ABSTRACT
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.
ABSTRACT
Background: Patients with relapsed/refractory follicular lymphoma (R/R FL) often experience multiple relapses and require various lines of therapy. The ELARA and ZUMA-5 trials demonstrated high response rates along with acceptable safety profiles. We perform a phase 1b/2 single-center clinical trial of autologous point-of-care (POC) academic anti-CD19 chimeric antigen receptor (CAR) T-cells for patients with R/R FL treated with at least 2 lines of systemic therapy (NCT02772198). Aims: To report outcomes of POC CAR T-cell therapy in patients with R/R FL. Methods: Adults with R/R FL underwent a single leukapheresis procedure. Fresh peripheral blood mononuclear cells were isolated, activated, and transduced with a gammaretrovirus encoding for a CD19 CAR (based on an FMC63-derived ScFv, a CD28 costimulatory domain, and a CD3-ζ signaling domain). Lymphodepletion included fludarabine 25 mg/m2 over 3 days (days-4 to-2) and cyclophosphamide 900 mg/m2 once (day-2), followed by infusion of 1×106/kg CAR T-cells in the inpatient setting. Primary endpoints were response (by PET-CT, per Lugano criteria) at day 28, best response, and safety. Secondary endpoints included overall survival, progression-free survival (PFS), and production feasibility. Last follow-up was as of 02/2022. Results: All 19 patients enrolled received CAR T-cell infusion in a median of 11 days (IQR 10-11) after leukapheresis. The median age was 61 years (IQR 52-66). Five (26%) patients had Karnofsky performance status < 90%. Disease stage at enrollment was III-IV in 16 (84%) patients. Two (11%) patients had bulky disease;8 (42%) had LDH > upper limit of normal;and 16 (84%) had Follicular Lymphoma International Prognostic Index ≥ 3. Disease status at enrollment was progressive disease (n=14, 74%), stable disease (n=3, 16%), or partial response (PR;n=2, 11%). Twelve patients (64%) were refractory to last treatment. Disease grade at most recent lymph node biopsy was 1 (n=3, 16%), 2 (n=11, 58%), or 3a (n=5, 26%). The median time from FL diagnosis was 3.9 years (IQR 2.5-4.6). Sixteen (84%) patients had progression of disease within 24 months of initial therapy. The number of prior therapies was ≥ 4 in 6 (32%) patients;and 5 (26%) patients underwent prior autologous transplantation. Grade III-IV cytokine release and immune effector cell-associated neurotoxicity syndromes occurred in 1 (5%) and 4 (21%) patients, respectively. One patient was infected with COVID-19 on the 5th day following cell infusion and was admitted to the intensive care unit. One patient had grade 3 atrial fibrillation. Severe neutropenia (absolute neutrophil count <500/μL), thrombocytopenia (platelets <50K/μL) and anemia (hemoglobin <10g/dl) occurred in 15 (79%), 5 (26%), and 7 (37%) patients, respectively. No bleeding events or death were recorded following cell infusion. Response was evaluated in all patients. Overall response rate on day 28 was 84% (79% complete response [CR]). One patient with PR on day 28 achieved a CR after a year of follow-up. Three patients (16%) continued to progress following CAR infusion. All patients were alive at the last follow-up (median follow-up, 11.5 months [IQR 4-21]). One-year PFS was 74% (95% CI, 53-100). The median duration of response (DOR) was not reached (95% CI, 12.5-not reached). Estimated DOR at 1-year was 89% (95% CI, 71-100). Image: Summary/Conclusion: Point-of-Care anti-CD19 CAR T-cell therapy, performed following a very short production time, induced high CR rate with an acceptable safety profile in a cohort of patients with high-risk R/R FL.
ABSTRACT
Background: Maintenance in FL patients (pts) improves progression free survival (PFS). SARS-Cov2 pandemic posed unique challenges for immunocompromised pts. Aims: The aim is to evaluate the outcome of FL pts in maintenance with antiCD20-MoAb during SARS-Cov2 pandemic and how suspension of therapy affected lymphoma outcome and the risk of SARS-Cov2 infection and its morbidity and mortality. Methods: This is an observational, multicenter, retrospective and prospective study. Results: A total of 420 from 18 Italian Hematological Centers were included in the analysis. Median age was 62 years old (range 27-91 years), 216 pts (51%) were male. Main clinical characteristics of the population were: histological grade 1-2 vs 3A in 288 (69%) vs 109 (26%), while not valuable in 23 (5%) pts;limited I-II vs advanced III-IV stage in 57 (14%) vs 361 (86%) pts, not reported in 2 cases. FLIPI score was low vs intermediate vs high in 71 (17%) vs 151 (36%) vs 192 (46%) patients, respectively, not valuable in 6 cases. All 420 patients included were in maintenance treatment with antiCD20 MoAb at the time of the onset of SARS-Cov2 pandemic (March 2020): 333 (79%) pts were receiving maintenance after a first line, while 87 (21%) after a second line. 342 (81%) pts were receiving Rituximab, while 75 (18%) Obinutuzumab, 3 patients did not start the planned maintenance because of pandemic spread. Status of disease after induction was complete remission (CR) in 374 (89%), partial response (PR) in 41 (10%), progressive disease (PD) in 1, not evaluated in 4 pts, respectively. At the end of maintenance was CR in 265 (63%), PR in 19 (4%), stable disease (SD) in one and PD in 14 (3%) patients, respectively, maintenance is stiil ongoing in 121 (29%) pts. Because of SARS-Cov2 pandemic from March 2020 consequences on maintenance treatment were: temporary suspension in 122 (29%), definitively interruption in123 (29%), no modification in 175 (42%) of pts, respectively. Median number of maintenance treatment administered at the time of SARS-Cov2 pandemic onset was 2 (range 1-12), median number of courses administered at the time of analysis was 8 (range 0-12), in patients who modified treatment because of pandemic median number of performed courses was 7 (range 0-11) and median number of lost cycles were 2 (range 1-12). Pts were divided into two groups according to type of approach to maintenance during pandemic: pts who interrupted maintenance (temporary or definitively): groups A (245 (58%) pts) vs pts who did not modified maintenance: group B (175 (42%) pts). No differences in clinical characteristics, type of therapy and response were observed between the two groups. 29(7%) relapses were observed: 16 (7%) vs 13 (7%) in group A vs B, respectively. 70 (17%) pts experienced SARS-Cov2 positivity: 47 (19%) vs 23 (13%) in group A vs B, respectively. 53 (76%) pts had symptomatic COVID syndrome and 43 (61%) were hospitalized, with no differences between the two groups. Anti-SARS-Cov2 vaccine was administered in 349 patients, serology assessment was done in 46% of cases, showing 21 (13%) reactive vs 138 (87%) not reactive pts, with no differences between the two groups. 21 (30%) pts died because of COVID: 9 (19%) vs 12 (52%) in groups A vs B, respectively. Summary/Conclusion: Suspension of maintenance treatment during SARS-Cov2 pandemic did not show a protection in terms of SARS-Cov2 positivity and morbidity. A trend in lower mortality is suggested. No differences in terms of relapse rate were observed, but longer follow up is needed.
ABSTRACT
Background: Maintenance in FL patients (pts) improves progression free survival (PFS). SARS-Cov2 pandemic posed unique challenges for immunocompromised pts. Methods: This is an observational, multicenter, retrospective and prospective study. The aim is to evaluate the outcome of FL pts in maintenance with antiCD20-MoAb during SARS-Cov2 pandemic and how suspension of therapy affected lymphoma outcome and the risk of SARS-Cov2 infection and its morbidity and mortality. Results: 420 pts from 18 Italian Centers were included. Median age was 62 years old (range 27-91), 216 pts (51%) were male. Main clinical characteristics were: histological grade 1-2 vs 3A vs not valuable in 288 (69%) vs 109 (26%) vs 23 (5%), respectively;advanced stage in 361 (86%), high FLIPI score in 192 (46%) pts. All 420 pts were in antiCD20-MoAb maintenance at the time of SARS-Cov2 pandemic onset (March 2020): 333 (79%) were receiving maintenance after a first line, while 87 (21%) after a second line. 342 (81%) pts were receiving Rituximab, while 75 (18%) Obinutuzumab, 3 pts did not start the planned maintenance. Status of disease after induction was complete remission (CR) in 374 (89%), partial response (PR) in 41 (10%), progressive disease (PD) in 1, not evaluated in 4 patients, respectively. At the end of maintenance was CR in 265 (63%), PR in 19 (4%), stable disease (SD) in one and PD in 14 (3%) pts, maintenance is ongoing in 121 (29%) pts. Because of SARS-Cov2 pandemic maintenance treatment was temporary suspended in 122 (29%), definitively interrupted in123 (29%), not changed in 175 (42%). Median number of maintenance treatment administered at March 2020 was 2 (range 1-12), in pts who modified treatment median number of performed vs lost courses was 7 (range 0-11) vs 2 (range 1-12). Patients were divided into two groups according to the approach to maintenance during pandemic: pts who interrupted maintenance (temporary or definitively): groups A (245 (58%) cases) vs pts who did not modified maintenance: group B (175 (42%)). No differences in clinical characteristics, type of therapy and response were observed between the two groups. 29(7%) relapses were observed: 16 (7%) vs 13 (7%) in group A vs B. 70 (17%) pts experienced SARS-Cov2 positivity: 47 (19%) vs 23 (13%) in group A vs B. 53 (76%) pts had symptomatic COVID and 43 (61%) were hospitalized, with no differences between the two groups. Anti-SARS-Cov2 vaccine was administered in 349 patients, serology assessment was done in 46% of cases, showing 21 (13%) reactive vs 138 (87%) not reactive patients, with no differences between the two groups. 21 (30%) pts died because of COVID: 9 (19%) vs 12 (52%) in groups A vs B. Conclusions: Suspension of maintenance during SARS-Cov2 pandemic did not show a protection in terms of SARS-Cov2 positivity and morbidity. A trend in lower mortality is suggested. No differences in terms of relapse rate were observed, but longer follow up is needed.
ABSTRACT
Background: Standard chemoimmunotherapy for first-line treatment of follicular lymphoma (FL) achieves high rates of disease control but is not curative and carries significant toxicities including prolonged immunosuppression that may attenuate response to vaccinations (Marcus et al., NEJM 2017). While proteasome inhibitors have shown modest activity in R/R FL (Goy et al., JCO 2005), limited data address their use frontline. The comparatively favorable toxicity profile and convenient oral dosing of ixazomib support its investigation in this space. Methods: We evaluated ixazomib and its combination with short-course rituximab (R) for FL as part of an open-label, phase II investigator-initiated trial at the University of Washington / Fred Hutch Cancer Research Center / Seattle Cancer Care Alliance (NCT 02339922). Eligibility included an indication for treatment per NCCN guidelines and no prior standard systemic FL therapy. Ixazomib was administered at 4 mg orally once a week until disease progression or unmanageable toxicity. One course of R at 4 weekly doses of 375 mg/m2 was added during the 7th 28-day cycle, after an initial 6-cycle “window” on ixazomib alone. Available pretreatment formalin-fixed, paraffin-embedded tissue biopsies were subjected to RNA extraction by standard methods and gene expression profiling (GEP) using the NanoString™ PanCancer IO 360 panel to query pathways in proteasomal degradation and lymphomagenesis. Standard GEP quality control and data processing were performed with the ROSALIND® platform. Patients vaccinated per standard of care for COVID-19 while actively receiving ixazomib and ≥ 6 mo after completing R were evaluated for serologic response ≥ 2 weeks after the final dose of vaccine using the Roche Elecsys® Anti-SARS-CoV-2 S assay against the spike protein receptor binding domain. Results: Twenty pts began therapy between Feb 2017 and January 2020. All had grade I/II FL and FLIPI score was 2 in 20% and ≥ 3 in 20%;FLIPI score in all other patients was 0 or 1. Eleven (55%) pts met GELF criteria for high tumor burden disease including 6 (30%) pts with a tumor mass ≥ 7 cm. Median follow-up was 32.1 months (range 5.7 - 51.6). The ORR by Lugano criteria was 35% (CR 5%) during the ixazomib window and 65% (CR 45%) overall. At data cut (June 15, 2021) all patients were alive and 8 (40%) remained progression-free on treatment (Figure 1). By KM estimate, median PFS was 25.8 mo and median DOR was not reached at a median follow-up of 29.6 mo. As expected, high-grade treatment-related AEs were infrequent for ixazomib and R, including grade ≥ 3 events in 3 unique pts (15%;diarrhea, transaminitis, and cytopenias). No grade ≥ 4 or serious AEs were observed. Toxicities led to study-directed drug interruptions in 4 (20%) pts and dose reduction to ixazomib 3 mg weekly in 2 pts (10%). Higher ORR to ixazomib monotherapy was associated with FLIPI > 1 (p = 0.04) and, by exploratory GEP, downregulation of components of proteasomal degradation and upregulation of NF-KB and chemokine signaling (Figure 2). High tumor burden by GELF (p = 0.89) and tumor mass ≥ 7 cm (p = 0.26) were not associated with ORR to ixazomib. All 6 of 6 patients evaluated to date for response to COVID-19 vaccination, administered at a median of 32.5 mo (range 7.0 - 41.0) after last dose of R, achieved positive anti-spike protein antibodies (median anti-S 163.8 AU/mL, range 13.3 - 1139);none was diagnosed with COVID-19. Conclusions: The simple outpatient regimen of weekly oral ixazomib and the addition of 4 doses of R shows significant long-term activity with low toxicity in untreated FL. Extended DOR is achievable especially in patients who respond to ixazomib monotherapy. Ixazomib efficacy was associated with higher FLIPI scores and gene expression signatures implicated in proteasomal degradation and B-cell signaling pathways. Ixazomib deserves further investigation as a biomarker-driven therapeutic in untreated FL, particularly as an option that prioritizes outpatient management and serologic responsiveness to im unization. (Figure Presented).
ABSTRACT
Introduction: Obinutuzumab-based induction immunochemotherapy was demonstrated to improve the outcome of patients with follicular lymphoma (FL) comparing to the regimens with rituximab in GALLIUM study (NCT01332968). The infusion related reactions (IRRs) occur in more than half of FL patients during the first obinutuzumab administration. Therefore, during the whole treatment period infusions lasting more than 3-4 hours are so far recommended. Shorter infusions would be more convenient for both patients and medical staff and could also contribute to the shorter hospitalization that is desirable during COVID-19 pandemic. The aim of the study was to evaluate the tolerance and early efficacy of obinutuzumab-based regimens in FL patients in clinical practice. Methods: We evaluated tolerability of obinutuzumab infusions and response rates to different regimens of chemotherapy combined with obinutuzumab in consecutive FL patients treated in hemato-oncology centers in Poland from Jan 2020 to Jan 2021. Obinutuzumab was combined with CHOP, CVP or bendamustine according to the treating physician choice. Obinutuzumab maintenance was offered to the patients who achieved at least partial response (PR) after induction immunochemotherapy. Response was evaluated with computed tomography or positron emission tomography according to 2014 Lugano criteria. Adverse events were assessed according to Common Toxicity Criteria (version 5). Results: The study group included 129 treatment-naive FL patients. The median age (range) was 52 (29 - 90) years, 35.7% of patients were males. According to FLIPI 46.5 % of patients were classified as high risk, 33.3% as intermediate and 20.2% as low risk, whereas 33.7%, 30.4% and 35.9% of patients were in PRIMA PI high, intermediate and low risk groups, respectively, Table 1. Median number of GELF criteria was 2 (range 1-6). Induction chemotherapy included: CVP in 48.1% (n=62), CHOP in 29.5% (n=38) and Benda in 22.5% (n=29) of patients. Median number of cycles was 6 (range 1 - 8). Maintenance was started in 85 patients (76.6%). The first obinutuzumab dose was administered as a single infusion during the first day of the first cycle in 43.4% of patients (n=56), whereas 56.6 % (n=73) of patients had initial infusion divided into 2 days (100 mg and 900 mg). During the first cycle 93.8% (n=121) of patients received three doses of obinutuzumab. The doses were omitted in 8 patients: in 4 due to Covid-19, in 1 due to pneumonia and neutropenia and in 3 cases due to neutropenia. IRRs were reported during the first Obinutuzumab administration in 10.1% of patients (n=13, grade 1/2 in 11 and grade 3 in 2 patients): in 7 patients who received obinutuzumab initial dose in single infusion and in 6 patients who received first obinutuzumab dose divided in two days. Median time of the first infusions was 4 hours and 55 min (range 1:30 - 9:45). There were no IRRs reported during the subsequent obinutuzumab infusions. The most common adverse event was neutropenia with grade 3/4 events reported in 51.1% of patients (n=66). G-CSF support was given in 70.4% (n = 81/115), and as the primary prophylaxis in 42.6 % (n=49) of patients. The SARS-CoV-2 infection occurred in 19 patients regardless of initial chemotherapy regimen. After induction immunochemotherapy complete response (CR), partial response (PR), stable disease (SD) and progression disease (PD) rates were: 71.8%, 23.9%, 0.9% and 3.4%, respectively, Table 2. With a median follow up of 8.7 months 5 patients (3.9%) relapsed, 4 died due to COVID infection. There were no deaths caused by FL. Conclusions: In our study obinutuzumab-based induction treatment was well tolerated. The low incidence and low grade of infusion related reactions in most of the patients, reported only during the first infusion, support the practice of administration of the first obinutuzumab dose in a single infusion. For convenience, the concept of short, 90 minutes infusion of Obinutuzumab starting from the second cycle could be considered (Canales MA, EHA 2021). During COVID-19 pandemic using obinutu umab with chemotherapy is feasible and justified by the high response rate to this treatment. [Formula presented] Disclosures: Paszkiewicz-Kozik: Roche: Honoraria, Other: congress fee;Servier: Other: congress fee;gillead: Other: travel grant;Takeda: Honoraria, Other: Travel Grants. Hus: Astra Zeneca: Honoraria, Research Funding;Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees;AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi: Membership on an entity's Board of Directors or advisory committees. Romejko-Jarosinska: roche: Other: congress fee;servier: Other: congress fee;gilead: Other: traver grant. Drozd-Sokolowska: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dlugosz-Danecka: Janssen: Consultancy, Research Funding;Roche: Consultancy, Research Funding, Speakers Bureau;Servier: Consultancy, Speakers Bureau;Acerta Pharma: Research Funding;AbbVie: Research Funding;Macrogenics: Research Funding;Beigene: Research Funding;MEI Pharma: Research Funding;Incyte Corp.: Research Funding;Takeda: Research Funding. Lech-Marańda: Amgen: Membership on an entity's Board of Directors or advisory committees;Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding;Roche: Membership on an entity's Board of Directors or advisory committees;AbbVie: Membership on an entity's Board of Directors or advisory committees;Sanofi: Membership on an entity's Board of Directors or advisory committees. Walewski: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees;Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Amgen: Consultancy, Honoraria;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS: Consultancy, Honoraria;Celgene: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Servier: Consultancy, Honoraria.