients were conducted. Eligible patients were aged 18 years or older, had a diagnosis of primary or secondary wAIHA or EVANS syndrome, refractory or dependent to glucocorticoids. Patients were given a single dose of 500 mg rituximab infusion on day 0 and a subcutaneous injection of 1.3 mg/m 2 bortezomib twice a week for two weeks on days 1, 4, 8, and 11. A same course was repeated after 3 months, with response assessment after 3 and 6 months. Patients with response were given rituximab 500mg every three months for 6 cycles. The primary endpoint was overall response rate (ORR) after 6 months; the co-primary endpoint was the days to hemoglobin (HGB) increase >20 g/L and transfusion independence. Findings Between Sep 2, 2019 and Jan 15, 2023, a total of 33 patients were enrolled, with 27 females (81.8%) and a median age of 56.5[interquartile range (IQR) 42.75 - 65.75]. There were 30 (91%) relapsed patients and 3 (9%) refractory patients, and 20 (60.6%) patients with primary wAIHA and 13 (39.4%) patients with secondary wAIHA. At 6 months, the ORR was 75.8%, with 11.7% of CR. The median days to HGB increase >20 g/L and transfusion independence was 19 days [interquartile range (IQR) 13 - 61.5]. After a median follow-up of 24 months [interquartile range (IQR) 6 - 24], the ORR was 84.8% with 21.2% of CR. 28.6% patients relapsed at a median interval of 12 months [interquartile range (IQR) 5.75 - 19]. 2 patients (6.1%) experienced adverse events grade ≥ 3, both of whom experienced severe pulmonary infection. There was a significant reduction in B cell counts (P = 0.011), but no significant change in quantitative measurement of serum immunoglubulin G (IgG) (P = 0.056), IgA (P = 0.052) and IgM (P = 0.057) after 6 months treatment. Mann-Whitney analysis showed that patients with a higher amount of B cells before RB regimen treatment were more likely to achieve CR (P = 0.02). Conclusion The combination of rituximab with bortezomib for RR wAIHA patients showed excellent efficacy with rapid responses and safety. The trial was registered at ClinicalTrials.gov as NCT04083014.