Anaplastic extramedullary plasmacytoma resistant to novel therapies: A case report

The treatment of choice for extramedullary plasmacytoma (EMP) is radiotherapy (RT). It is under discussion whether the management of an anaplastic form of EMP requires the addition of systemic therapy. We present a case of a 66-year-old male who was diagnosed with anaplastic plasmacytoma of the maxillary sinus. After the exclusion of multiple myeloma, Dara-VMP (daratumumab, bortezomib, melphalan, and prednisolone) regimen was initiated. During the third cycle of Dara-VMP, a progression of the tumor was observed. RT and BRd (bendamustine, dexamethasone, and lenalidomide) regimen were initiated. After 4 cycles of BRd, disease progression was established. KRd (carfilzomib, lenalidomide, and dexamethasone) regimen was initiated. The first cycle of KRd was not completed, as the patient was diagnosed with COVID-19. After the infection, the progression of EMP was observed. In this case, the anaplastic EMP was resistant to RT and chemotherapy regimens with novel agents, including a monoclonal antibody, an immunomodulatory drug, and proteasome inhibitors. Copyright © 2023 the author(s), published by De Gruyter, Berlin/Boston.

Persistent SARS-CoV-2 infection with multiple clinical relapses in two patients with follicular lymphoma treated with bendamustine and obinutuzumab or rituximab.

PURPOSE: People with hematologic malignancies have a significantly higher risk of developing severe and protracted forms of SARS-CoV-2 infection compared to immunocompetent patients, regardless of vaccination status. RESULTS: We describe two cases of prolonged SARS-CoV-2 infection with multiple relapses of COVID-19 pneumonia in patients with follicular lymphoma treated with bendamustine and obinutuzumab or rituximab. The aim is to highlight the complexity of SARS-CoV-2 infection in this fragile group of patients and the necessity of evidence-based strategies to treat them properly. CONCLUSIONS: Patients with hematological malignancies treated with bendamustine and anti-CD20 antibodies had a significant risk of prolonged and relapsing course of COVID-19. Specific preventive and therapeutic strategies should be developed for this group of patients.

Anti-CD20 antibodies and bendamustine attenuate humoral immunity to COVID-19 vaccination in patients with B-cell non-Hodgkin lymphoma.

Serologic responses of COVID-19 vaccine are impaired in patients with B-cell lymphoma, especially those who had recently been treated with anti-CD20 monoclonal antibodies. However, it is still unclear whether those patients develop an immune response following vaccination. We investigated the efficacy of vaccination against SARS-CoV-2 in 171 patients with B-cell non-Hodgkin lymphoma (B-NHL) who received two doses of an mRNA-based COVID-19 vaccine and we compared the efficacy of vaccination to that in 166 healthy controls. Antibody titers were measured 3 months after administration of the second vaccine dose. Patients with B-NHL showed a significantly lower seroconversion rate and a lower median antibody titer than those in healthy controls. The antibody titers showed correlations with the period from the last anti-CD20 antibody treatment to vaccination, the period from the last bendamustine treatment to vaccination and serum IgM level. The serologic response rates and median antibody titers were significantly different between diffuse large B-cell lymphoma (DLBCL) patients in whom anti-CD20 antibody treatment was completed within 9 months before vaccination and follicular lymphoma (FL) patients in whom anti-CD20 antibody treatment was completed within 15 months before vaccination. Moreover, the serologic response rates and median antibody titers were significantly different among FL patients in whom bendamustine treatment was completed within 33 months before vaccination. We demonstrated that B-NHL patients who were recently treated with anti-CD20 antibodies and bendamustine had a diminished humoral response to COVID-19 vaccination. UMIN 000,045,267.

Bendamustine and rituximab is well-tolerated and efficient in the treatment of indolent non-Hodgkin's lymphoma and mantle cell lymphoma in elderly: A single center observational study.

Bendamustine and rituximab (BR) is a preferred first-line therapy for indolent non-Hodgkin's lymphoma (iNHL) and mantle cell lymphoma (MCL); however, few reports on BR performance in elderly patients are available to date. We compared safety and efficacy of BR in patients ≥70 years (elderly) vs <70 years (younger) treated at our institution. Among 201 patients, 113 were elderly (median age: 77 years), including 38 patients ≥80 years, and 88 were younger (median age: 62 years). Elderly patients had more bone marrow involvement by lymphoma, anemia, ECOG status 3 and high-risk disease follicular lymphoma (P < .05 for all). Fifty-four percent of elderly received full dose of bendamustine vs 79.5% of younger patients. More elderly patients (54%) vs younger (43.2%) experienced treatment delay. Less elderly proceeded to rituximab maintenance. Overall, the number of adverse events per patient and transformed B-Cell lymphoma/secondary malignancies were similar between groups. Elderly patients had less febrile neutropenia, rituximab-associated infusion reactions, but more herpes zoster reactivation. There were more deaths in the elderly (37.2%) vs younger (10.2%) groups (P < .001), mainly due to non-lymphoma-related causes. With median follow-up of 42 months [4.0-97.0] disease-free survival for the elderly was similar to younger patients. There was no difference between patients <80 and ≥80 years (P = .274). In conclusion, the real-world elderly patients have more advanced disease and higher ECOG status. BR is well-tolerated; elderly patients had lower incidence of febrile neutropenia. Dose reduction and treatment delays are common, but BR efficacy was not affected even in very old patients (≥80 years).

Impact of anti-SARS-CoV-2 monoclonal antibodies in the management of patients with lymphoma and COVID19: A retrospective study.

COVID19 in patients affected by lymphoma represents an important challenge because of the higher mortality rate. Anti-SARS-CoV-2 monoclonal antibodies (anti-S MoAbs) appear promising in this setting. We report a monocentric retrospective study including 176 patients affected by lymphoma which developed SARS-CoV-2 infection since the start of COVID19 pandemic. Overall, mortality was 13.1%, with a decreasing trend between first waves to the last wave of pandemic (18.5% vs. 9.4%, p 0.076). Patients receiving anti-S MoAbs (41.3%) showed inferior mortality rate (overall survival, OS 93.2% vs. 82.7%, p 0.025) with no serious toxicity, reduced documented pneumonia (26% vs. 33%, p 0.005), and reduced need of oxygen support (14.5% vs. 35.7%, p 0.003). Among patients who received 3 doses of vaccine, the employment of anti-COVID MoAbs showed a trend of superior survival versus those who did not receive Anti-S MoAbs (OS rates 97.3% vs. 84.2%, p 0.064). On multivariate analysis, active haematological disease (OS 72% (HR 2.49 CI 1.00-6.41), bendamustine exposure (OS 60% HR 4.2 CI 1.69-10.45) and at least one comorbidity (HR 6.53 CI 1.88-22.60) were independent prognostic factors for death. Our study confirms the adverse prognostic role of COVID-19 in lymphoma patients in presence of active disease, comorbidities and previous exposure to bendamustine. In our experience, anti-S MoAbs represented a therapeutic option in vaccinated patients.

SARS-COV-2 INFECTION WITH RITUXIMAB THERAPY

SESSION TITLE: COVID-19 Case Report Posters 3 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Exposure to anti-CD20 treatment affects B cell functions involved in anti-COVID immunity and impacts the clinical course of infection. We present two patients with persistent respiratory symptoms and persistent SARS-COv-2 PCR positivity months after initial infection. The aim of presenting these cases is to highlight how exposure to Rituximab can result in patients having significantly prolonged SARS-CoV-2 infections that may require special treatment compared to immunocompetent patients. CASE PRESENTATION: Patient A is a 46-year-old man with a history of marginal zone lymphoma, who was treated with six cycles of bendamustine with rituximab and monthly maintenance rituximab. He has been hypoxic for 7 months after COVID infection with ground glass opacities on imaging, elevated CRP of 58.4, positive PCR, undetectable CD3/CD4 and low cycle threshold of 28, suggesting rapid active viral replication. COVID IGG was negative. T cell subsets counts were undetectable. IgG 351, IgA 59, IgM less than 10. He was treated with a 10-day course of Remdesevir and steroids. Given lack of humoral immunity, he was given convalescent plasma. At discharge he developed positive COVID IgG and remained COVID positive by PCR. He had complete resolution of hypoxia. Patient B is a 68-year-old man with a history of chronic lymphocytic leukemia, who was treated with six years of rituximab maintenance therapy, last rituximab was three years ago. He was diagnosed with SARS-CoV-2 three months prior to admission with worsening hypoxia. He remained PCR positive with persistent respiratory symptoms. At readmission his imaging showed ground glass opacities, CRP 6.6 and cycle threshold was 27.8. The follow studies were abnormally low:IgG 541, IgA 25, IgM 14, absolute CD3 171, absolute CD4 68. He was treated with remdesivir, steroids, granulocyte colony stimulating factor and sotrovimab. Despite these therapies, his hypoxia worsened, and he pursued comfort care. DISCUSSION: There are reports of patients receiving B cell depleting therapy who have persistent shedding of viable SARS-CoV. Persistent viral infection may be suspected in patients with relapsing symptoms, elevated CRP, D-dimer and active ground glass changes imaging. Low T cell subsets and low immunoglobulin levels indicate a CD20 related impairment of adaptive immunity. Time to viral clearance appears to be prolonged compared to general population in immunocompromised patients. There is some published experience using convalescent plasma in this setting. SARS-CoV-2 viremia has been demonstrated to predict adverse outcomes. Median cycle threshold has been shown to be lower, reflecting a high viral load comparable with acute infectious phase of COVID. CONCLUSIONS: To achieve stable clinical responses this subset of patients may benefit from early administration of combination regimens, including both passive immunotherapy and prolonged antiviral treatment. Reference #1: Furlan A, Forner G, Cipriani L, Vian E, Rigoli R, Gherlinzoni F, Scotton P. COVID-19 in B Cell-Depleted Patients After Rituximab: A Diagnostic and Therapeutic Challenge. Front Immunol. 2021 Nov 3;12:763412. doi: 10.3389/fimmu.2021.763412. PMID: 34804051;PMCID: PMC8595333. DISCLOSURES: No relevant relationships by Cheryl Augenstein Primary Investigator relationship with Boehringer Ingelheim Please note: 2/2022-2/2024 Added 04/01/2022 by A. Thanushi Wynn, value=Grant/Research Support

A CASE OF REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA INDUCED IMMUNE THROMBOCYTOPENIC PURPURA SUCCESSFULLY TREATED WITH VENETOCLAX

Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. Approximately 2% of patients with CLL develop immune thrombocytopenic purpura (ITP) during the course of the disease. When resistant to steroids, this constitutes as indication for treatment of the CLL. Here we report a patient with refractory ITP secondary to CLL successfully treated with venetoclax. Aims: To present an interesting case with CLL related refractory ITP treated successfully with novel agent venetoclax. Methods: Patient data was taken from the patient herself and Hospital records. Informed consent to publish the case is obtained from patient. Permission for off-label venetoclax and eltrombopag was obtained from Ministry of Health of Turkey. Results: 46-year-old female patient presented with lumps on her neck that were present for the last 9 months in November 2020. She has a history of frequent pneumonia and otitis but no constitutional symptoms. Her physical examination reveals multiple 2cm lymphadenopathies on her neck and no organomegaly or other pathological features. Blood work shows mild lymphocytosis (6800/mm3) with no serious cytopenias. Peripheral blood smear, flow cytometry and bone marrow biopsy were all compatible with CLL. She was classified as Binet A CLL and was followed up with no treatment after appropriate vaccinations against capsulated pathogens. In July and August 2021 she received two doses of mRNA vaccination against COVID-19. On 1st November 2021 she experienced excessive menstrual bleeding and blood work showed platelet count of 23000/mm3, she was started on steroids (1 mg/kg/day) and after 4 days platelet count has risen to 55000/mm3, she discontinued steroids on her own against medical advice. On 13th of November she presented with extensive petechiae and purpura and was again started on steroids and was given the courses of intravenous immunoglobulins (IVIG) without any sustained response. She was refractory to platelet transfusions too. She was transferred to our clinic. She was found to have del11q and del13q. She refused bone marrow examination. She was treated with rituximab, steroids, vincristine, IVIG and eltrombopag for ITP without success (Fig. 1). She had a minimal response to IVIG only. She received two courses of bendamustine (90 mg/kg for two days) also without success. Three courses of plasmapheresis yielded no response either. After mild success with immunadsorbtion apharesis she was started on venetoclax plus rituximab with ramp-up. Sustained response was achieved within the first week of venetoclax therapy. (Figure Presented ) Summary/Conclusion: Gordon et al. reported 2 CLL cases one with ITP and other with Evans syndrome successfully treated with venetoclax. We think, this treatment should be considered in patients with refractory immune cytopenias secondary to CLL and assessed with prospective clinical trials.

CLINICAL EFFICACY AND TOLERABILITY OF VENETOCLAX PLUS RITUXIMAB IN RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA - REAL WORLD ANALYSIS OF POLISH ADULT LEUKEMIA STUDY GROUP

Background: The introduction of venetoclax into clinical practice has improved the outcome of patients with relapsed/refractory chronic lymphocytic leukemia (RR-CLL). The results of the MURANO trial published in March 2018 showed significantly longer progression-free survival (PFS) and overall survival (OS) in RR-CLL patients treated with venetoclax and rituximab (VEN-R) comparing to bendamustine and rituximab (BR) and resulted in the approval of VEN-R in the therapy of RR-CLL in the European Union and the United States. It should be noted that the results of registration studies often do not correspond with the data from real-life observations. Aims: To study the clinical efficacy and safety profile of VEN-R treatment in RR-CLL patients outside clinical trials. Methods: We performed retrospective analysis of RR-CLL patients treated with VEN-R in hematology centers of the Polish Adult Leukemia Study Group (PALG) from 2019 to 2021. Results: Clinical data of 117 RR-CLL patients treated with VEN-R were collected. Median patient age upon initiation of VEN-R therapy was 67 years (range 33 - 84 years). Seventy-two patients (61.5%) were men. Median Cumulative Illness Rating Scale (CIRS) was 6 (range 2 -16). Patients were treated with a median of 2 (range 1-9) previous lines of therapy, whereas 32 patients (27.4%) had relapsed following the first line of treatment. Overall, 25 patients (21.4%) had 17p deletion, whereas TP53 mutation was identified in 13 patients (11.1%). The median follow-up was 9.96 months (range 0.27 -29.13). The overall response rate (ORR) was 95.2%. Seventeen patients (14.5%) achieved complete remission (CR), 83 (70.9%) partial remission (PR), while in 5 patients (4.3%) disease progression was noted. In the patients with 17p deletion (n=22) or TP53 mutation (n=11), CR and PR were observed in 4 (12.1%) and 29 (87.9%) patients, respectively. The median PFS in the whole cohort was 20.8 (95% CI 18.43 -not reached) months and the median OS was not reached. In our study none of the analyzed clinico-pathological factors had significant impact on ORR, PFS and OS. During the follow-up time four (3.4%) cases of Richter transformation were diagnosed. There were 18 deaths recorded during the course of observation;3 (16.7%) due to disease progression and 7 (38.9%) due to COVID-19 infection. The others were due to infections other than SARS-CoV-2 (n=3, 16.7%) and the cause of death could not be specified in five cases (27.8%). Eighty-three patients (70.9%) remain on treatment, while treatment was discontinued in thirty-four cases (29.1%). Reasons for therapy discontinuation included patient's death (52.9%), treatment-related cytopenias (17.6%), disease progression (14.7%), Richter's transformation (11.8%), autoimmune hemolytic anemia (5.9%), diarrhea (2.9%) and infections (8.8%). In one case treatment discontinuation was due to consent withdrawal and one patient was lost to follow-up. The following adverse events of VEN-R treatment were reported during the study: all grade neutropenia (71.8% with grade 3/4 in 55.6%), anemia (51.3%), thrombocytopenia (47%), pneumonia (9.4%), neutropenic fever (6.8%), autoimmune hemolytic anemia (4.3%), immune thrombocytopenic purpura (1.7%), diarrhea (4.3%) and in one case exacerbation of heart failure was observed. Summary/Conclusion: In this retrospective analysis the outcomes of treatment with the VEN-R regimen in real-life setting were worse than those reported in the MURANO trial.

A PHASE 1 STUDY OF PARSACLISIB IN COMBINATION WITH RITUXIMAB, BENDAMUSTINE + RITUXIMAB, OR IBRUTINIB IN PATIENTS WITH PREVIOUSLY TREATED B-CELL LYMPHOMA (CITADEL-112): PRELIMINARY SAFETY RESULTS

Background: Rituximab-based chemoimmunotherapy regimens are backbone treatment (Tmt) for both indolent (follicular [FL], marginal zone [MZL]) and aggressive (diffuse large B-cell [DLBCL], mantle cell [MCL]) B-cell lymphomas. Standard of care (SoC) for relapsed or refractory (R/R) disease includes anti-CD20 in combination with chemotherapy and targeted therapies, such as Bruton's tyrosine kinase inhibitors (eg, ibrutinib) and phosphoinositide 3-kinase (PI3K) inhibitors. Parsaclisib is a potent and highly selective next generation PI3Kδ inhibitor that is currently being investigated in hematological malignancies. Aims: CITADEL-112 (NCT03424122) is an open-label phase 1 study evaluating the safety and tolerability of adding parsaclisib to investigator choice SoC Tmt rituximab (RIT), RIT + bendamustine (BEN), or ibrutinib (IBR) in patients (pts) with R/R B-cell lymphoma. Methods: Enrolled pts were ≥18 years and had histologically confirmed DLBCL, FL, MCL, or MZL, ECOG PS 0-2, were R/R to ≥1 (≥2 for FL) prior systemic therapy, and ineligible for stem cell transplant. Pts received parsaclisib 20 mg orally once daily (QD) for 8 weeks then 20 mg once weekly (QW) in combination with either: RIT 375 mg/m2 IV QW for 4 doses in cycle 1 (± cycle 2) (Tmt A);RIT 375 mg/m2 IV on day 1 + BEN 90 mg/m2 on day 1 and day 2 of each 28-day cycle for ≤6 cycles (Tmt B);or IBR 560 mg QD (Tmt C). Pts received treatment until disease progression, unacceptable toxicity, or withdrawal. Results: At data cutoff (May 14, 2021), 50 pts were treated (16 pts each in Tmt A and C, 18 pts in Tmt B) and 13 pts were ongoing treatment (3 pts in Tmt A, 8 pts in Tmt B, 2 pts in Tmt C). Most pts had received ≥2 prior systemic treatments (81.3%, 61.1%, and 68.8% in Tmt A [range 1-4], B [range 1-4], and C [range 1-7], respectively). The most common reasons for discontinuation were progressive disease (56.3%, 38.9%, and 50.0%) and adverse events (AEs) (12.5%, 11.1%, and 6.3% in Tmt A, B, and C, respectively). One pt in Tmt B experienced a dose-limiting toxicity of grade 4 neutropenia for >14 days. All pts experienced at least 1 treatment-emergent AE (TEAE);in Tmt A, 75.0% had grade ≥3 and 37.5% had serious TEAEs;Tmt B, 83.3% had grade ≥3 and 27.8% had serious TEAEs;and Tmt C, 62.5% had grade ≥3 and 43.8% had serious TEAEs. Common any-grade TEAEs (≥30%) included neutropenia (62.5%), diarrhea (37.5%), and anemia (31.3%) in Tmt A;neutropenia (50.0%), abdominal pain, asthenia, diarrhea, and nausea (each 33.3%) in Tmt B;neutropenia (50.0%) and increased ALT and increased AST (each 37.5%) in Tmt C. Most common grade ≥3 TEAEs (≥15%) were neutropenia (50.0%) and diarrhea (18.8%) in Tmt A, and neutropenia (38.9% and 25.0%) in Tmt B and Tmt C, respectively. Serious TEAEs occurring in >1 pt were COVID-19, diarrhea, and pneumonia (n = 2 each) in Tmt A, and atrial fibrillation (n = 2) in Tmt C. TEAEs with fatal outcome were reported in 2 pts in Tmt A (COVID-19 and COVID-19 pneumonia [n = 1], interstitial lung disease [n = 1]) and 1 pt in Tmt C (COVID-19, acute kidney injury). Parsaclisib dose interruption or dose reduction due to TEAEs occurred in 75.0% and 18.8% of pts, respectively, in Tmt A;66.7% and 27.8% of pts, respectively, in Tmt B;and 56.3% and 18.8% of pts, respectively, in Tmt C. Summary/Conclusion: Parsaclisib 20 mg QD for 8 weeks followed by 20 mg QW can be safely combined with RIT, RIT + BEN, or IBR in pts with R/R B-cell lymphomas. The tolerability profile of the combination regimens was manageable, with no unexpected safety concerns.

TREATING BING-NEEL SYNDROME USING A TAILORED APPROACH: EXPERIENCE OF A SPECIALIST NEUROHAEMATOLOGY CLINIC

Background: Bing-Neel syndrome (BNS) is a rare complication of lymphoplasmacytic lymphoma (LPL) comprising LPL infiltration in the central nervous system (CNS). Clinical and radiological features are diverse;the diagnosis is confirmed by cerebrospinal fluid (CSF) analysis using immunological and molecular techniques. Rarely, a tissue biopsy is required. The pattern of presentation including systemic involvement and CSF features inform treatment strategies, which include CNS-penetrating therapies. Aims: To evaluate the diagnostic characteristics of patients with BNS and their influence on therapy. Methods: Data from patients referred between 2011-2021 for management of BNS to our academic neurohaematology centre were retrospectively reviewed. Those with imaging features alone or where it was not possible to distinguish from high-grade transformation were excluded. Results: Thirty-five patients (22 male, 13 female) were identified. Median age at diagnosis of BNS was 65 years (range 48-85). All patients were symptomatic. In 12 patients (34%) BNS was the de novo presentation of the IgM-related disorder, of which 3 (25%) had no detectable bone marrow (BM) infiltration of LPL at diagnosis. Approximately half (17;49%) had previously received therapy for LPL;median time to BNS diagnosis in these was 49 months (range 3-125). At BNS diagnosis, BM involvement with LPL ranged from 0-95%. More than half (14/26;54%) had <10% infiltrate and almost a fifth (4/26) >60%. All patients had leptomeningeal involvement and 8 (23%) additionally had parenchymal CNS disease. The majority had kappa light-chain predominance: IgMκ (n=26), non-IgMκ (n=5), IgMλ (n=3), one unknown. The BNS diagnosis was made on CSF analysis (n=28;80%), leptomeningeal tissue biopsy (n=3;9%) where CSF was non-informative, or by expert opinion based on supportive clinical, radiological and non-definitive CSF features (n=4;11%). Of those with a diagnosis based on CSF studies, B-cell clonality was confirmed by flow cytometry (27/28;96%), MYD88L265P mutation (18/28;64%) and immunoglobulin gene rearrangement (12/28;43%). In 22 samples with a full dataset, median CSF white cell count was 25/ul (1-233), CSF protein 1.69g/l (0.35-6), CSF IgM 9.49mg/l (1.07-61.5). The majority were treated with intensive regimens (rituximab, methotrexate (MTX), cytarabine (ARA-C) + thiotepa/idarubicin;n=30) due to the presence of CNS disease bulk and clinical need, and less commonly ibrutinib (n=3), bendamustine-rituximab (BR, n=1);one patient had intrathecal therapy (MTX, ARA-C) at the height of the COVID pandemic. Of those who received 2 cycles of intensive chemotherapy, 3 had >4 cycles followed by BCNU/thiotepa autologous stem cell transplant;10 proceeded to 'consolidation' (indefinite) ibrutinib to limit intensive chemotherapy or tackle systemic disease. At a median follow up of 26 months (range 1-121), median survival was not reached;2-year overall survival was 91% (95% CI 74-97). Three patients died during treatment (1 invasive fungal infection post COVID-19 during ibrutinib consolidation post MTX/ARA-C based therapy) and 2 during MTX-ARA-C based therapy;7 patients relapsed or progressed and were treated with ibrutinib: 1 relapsed after ibrutinib use, 1 patient was intolerant of ibrutinib and switched to BR. Image: Summary/Conclusion: Our cohort confirms that BNS may present with leptomeningeal disease and/or parenchymal disease, de novo and without systemic disease. Overall outcomes are excellent with intensive regimens, consolidated with or followed by ibrutinib;however, there are treatment-related toxicities emphasising the need for a tailored approach.

A PHASE 1 STUDY EVALUATING SAFETY AND EFFICACY OF PARSACLISIB IN COMBINATION WITH BENDAMUSTINE + OBINUTUZUMAB IN PATIENTS WITH RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA (CITADEL-102)

Background: Patients (pts) with follicular lymphoma (FL) generally respond well to first-line CD20-targeted therapies, such as obinutuzumab or rituximab-based regimens. However, many pts relapse and studies suggest that each subsequent relapse is associated with shorter durations of response to the next treatment. Parsaclisib is a potent and highly selective next generation PI3Kδ inhibitor. The combination of bendamustine + obinutuzumab is approved for pts with relapsed/refractory (R/R) FL. We hypothesized that adding parsaclisib may improve clinical benefit with a manageable safety profile in this pt population. Aims: CITADEL-102 (NCT03039114) is an open-label, phase 1, dose-finding study that investigated safety and efficacy of parsaclisib in combination with bendamustine + obinutuzumab in pts with R/R FL following rituximabcontaining regimens. Methods: Pts enrolled were ≥18 years with histologically confirmed CD20-positive FL, R/R to any prior rituximabcontaining regimen, ECOG PS 0-2, ≥1 measurable lesion, and ≤4 prior therapies. Pts received parsaclisib 20 mg orally once daily (QD) for 8 weeks then 20 mg once weekly (QW);bendamustine 90 mg/m2 infusion on days 1 and 2 of cycles 1-6;and obinutuzumab 1000 mg infusion on days 1, 8, and 15 of cycle 1, and day 1 of cycles 2-6, and on every second cycle of cycles 8-30 in pts having complete response/complete metabolic response (CR/CMR), partial response/partial metabolic response (PR/PMR), or stable disease/no metabolic response. Part 1 (safety run-in) used a 3+3 design with dose de-escalation to identify the maximum tolerated dose (MTD) of parsaclisib in combination with bendamustine + obinutuzumab. In Part 2 (dose expansion), the safety and efficacy of this combination were further evaluated. The primary study endpoint was safety and tolerability;secondary endpoints included efficacy outcomes (ORR, DOR, PFS, and OS). Results: A total of 26 pts were enrolled and treated;median (range) age was 65.0 (44-80) years, 25 (96.2%) had ECOG PS ≤1, 11 (42.3%) had ≥2 prior systemic therapies, and 6 (23.1%) had received prior bendamustine. Median (range) parsaclisib exposure was 10.6 (0.4-32.8) months. Main reasons for treatment discontinuation included adverse events (AEs) (8 pts, 30.8%) and progressive disease (6 pts, 23.1%). All pts experienced treatment-emergent AEs (TEAEs);most common any-grade TEAEs (≥10 pts) were pyrexia (53.8%), neutropenia (50%), diarrhea (46.2%), thrombocytopenia, and nausea (each 38.5%). Grade ≥3 TEAEs were experienced by 88.5% of pts;most common grade ≥3 TEAEs (≥2 pts) were neutropenia (34.6%), febrile neutropenia (23.1%), thrombocytopenia (19.2%), ALT and AST increase (each 11.5%), and diarrhea, neutrophil count decreased, and rash maculopapular (each 7.7%). One of 6 evaluable pts in Part 1 had a DLT of grade 4 QTc elongation. The MTD was not reached, and parsaclisib 20 mg QD for 8 weeks then 20 mg QW was the selected dosage for dose expansion in Part 2. Treatment discontinuation due to TEAEs was 30.8%, 7.7%, and 15.4% for parsaclisib, bendamustine, and obinutuzumab, respectively. One fatal TEAE (COVID-19 pneumonia) occurred. ORR (95% CI) as reported by the investigator was 76.9% (56.4-91.0), with 17 pts (65.4%) achieving CR/CMR and 3 pts (11.5%) achieving PR/PMR as the best overall response. Median DOR, PFS, and OS were not reached. Summary/Conclusion: Parsaclisib in combination with bendamustine + obinutuzumab appears to have a manageable safety profile and demonstrated promising efficacy in pts with R/R FL.

CELLULAR IMMUNE RESPONSE TO THE BNT162B2 VACCINE IN LYMPHOMA PATIENTS

Background: In most individuals, protective humoral and cellular immunity develops after two doses of the BNT162b2 Pfizer vaccine. In patients with lymphoma, humoral response is weaker and almost universally abrogated in patients who received anti-CD20 monoclonal antibodies. Whether cellular immune response is also abrogated is unknown. Aims: To determine whether patients with lymphoma develop specific T-cell mediated cellular response to BNT162b2 Pfizer vaccine. Methods: We included patients with lymphoma above the age of 18 years who received two doses of the BNT162b2 Pfizer vaccine and collected clinical and demographics data. T-cell immune response to the vaccine was analysed in patients' blood samples stimulated by spike antigen and quantified by two methods: (1) Interferon-gamma (IFNg)- release assay (IGRA, EuroImmun, Germany)- IFNg was quantified by ELISA (DuoSet, R and D Systems, Minneapolis, Minnesota, USA) and response above 50 pg/ml was considered positive. (2) Flow cytometry- Quantification of the T cell activation markers, CD134+ CD25+CD4+ T-cells was performed (Act-T4 CellTM kit, Cytognos, Spain), and any response above 0 was considered positive. Humoral response was measured by SARS-CoV-2 IgG II Quant (Abbott©) assay. The positive cut-off was set at 50AU/ml. Blood samples were drawn approximately 4 months after the second vaccination. Results: Sixty-nine lymphoma patients, treated with two vaccine doses, were included in this study. Median age was 66 (range: 30-84) and 39 (57%) were males. Sixty-two patients (90%) had non-Hodgkin lymphoma (NHL) including 18 with DLBCL, 26 with follicular lymphoma and 14 with marginal zone lymphoma. Seven (10%) patients had Hodgkin lymphoma. In this cohort, 70% (n=49) of the patients received anti CD20 MoAb, and 35% of them (n=27) were still on anti CD20 treatment. Thirteen patients received bendamustine-based immunochemotherapy. At the time of assessment (median 4.8 months after the 2nd vaccine) anti-spike antibodies were detected in only 42% (N = 29) of patients. In comparison, there was an increase in specific T cell response by any assay (IGRA and Flow) in 49% of patients (n = 34). The correlation between the IGRA and flow data was 0.7 (pearson correlation, P = 0.01). However, no correlation between humoral (qualitative and quantitative) and T cell response was shown, regardless of the assay applied. Cellular response was not corelated with the time elapsing from last immunochemotherapy. In the anti-CD20 MoAb treated cohort, of which 27 patients were still on active treatment at the time of vaccination, only 2 patients (7%) developed a humoral immune response, while cellular immunity was elicited in 52% (N = 15) patients (ELISA assay). In the Bendamustine treated cohort, with a median time from end of treatment to vaccination of 23 months (1-106 months), humoral but not cellular response correlated positively with the time from treatment completion to vaccination (p=0.04). Summary/Conclusion: The rate of cellular and humoral response to two doses of the BNT162b2 Pfizer vaccine in lymphoma patients was found to be significantly abrogated. In this small cohort, 49% of patients developed a cellular response despite a severely abrogated humoral immunity. These findings suggest that vaccine administration should be considered even early after anti CD20 therapy despite the reduced humoral immunity. These findings should be validated in studies with a higher number of patients.

EFFICACY AND SAFETY OF IMMUNOCHEMOTHERAPY IN TREATMENT OF FOLLICULAR NONHODGKIN'S LYMPHOMA DURING COVID-19 PANDEMIC: A STUDY OF KROHEM, THE CROATIAN COOPERATIVE GROUP FOR HEMATOLOGIC DISEASES

Background: Follicular lymphoma (FL) is a systemic neoplasm of the lymphoid tissue arising from B cell proliferation. The novel monoclonal anti-CD20 antibody obinutuzumab in combination with chemotherapy has been widely accepted as the first choice in front line treatment of FL. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19) is causing increased mortality among patients with lymphoproliferative disorders compared with the general population. Furthermore, there are some concerns in terms of morbidity and mortality for patients with FL because of their immunocompromised status induced by recent exposure to cytotoxic chemotherapy, especially bendamustine and anti-CD20. Aims: To investigate efficacy and safety of immunochemotherapy protocols for patients with newly diagnosed FL during COVID-19 pandemic. Methods: We retrospectively investigated medical data of all patients with newly diagnosed FL grade 1, 2 or 3A from Croatian hematologic registry in period from April 2019 to March 2021. Only patients which required systemic treatment were included in the analysis. All patients received obinutuzumab (G) in combination with either CHOP, bendamustine (B) or CVP chemotherapy protocol. Treatment response was evaluated using international lymphoma response criteria. Results: We analyzed a total of 114 FL patients treated with G-chemotherapy. Mean age was 62.4 ±10.5 years. Majority of patients were female (71/114 (62.3%)). FL grade I was present in 45/114 (39.5%), grade II in 28/114 (24.6%), grade III in 27/114 (23.7%) and not specified (but not IIIB) in 14/114 (12.3%) patients. A total of 61/114 (53.5%) patients were treated with G-B, 49/114 (43%) with G-CHOP and 4/114 (3.5%) with G-CVP immunochemotherapy. Similar rates of adverse events were observed in patients treated with G-CHOP and G-B Median follow up was 17 months. Overall response rate was 94%, complete remission (CR) in 68% and partial remission (PR) in 25% of patients. Median overall survival (OS) and progression free survival (PFS) were not reached with 12-months rates of 94% and 92%, respectively. Patients treated with G-CHOP had statistically significantly superior OS and PFS compared to patients treated with G-B (P=0.002 and P=0.006, respectively, Fig. 1). More favorable survival course associated with G-CHOP in comparison to G-B persisted in multivariate analysis (P=0,026, HR=15,12) after adjustment for age, sex, FLIPI grade and SARS-CoV-2 infection. Total of 12 patients died during the follow up and COVID-19 was cause of death in 5 patients. During the follow-up SARS-CoV-2 infection was diagnosed in 20/114 (17,5%) patients with overall mortality rate of 25%. All of the 7 patients treated with GCHOP recovered from SARS-CoV-2 infection and mortality rate in infected group of patients treated with G-B was 33% (4/12 patients). Image: Summary/Conclusion: Increased COVID-19 mortality in patients with lymphoproliferative disorders was observed in this study. Our group of patients had reduced OS and PFS compared to the GALLIUM trial and SARS-CoV-2 infection was the most pronounced risk factor for death. Even though in some studies bendamustine has shown to be less toxic and more effective than CHOP in FL, there are some important pandemic aspects that must be considered. Bendamustine exposure seems to be associated with worse outcome in case of the infection with SARS-CoV-2. These intriguing differences could play important role in treatment approach in COVID-19 pandemic. Future studies investigating hematological malignancies in COVID-19 pandemic are warranted.

PATIENTS WITH HODGKIN LYMPHOMA DEVELOP ADEQUATE HUMORAL SEROLOGICAL RESPONSE TO VACCINATION WITH TWO DOSES OF BNT162B2 AND THEIR IGG ANTIBODY LEVELS MARKEDLY INCREASE AFTER A THIRD VACCINE DOSE

Background: In patients (pts) with hematological malignancies, COVID-19 is considered to be associated with a high risk of severe morbidity and mortality. While anti-COVID-19 vaccination of such pts has become the standard of care, pts undergoing lymphodepleting therapy fail to generate protective serological response due to either the nature of their underlying disease or exposure to therapy. Aims: This study aimed to assess serological response to vaccination with BNT162b2 (Pfizer) as well as COVID-19-related morbidity and mortality in Hodgkin lymphoma (HL) pts. Methods: The above vaccine was available in Israel from January 2021 and all pts with hematological malignancies were recommended to undergo vaccination with 2 doses of this vaccine, injected 21 days apart. Six months later a 3rd dose was recommended and in another 3 months a 4th dose was available for pts at risk. Serology tests were performed at least 2 weeks after the 2nd vaccination. The SARS-CoV-2 IgG II Quant (Abbott©) assay was used to measure levels of IgG antibodies (Abs) against the SARS-CoV-2 spike protein. A result was considered positive if the IgG level was ≥150 AU/ml, which was defined as an adequate serological response. Results: The current non-interventional single-center study evaluated the outcome of 55 HL pts (median age 46 years, 53% females);51% of pts had advanced HL. Study participants received 1-9 lines of therapy (median 1 line). Six pts had COVID-19 prior to vaccination, 49 were vaccinated: 9 with 2 doses, 36 with 3 doses and 4 with 4 doses of BNT162b2. Following initial 2 vaccine doses and after a 3rd dose Ab levels >150 AU/ml were developed in 85% and 89.5% of pts, respectively. At a median of 95 days post-2nd vaccination, Ab levels were 2024 (1-29400) and 4 (0-7539) in 48 patients with no background disease versus 7 pts treated with lymphodepleting drugs or having a background disease, respectively. During the follow-up, 5 vaccinated pts were diagnosed with COVID-19 when the Delta variant was prevalent and 9-during the Omicron wave. Notably, similar Ab levels were observed in those infected with Omicron and in non-infected pts, reflecting the genetic drift of this variant. A further analysis was performed to compare findings in a subgroup of 7 pts who had an additional background disease along with HL, such as chronic lymphocytic leukemia, s/p kidney transplantation, solid tumor, or those who were heavily pretreated, including therapy with bendamustine, versus the values observed in the rest 48 pts. The median age in the former subgroup was 58 (31-80) years, which was significantly older than in the remaining pts [median 45 (18-78) years] and median Ab levels were 4 (0-7539) AU/ml and 2024 (1-2940) AU/ml, respectively. Notably, after the 3rd vaccination, the median Ab level in both groups was 7000 AU/ml. Summary/Conclusion: The results of the current study show that at least 85% of HL pts develop a high titer of anti-spike antibodies after vaccination with 2 BNT162b2 doses. These titers substantially increased post the 3rd vaccine dose. Only a minority of HL pts who had additional background diseases or were heavily pretreated, failed to develop an adequate serological response;however, some of them had high Ab titers post-3rd and 4th vaccinations. In this study, morbidity and mortality rates of HL pts infected with COVID-19 were lower than those reported in pts with other lymphoma types.

REAL WORLD EXPERIENCE WITH POLATUZUMAB IN COMBINATION WITH BENDAMUSTINE AND RITUXIMAB FOR R/R DLBCL IN 3 ACADEMIC CENTERS IN MADRID, SPAIN

Background: On 2019, the FDA and later the EMA granted approval to polatuzumab vedotin-piiq, a CD79b-directed antibodydrug conjugate indicated in combination with bendamustine and rituximab (P-BR) for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), after at least two prior therapies. P-BR has demonstrated (NCT02257567) better overall response rates (complete and partial responses) compared with BR alone (63% vs 25%) and response durations of at least 12 months in 48% of the patients. The most common adverse reactions with P-BR (incidence at least 20%) included cytopenias (most common reason for treatment discontinuation), peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite and pneumonia. Serious adverse reactions occurred in 64%, most often from infection. Aims: To analyze results in terms of efficacy and safety of the P-BR regimen in real life conditions. Methods: Observational, retrospective study in 3 academic centers. Adult patients (≥ 18 years old) diagnosed with DLBCL NOS R/R who received P-BR between July 2019 and December 2021 were included in the analysis. Results: 11 patients were treated with P-BR. The mean (SD) age was 70.1 (8.2) years (Range 57-81 years). Cell of origin was informed in 9/11 cases, 6 of them were activated B-cell (ABC) subtype. No double-/triple-hit lymphomas were confirmed. The median number of prior lines of therapy before P-BR was 2, with most patients (63%) refractory to the last treatment. All patients had received anti-CD20 (Rituximab) on prior treatments and only 2 (18%) Bendamustine. Baseline characteristics are shown in table 1. Efficacy Seven patients were evaluated by PET-CT after 3 cycles, 4 (57%) achieved CR and 3 PR (43%). Five patients achieved CR by PET-CT at the end of treatment. One of these patients is still in CR after 12 months of follow up and three of them after 24 months from the start of P-BR. One patient relapsed after 19 months. Of the patients achieving CR, all of them had responses >12 months. Only 3/5 completed the 6 cycles scheme, 1 patient received 5 cycles (treatment was interrupted due to an invasive fungal infection) and 1 patient received only 2 cycles as bridge therapy for and autoHCT and achieved CR after transplantation. 1 patient was refractory to treatment and progressed after 2 cycles. Toxicity: All patients were evaluated for toxicity. 63% (7/11) of them presented hematological toxicity, mainly neutropenia which required GCSF administration and 71% RBC transfusion. Two patients required hospital admission because of neutropenic fever. There were 3 documented cases of SARS-CoV-2 infection. Two patients had moderate disease with bilateral pneumonia (vaccinated) after the 2° cycle of treatment which is temporarily interrupted. One patient completed 6 cycles but died of severe SARS-CoV2 infection (unvaccinated) before being assessed for response at end of treatment. Two patients interrupted treatment definitely because of toxicity: severe cytopenia and invasive fungal infection. No other extra hematological toxicities were reported. Image: Summary/Conclusion: The P-BR regimen provides sustained good results for patients with R/R DLBCL who have failed treatment with prior therapies. Cytopenias were the most frequent form of toxicity and were easily addressed in most cases. In our experience, SARS-CoV2 infection has been a challenge due to delay in treatment and high morbidity and mortality.

Txagorrapid: Ultrarapid infusion in 30 minutes of the biosimilar of rituximab truxima- A cohort study

Background: Rituximab (anti-CD20 Ab) is the cornerstone of the treatment of non-Hodgkin B lymphomas. Infusion-related reactions (IRR) are the most common adverse effects. To reduce them, intravenous premedication with antihistamine and acetaminophen is administered prior to rituximab. If no IRR after first infusion, subsequent infusions time takes 3-6 hours. Many centers use the rapid 90-minute infusion (off-label). Since 2017 subcutaneous rituximab formulation is available, that takes 5 minutes of administration. Nevertheless, in order to reduce cost, due to approval of biosimilars, some health providers continue using intravenous rituximab. On the other hand, with COVID pandemic, an effort to reduce visits and day-care hospitals stays has been made. In the current situation, it would be convenient to reduce day-care stay and the nursing care burden. We wanted to evaluate the safety of an ultrarapid infusion of biosimilar rituximab in a total time of 30 minutes by analyzing IRR and adverse events (AE). Methods: Since November 2021, 3 cohorts of ultrafast infusion have been studied as follows: One cohort (Cohort 1) with intravenous premedication with dexchlorpheniramine and acetaminophen, followed by rituximab infusion over 1 hour, and 2 cohorts with rituximab infusion over 30 minutes: Cohort 2: with intravenous premedication, and cohort 3 with oral premedication. IRR and adverse events have been independently reviewed and graded using Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (November 27, 2017). Results: 34 patients have been included receiving 48 rituximab infusions (16 infusions in each cohort). Median age was 64 years old (range: 51-91). Diagnostic of NHL were as follows: large b cell: 10;follicular: 13;marginal: 7;mantle cell: 1, Waldeström: 1;Ritcher transformation: 2. Rituximab infusion was in monotherapy (21), and in combination (27) with: bendamustine: 9, CHOP: 17, GEMOX: 1. Considering safety, no IRR has been observed in cohort 1 (1 hour infusion), and 1 IRR grade II in cohort 3 (30 minutes, oral premedication). Other AE were: hypertension grade I and hypotension grade I, both in cohort 2. Conclusions: Ultrarapid rituximab infusion is safe. Oral premedication is feasibly allowing a total infusion time of 30 minutes. This infusion rate alleviates day-care burden saving between 75-90% of time in each rituximab infusion, reduce day-care stay and is comfortable for the patients.

Prolonged COVID-19 in an Immunocompromised Patient Treated with Obinutuzumab and Bendamustine for Follicular Lymphoma.

A patient with follicular lymphoma treated with obinutuzumab and bendamustine experienced prolonged coronavirus disease-2019 (COVID-19). One month after the symptoms transiently improved, the patient experienced exacerbated COVID-19 symptoms. The patient recovered from COVID-19 with remdesivir and dexamethasone and was discharged 77 days after the disease onset. The patient completed a primary series of SARS-CoV-2 vaccinations on day 176, but the anti-spike protein IgG was not detected later. A careful observation to detect any subsequent relapse of COVID-19 symptoms is necessary in immunocompromised patients. Chemotherapy should be based on the disease status and type of lymphoma.

Bendamustine in combination with pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: A phase II trial.

Treatment of patients with resistant/refractory multiple myeloma (MM) is an unmet need. In this phase II study, we evaluated the role of bendamustine, pomalidomide and dexamethasone combination in this setting. Between February 2020 and December 2021, 28 patients were recruited. Patients received bendamustine 120 mg/m2 day 1, pomalidomide 3 mg days 1-21, and dexamethasone 40 mg days 1, 8, 11, 22, regimen given for a maximum of six cycles. The median (range) age of the patients was 54 (30-76) years and 15 (53.6%) were males. Patients had received a median (range) of three (two-six) prior lines and 85.7% were refractory to both lenalidomide and bortezomib. The primary end-point was the overall response rate (ORR) defined as ≥partial response after at least three cycles. Secondary objectives were toxicity, progression-free survival (PFS), time to progression and overall survival (OS). An intent-to-treat analysis was done. An ORR of 57.6% was achieved. Patients with extramedullary myeloma had a better response rate. At a median follow-up of 8.6 months, the median PFS and OS were 6.2 and 9.7 months respectively. Toxicity was manageable; mainly haematological (neutropenia, 46.4%; anaemia, 42.8%; and thrombocytopenia, 7.1%). Bendamustine, pomalidomide and dexamethasone could be a novel combination for the heavily pretreated, lenalidomide-refractory myeloma population.

Successful Elimination of SARS-CoV-2 Following Vaccination with BNT162b2 after Prolonged Viral Infection in an Immunocompromised Lymphoma Patient.

A 52-year-old man with mantle cell lymphoma treated with bendamustine and rituximab developed prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Despite elevated titers of anti-spike IgG antibody, protracted pancytopenia persisted for more than six months. Finally, the anti-SARS CoV-2 vaccine, BNT162b2, was administered, which improved his blood cell count and eliminated the virus. The increased anti-spike IgG titer and lymphocyte count after vaccination suggested that both humoral and cellular immunity acted in coordination to eliminate the virus.