A Review of Selected Presentations From the All-Virtual 62nd ASH Meeting and Exposition • December 5-8, 2020
Analyzing Efficacy Outcomes From the Phase 2 Study of Single-Agent Tazemetostat as Third-Line Therapy in Patients With Relapsed or Refractory Follicular Lymphoma to Identify Predictors of Response
Follicular lymphoma is the most common subtype of non-Hodgkin lymphoma (NHL) and typically follows an indolent course. Tazemetostat is a first-in-class, oral inhibitor of the histone methyltransferase EZH2, a gene that is mutated in up to 25% of patients with follicular lymphoma.1,2 The US Food and Drug Administration (FDA) recently approved tazemetostat for the treatment of patients with relapsed or refractory follicular lymphoma. The approval includes patients whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least 2 prior systemic therapies, as well as patients who lack satisfactory alternative treatment options.
The FDA granted accelerated approval to tazemetostat after positive results from the open-label, single-arm, multicenter phase 2 E7438-G000-101 trial. This study included 99 heavily pretreated patients with follicular lymphoma who had wild-type or mutated EZH2.3 Tazemetostat was administered at a dose of 800 mg twice daily, in continuous 28-day cycles.3 Tazemetostat was generally well tolerated and demonstrated clinically meaningful responses. In the entire study population, tazemetostat yielded an objective response rate (ORR) of 51% (95% CI, 40%-61%), a median duration of response of 11 months (95% CI, 7-19 months), and a median progression-free survival (PFS) of 12 months (95% CI, 8-15 months). The median overall survival (OS) was not reached. The ORR was 69% in patients with the EZH2 mutation vs 35% in those with wild-type disease. However, patients in the mutated and wild-type cohorts had similar median durations of response (11 months vs 13 months) and PFS (14 months vs 11 months). The median OS was not reached in either cohort.
A post hoc exploratory analysis evaluated whether outcomes were affected by factors such as progression of disease within 24 months after first-line therapy (POD24), prior lines of therapy, and disease that is refractory to rituximab. These factors are known to affect outcomes in patients receiving second- or third-line treatment for follicular lymphoma.4-7 An initial analysis evaluated data from patients in the phase 2 study with wild-type or mutated EZH2. Predictive modeling was used to identify variables that were associated with response. The modeling suggested that a decreased ORR was associated with an increased number of prior therapies (>2) and POD24. Both variables showed a potential correlation with PFS.
An extended exploratory analysis was performed to identify clinical variables that could predict ORR, duration of response, and PFS.7 Variables evaluated in the exploratory analysis included levels of lactate dehydrogenase, presence of double-refractory disease, presence of extranodal lesions, number of prior therapies, POD24 status, disease that was refractory to the most recent prior therapy, disease that was refractory to a rituximab regimen, and prior stem cell transplant. Two variables showed a potential correlation with shorter ORR: increased number of prior therapies (1 or 2 vs >2 prior therapies; odds ratio [OR], 2.81; 95% CI, 1.19-6.61; P=.02) and POD24 (OR, 2.46; 95% CI, 1.08-5.61; P=.04). Disease that was refractory to rituximab corresponded to a shorter duration of response (Figure 1; hazard ratio [HR], 0.43; P=.0335). Variables that correlated with a shorter median PFS included disease that was refractory to rituximab (HR, 0.37; P=.0006), a high level of lactate dehydrogenase (HR, 2.10; P=.007; Figure 2), and double-refractory disease (HR, 0.52; P=.03). Variables that did not show an effect on response outcomes included prior stem cell transplant, disease that was refractory to the most recent prior therapy, and the presence of an extranodal target lesion.
References
1. Tazverik [package insert]. Cambridge, MA; Epizyme, Inc.; 2020.
2. Lue JK, Amengual JE. Emerging EZH2 inhibitors and their application in lymphoma. Curr Hematol Malig Rep. 2018;13(5):369-382.
3. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442.
4. Jurinovic V, Kridel R, Staiger AM, et al. Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy. Blood. 2016;128(8):1112-1120.
5. Li M, Dave N, Salem AH, Freise KJ. Model-based meta-analysis of progression-free survival in non-Hodgkin lymphoma patients. Medicine (Baltimore). 2017;96(35):e7988.
6. Nastoupil LJ, Flowers CR, Leonard JP. Sequencing of therapies in relapsed follicular lymphoma. Hematology Am Soc Hematol Educ Program. 2018;2018(1):189-193.
7. Salles G, Tilly H, Chaidos A, et al. Analyzing efficacy outcomes from the phase 2 study of single-agent tazemetostat as third-line therapy in patients with relapsed or refractory follicular lymphoma to identify predictors of response [ASH abstract 2047]. Blood. 2020;136(suppl 1).
Umbralisib, the Once-Daily Dual Inhibitor of PI3Kδ and Casein Kinase-1ε Demonstrates Clinical Activity in Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma: Results From the Phase 2 Global UNITY-NHL Trial
B-cell receptor signaling plays a key role in normal B-cell development and in the development of B-cell malignancies.1 A recent mouse model demonstrated that the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin pathway drives the pathogenesis of marginal zone lymphoma.2 Umbralisib (TGR-1202) is a dual inhibitor of PI3Kδ and CK1ε, with a highly selective preference for PI3Kδ compared with the α, β, and γ isoforms. The phase 2b UNITY-NHL study evaluated umbralisib monotherapy in previously treated NHL patients.3 The study enrolled adults with histologically confirmed relapsed or refractory marginal zone lymphoma, follicular lymphoma, or small lymphocytic lymphoma (SLL) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patients received umbralisib (800 mg, twice daily) until disease progression, unacceptable toxicity, or study withdrawal. The first assessment of response was conducted at the end of cycle 3. The primary endpoint was independently assessed ORR. The study included 117 patients with follicular lymphoma, 69 with marginal zone lymphoma, and 22 with SLL. The baseline characteristics were generally well balanced across the 3 arms. The median age was 66 years (range, 29-88 years), and 57% of patients were male. An ECOG performance status of 2 was reported in 3% of patients, and 77% had stage III/IV disease. In the marginal zone lymphoma arm, 55% of patients had the mucosa-associated lymphoid tissue subtype. Patients had received a median of 2 prior therapies (range, 1-10), and all patients had received prior anti-CD20 therapy. Ninety-one percent of patients had received prior chemoimmunotherapy. Approximately one-third of patients were refractory to their most recent prior therapy, and the median time since the last therapy was 14 months.
The median follow-up was 27.7 months. The median time of exposure to study treatment was 8.4 months (range, 0.2-27 months). Treatment was ongoing in 29% of patients. The most common reasons for discontinuing the study treatment included progressive disease (42%) and adverse events (AEs; 15%). The most common AEs of any grade included diarrhea (59.1%), nausea (39.4%), and fatigue (30.8%). Discontinuation owing to transaminase elevation occurred in 2.9% of patients. Grade 3 diarrhea led to discontinuation in 2.9% of patients. Among 4 patients (1.9%) with noninfectious colitis, symptoms resolved in 3 patients, who continued to receive umbralisib. Grade 3/4 AEs of interest included opportunistic infections (3.4%), rash (1.9%), and pneumonitis (1.0%).
Among patients with follicular lymphoma, the independently assessed ORR was 45.3%, with a complete response (CR) rate of 5% (Figure 3). These rates were 49.3% and 15%, respectively, in patients with marginal zone lymphoma, and 50.0% and 5%, respectively, in SLL patients. Disease reduction was reported in 90.6% of the marginal zone lymphoma patients, 83.5% of those with follicular lymphoma, and 89.5% of those with SLL. The median duration of response was not reached (95% CI, 10.3 months to not evaluable) in marginal zone lymphoma patients, 11.1 months (95% CI, 8.3-15.6 months) in follicular lymphoma patients, and 18.3 months (95% CI, 2.4 months to not evaluable) in SLL patients. PFS was not reached (95% CI, 12.1 months to not evaluable) in the marginal zone lymphoma cohort, 10.6 months (95% CI, 7.2-13.7 months) in those with follicular lymphoma, and 20.9 months (95% CI, 7.4-24.1 months) in those with SLL.
References
1. Niemann CU, Wiestner A. B-cell receptor signaling as a driver of lymphoma development and evolution. Semin Cancer Biol. 2013;23(6):410-421.
2. Sindel A, McConnell I, Windle J, et al. Role of the PI3K pathway in the pathogenesis of marginal zone lymphoma [ASH abstract 622]. Blood. 2018;132(suppl 1).
3. Zinzani P, Samaniego F, Jurczak W, et al. Umbralisib, the once daily dual inhibitor of PI3Kδ and casein kinase-1ε demonstrates clinical activity in patients with relapsed or refractory indolent non-Hodgkin lymphoma: results from the phase 2 global UNITY-NHL trial [ASH abstract 2934]. Blood. 2020;136(suppl 1).
Primary Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel in Patients With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma
Among patients with indolent NHL who have received 2 or more lines of treatment, approved therapies yield low rates of CR, and the median duration of response is approximately 13 months or less.1-5 The phase 2 ZUMA-5 trial evaluated axicabtagene ciloleucel, an autologous chimeric antigen receptor (CAR) T-cell therapy, in patients with follicular lymphoma who had received at least 2 prior lines of therapy. Eligible patients had relapsed or refractory follicular lymphoma of grade 1 to 3a or marginal zone lymphoma.6 Prior treatment included an anti-CD20 monoclonal antibody combined with an alkylating agent. Patients received standard conditioning treatment followed by administration of 2 × 106 CAR-positive cells per kilogram. The primary endpoint was ORR, based on the Lugano criteria.7
The trial enrolled 151 patients. All patients underwent leukapheresis, and 146 underwent conditioning chemotherapy. An infusion of axicabtagene ciloleucel was administered to 124 patients with follicular lymphoma and 22 patients with marginal zone lymphoma. The safety analysis included 146 patients, whereas the efficacy analysis included 104 patients. Axicabtagene ciloleucel therapy was successfully manufactured for all enrolled patients. Delivery to the study site occurred at a median of 17 days after leukapheresis. The patients’ median age was 61 years (range, 34-79 years), and 57% of patients were male. Eighty-six percent of patients had stage III/IV disease, and 49% had high tumor bulk. Patients had received a median of 3 prior therapies (range, 1-10), and 68% had refractory disease.
Based on an independent review of the overall study population, the ORR was 92% (95% CI, 85%-97%), with a CR rate of 76% (95% CI, 67%-84%). The ORR was 94% in patients with follicular lymphoma (n=84) and 85% in patients with marginal zone lymphoma (n=20). The median time to first response was 1 month (range, 0.8-3.1 months). Among the 25 patients with follicular lymphoma who had an initial partial response, 13 (52%) subsequently achieved a CR after a median of 2.2 months (range, 1.9-11.2 months).
The ORR was consistent across key subgroups, including patients with high tumor burden (96%), patients who had received 4 or more prior therapies (93%), and those with POD24 following their first anti-CD20 treatment (93%). After a median follow-up of 17.5 months, the median duration of response was not reached for the 104 evaluable patients (Figure 4), and 64% of patients with follicular lymphoma had an ongoing response. Among the 104 evaluable patients, the median PFS (Figure 5) and OS were not reached. Twelve-month PFS was 73.7%, and 12-month OS was 92.9%.
AEs of grade 3 or higher occurred in 86% of patients, and most commonly consisted of cytopenias (70%) and infections (16%). A grade 5 AE occurred in 3 patients. One death was attributed to multisystem organ failure in a patient with cytokine release syndrome, which was related to treatment with axicabtagene ciloleucel. Overall, 7 patients (10%) experienced grade 3 or higher cytokine release syndrome. The median time to onset of cytokine release syndrome of any grade was 4 days (range, 1-15 days), and the median duration was 6 days (range, 1-27 days). Neurologic events of grade 3 or higher occurred in 28 patients (19%). The median time to onset of neurologic events of any grade was 7 days (range, 1-177 days), and the median duration was 14 days (range, 1-452 days). Neurologic events of any grade resolved in 93% of patients.
References
1. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35(35):3898-3905.
2. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922.
3. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-1018.
4. Wang TP, Scott JH, Barta SK. The evolving role of targeted biological agents in the management of indolent B-cell lymphomas. Ther Adv Hematol. 2017;8(12):329-344.
5. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442.
6. Jacobson CA, Chavez JC, Sehgal AR, et al. Primary analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) [ASH abstract 700]. Blood. 2020;136(suppl 1).
7. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
Tazemetostat Is Associated With Lower Risk for Safety Outcomes Versus the PI3-Kinases Idelalisib, Duvelisib, and Copanlisib in Patients With Relapsed/Refractory Follicular Lymphoma Who Have Received at Least 2 Prior Systemic Treatments: A Matching-Adjusted Indirect Comparison of Single-Arm Trials
Copanlisib, duvelisib, and idela-lisib are approved for the treatment of patients with relapsed or refractory follicular lymphoma after 2 systemic treatments. However, these PI3-kinase inhibitors were approved based on single-arm studies, and they are associated with safety concerns. An indirect treatment comparison was conducted to evaluate tazemetostat vs copanlisib, duvelisib, and idelalisib as third-line or later treatment of patients with relapsed or refractory follicular lymphoma.1 The investigators conducted a systematic literature review to identify publications of relevant clinical trials (Table 1).2-6 All of the trials were phase 2, open-label, single-arm studies. Three pairwise analyses were conducted using a matching-adjusted indirect comparison methodology. The patients were matched according to their age, ECOG performance status, disease stage, histology, number of prior lines of treatment, prior stem cell therapy, refractory status, and POD24. The study evaluated safety and efficacy outcomes.
Baseline characteristics and outcome data for the subpopulation with follicular lymphoma were reported for matching idelalisib (n=72). Full-trial mixed-NHL populations were available for duvelisib (n=129, 64% with follicular lymphoma) and copanlisib (n=142, 73% with follicular lymphoma). Only the trial of tazemetostat included patients with grade 3b or transformed follicular lymphoma.
Grade 3 and higher treatment-emergent AEs are shown in Table 2. After matching for baseline characteristics, tazemetostat was associated with a lower risk of any-grade treatment-emergent AE, any treatment-emergent serious AE, and any treatment-emergent AE leading to dose reduction, drug discontinuation, or treatment interruption. The results were significant (P<.05) for all but 2 comparisons (vs idelalisib for any treatment-emergent serious AE, P=.06; and vs duvelisib for a treatment-emergent AE that led to discontinuation, P=.05). Several treatment-emergent AEs were observed at a significantly lower incidence with tazemetostat compared with the PI3K inhibitors. For example, neutropenia rates varied from 3% to 4% with tazemetostat vs 22% to 25% with the PI3K inhibitors.
Comparisons of ORR showed no statistically significant differences between tazemetostat and each of the comparators. However, the study investigators identified some limitations to the analysis of response. For example, the comparator trial data were not adjusted for the effect modifier of EZH2 mutation status. The comparator trials also excluded patients with grade 3b tumors or transformed NHL, who may have had a worse prognosis. The authors noted that the efficacy data are not expected to have affected the safety results. They concluded that tazemetostat was associated with a significantly lower relative risk for adverse events as compared with idelalisib, duvelisib, and copanlisib, while exhibiting similar efficacy outcomes
References
1. Proudman D, Nellesen D, Gupta D, et al. Tazemetostat is associated with lower risk for safety outcomes versus the PI3-kinases idelalisib, duvelisib and copanlisib, in patients with relapsed/refractory follicular lymphoma who have received at least 2 prior systemic treatments: a matching-adjusted indirect comparison of single-arm trials [ASH abstract 2064]. Blood. 2020;136(suppl 1).
2. Dreyling M, Santoro A, Mollica L, et al. Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study. Am J Hematol. 2019;95(4):362-371.
3. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35(35):3898-3905.
4. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922.
5. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-1018.
6. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442.
Treatment and Outcome of Patients With Follicular Lymphoma Relapsed or Progressed After Frontline Lenalidomide and Rituximab
A retrospective analysis evaluated salvage treatment strategies and survival outcomes in patients with grade 1 to 3a follicular lymphoma after first-line treatment with lenalidomide plus rituximab.1-3 The study included patients with follicular lymphoma who were treated between August 2008 and January 2020 at a single center. Responses were evaluated based on the Lugano 2014 criteria.4 Survival results were calculated from the time of second-line therapy. Among 156 patients who met the inclusion criteria, 33 (21%) had relapsed or progressive disease. The 33 patients whose disease had relapsed or progressed included 21 patients (64%) who were 60 years or younger. Eighty-five percent of patients had a hemoglobin level of at least 12 g/dL, and 24% of patients had an elevated level of lactate dehydrogenase. Bone marrow involvement was observed in 22% of patients, and 9% had grade 3a disease. B symptoms were present in 6% of patients, and 97% had Ann Arbor stage III/IV disease. Thirty percent of patients had more than 4 involved nodal areas, and 27% had a high FLIPI score.
The median time to second-line treatment was 33 months (range, 1-122 months). The POD24 rate was 8%, and no patients developed transformation of follicular lymphoma at the time of the first relapse. The median follow-up after the first relapse was 51 months (95% CI, 27-75 months). The response rate to first salvage therapy after first-line lenalidomide plus rituximab was 78%, including a CR rate of 72%, and the median PFS was 38 months (95% CI, 1-82 months). Treatment with chemoimmunotherapy after progression yielded a superior median PFS compared with biologic therapy (99 vs 25 months; P=.004; Figure 6). Follicular lymphoma transformation occurred in 2 patients (7%), at 2 and 20 months after initiation of second-line therapy. With 4 years of follow-up after failure of first-line therapy, the median OS was not reached.
References
1. Morschhauser F, Fowler NH, Feugier P, et al; RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379(10):934-947.
2. Strati P, Jain P, Johnson RJ, et al. Long term follow-up of lenalidomide and rituximab as initial treatment of follicular lymphoma [published online September 15, 2020]. Blood. doi: 10.1182/blood.2020007994.
3. Strati P, Samaniego F, Gallardo M, et al. Treatment and outcome of patients with follicular lymphoma relapsed or progressed after frontline lenalidomide and rituximab [ASH abstract 1128]. Blood. 2020;136(suppl 1).
4. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
Mosunetuzumab Shows Promising Efficacy in Patients With Multiply Relapsed Follicular Lymphoma: Updated Clinical Experience From a Phase 1 Dose-Escalation Trial
Mosunetuzumab is a full-length, humanized, bispecific antibody that binds to CD20 and CD3, thus redirecting T cells to target malignant B cells. The ongoing phase 1/1b GO29781 trial is investigating mosunetuzumab monotherapy in patients with relapsed or refractory B-cell NHL.1 Eligible patients had relapsed or refractory follicular lymphoma of grade 1 to 3a, had received 2 or more prior systemic therapies, and had an ECOG performance status of 0 or 1. Mosunetuzumab was administered in eight 21-day cycles. Dose levels ranged from 0.4 mg to 13.5 mg. Among the 62 patients, the median age was 59 years (range, 27-85 years), and 64.5% were male. High-risk subgroups included 61.3% with double-refractory disease and 46.8% with POD24. Patients had received a median of 3 prior therapies (range, 2-11), and all patients had received prior anti-CD20 therapy and an alkylating agent.
Across all 62 patients, the ORR was 67.7%, including a CR rate of 51.6% (Figure 7). High response rates were observed in high-risk patients. Among patients with refractory disease or POD24, the ORR ranged from 65.2% to 75.9%. Among 13 patients whose disease was refractory to PI3K inhibitors, the ORR was 92.3%. Four patients had received prior treatment with CAR T-cell therapy, and all of these patients demonstrated a response. After a median follow-up of 18.4 months (range, 2-34 months), the median duration of response was 20.4 months (95% CI, 9.4-22.7 months). Among patients who achieved a CR, the median duration of response was slightly higher, at 21.0 months (95% CI, 16.0-22.7 months).
Treatment-related AEs of any grade were observed in 72.6% of patients. Treatment-related serious AEs were noted in 14.5% of patients, and treatment-related AEs of grade 3 or higher occurred in 35.5% of patients. Treatment-related AEs of grade 3/4 included hypophosphatemia (21.0%) and neutropenia (15.1%). All cytokine release syndrome events were grade 1 (n=12) or 2 (n=1). These events occurred in 17.7% of patients during dose escalation in the first treatment cycle. Serious cytokine release syndrome events were observed in 4 patients (6.5%). The median time of onset for cytokine release syndrome was 1 day (range, 1-24 days), and the median duration was 2 days (range, 1-8 days). All cytokine release syndrome events resolved without the use of tocilizumab, admission to an intensive care unit, or use of vasopressors. CR rates were similar among patients who developed cytokine release syndrome (45.5%) and those who did not (52.9%). A phase 3 trial will investigate mosunetuzumab combined with lenalidomide in previously treated patients with follicular lymphoma.2
References
1. Assouline S, Kim WS, Sehn LH, et al. Mosunetuzumab shows promising efficacy in patients with multiply relapsed follicular lymphoma: updated clinical experience from a phase I dose-escalation trial [ASH abstract 702]. Blood. 2020;136(suppl 1).
2. ClinicalTrials.gov. A study evaluating the safety, pharmacokinetics, and efficacy of mosunetuzumab + lenalidomide, glofitamab + lenalidomide, and glofitamab + lenalidomide + obinutuzumab in participants with relapsed or refractory follicular lymphoma. https://clinicaltrials.gov/ct2/show/NCT04246086. Identifier: NCT04246086. Accessed December 17, 2020.
Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients With Relapsed or Refractory Follicular Lymphoma (CITADEL-203)
The CITADEL-203 study evaluated parsaclisib monotherapy in patients with relapsed or refractory follicular lymphoma.1 The study enrolled patients with grade 1, 2, or 3a follicular lymphoma who had received 2 or more prior systemic therapies. Patients in the weekly group received parsaclisib at 20 mg once daily for 8 weeks, followed by parsaclisib at 20 mg once weekly. Patients in the daily group received parsaclisib at 20 mg once daily for 8 weeks, followed by parsaclisib at 2.5 mg once daily. During the study, the daily group regimen was chosen as the preferred regimen. The primary endpoint was ORR based on the 2014 Lugano criteria.2
The study enrolled 125 patients: 23 were treated with the weekly regimen and 102 with the daily regimen. Their median age was 68 years (range, 20-88 years). The median time since the diagnosis of follicular lymphoma was 6 years (range, 0.2-32 years). Seventy-eight percent of patients had Ann Arbor stage III/IV disease, and 46% had a FLIPI risk category of 3 or higher. Patients had received a median of 2 prior therapies (range, 1-8), and 18% of patients had undergone hematopoietic stem cell transplant. The median follow-up was 14.5 months (range, 0.2-28.0 months), and the median duration of parsaclisib therapy was 7.1 months (range, 0.2-21.0 months). The most common reasons for discontinuing parsaclisib were progressive disease (29%) and AEs (19%), followed by patient withdrawal (7%).
Among 118 evaluable patients, the ORR was 73% (95% CI, 64%-81%), with a CR rate of 14%. Among 95 evaluable patients treated in the daily group, the ORR was 75% (95% CI, 65%-83%). A reduction in the target lesion size was observed in 90% (106/118) of evaluable patients across the entire study group, and in 91% (86/95) of evaluable patients treated with the daily regimen. The median duration of response was 15.9 months (95% CI, 12.0 months to not evaluable) among 86 responders in both treatment arms, and 14.7 months (95% CI, 12.0-17.5 months) among 71 responders treated with the daily regimen (Figure 8). The median PFS was 15.8 months (95% CI, 13.2-19.3 months) among 118 evaluable patients from both arms, and also 15.8 months (95% CI, 13.8-19.1 months) among 95 patients treated with the daily regimen.
Across the entire study cohort of 125 patients, the most common AEs of grade 3 or higher were diarrhea (10%) and neutropenia (10%). The most common serious treatment-emergent AEs were diarrhea (7%) and colitis (6%).
References
1. Lynch RC, Paneesha S, Avigdor A, et al. Phase 2 study evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory follicular lymphoma (CITADEL-203) [ASH abstract 2935]. Blood. 2020;136(suppl 1).
2. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
Efficacy and Safety of Tisagenlecleucel in Adult Patients With Relapsed/Refractory Follicular Lymphoma: Interim Analysis of the Phase 2 ELARA Trial
The international phase 2 ELARA trial evaluated the CAR T-cell therapy tisagenlec-leucel in adults patients with relapsed or refractory follicular lymphoma.1 The trial enrolled patients with histologically confirmed follicular lymphoma of grade 1 to 3a. Patients had refractory disease, had relapsed within 6 months of second-line or later therapy, or had relapsed after autologous hematopoietic stem cell transplant. Patients received lymphodepleting chemotherapy followed by a single tisagenlecleucel infusion of 6 × 107 to 6 × 108 CAR T cells. Prior bridging therapy was permitted. The primary endpoint was the CR rate by independent review, based on the 2014 Lugano criteria.2
Among the 97 enrolled patients, the median age was 57 years (range, 29-73 years). Most patients (83.5%) had stage III/IV disease at baseline, and 59.8% had a FLIPI score of 3 or higher. Patients had received a median of 4 (range, 2-13) prior therapies, and 77.3% were refractory to their most recent prior therapy. The median dose was 2.06 × 108 CAR-positive T cells.
At the first interim analysis, the median follow-up was 9.9 months, and 52 patients were evaluable for efficacy. The ORR was 82.7%, with a CR rate of 65.4%. The median duration of response (Figure 9), median PFS, and median OS were not reached. The 6-month PFS was 73.2% (95% CI, 58.2%-83.5%). At the time of data cutoff, 69% of patients had an ongoing response.
Serious AEs and grade 3/4 AEs that were considered related to study treatment were observed in 26.8% and 38.1% of patients, respectively. There were no cases of grade 3/4 cytokine release syndrome or grade 3/4 tumor lysis syndrome. All reported cases of cytokine release syndrome and neurologic events resolved with appropriate management.
References
1. Fowler NH, Dickinson M, Dreyling M, et al. Efficacy and safety of tisagenlecleucel in adult patients with relapsed/refractory follicular lymphoma: interim analysis of the phase 2 ELARA trial [ASH abstract 1149]. Blood. 2020;136(suppl 1).
2. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
Highlights in Relapsed/Refractory Follicular Lymphoma From the 62nd American Society of Hematology Annual Meeting and Exposition: Commentary
Gilles Salles, MD, PhD
Among cases of lymphoma, follicular lymphoma is the second most frequent subtype throughout the United States and Europe.1 The disease is characterized by an indolent course. When follicular lymphoma first manifests, patients usually have few symptoms. Although there are effective first-line treatments, many patients will relapse.2 New treatment interventions are needed for disease control, remission, and improved survival.
Studies presented at the 62nd American Society of Hematology (ASH) meeting provided interesting data regarding several types of treatments for these patients. These treatments included a new generation of phosphoinositide 3-kinase (PI3K) inhibitors; immunotherapies; antibody-drug conjugates; and a newer intervention, tazemetostat, which is an EZH2 inhibitor. Tazemetostat is a first-in-class agent approved by the US Food and Drug Administration for the treatment of lymphoid malignancies. Data for new interventions targeting different pathways brought hope for the treatment of relapsed/refractory follicular lymphoma.
PI3K Inhibitors
Among the PI3K inhibitors already approved for patients with follicular lymphoma in the relapsed/refractory setting are idelalisib, duvelisib, and copanlisib. At the ASH meeting, Dr Pier Luigi Zinzani presented data for the PI3K inhibitor umbralisib.3 Unlike other agents, umbralisib specifically targets the PI3Kδ isoform, as well as the casein kinase 1ε.4 The study enrolled more than 200 patients with indolent disease, including 117 patients with relapsed/refractory follicular lymphoma. Most of the patients had advanced disease. The median number of prior therapies was 3, and approximately one-third of patients were refractory to their previous line of therapy.
The dose of umbralisib was 800 mg/day, and the median duration of exposure was 7.6 months. An interesting finding was that the adverse event (AE) profile of umbralisib appeared to be more limited compared with other PI3K inhibitors.5-7 The main grade 3/4 AEs were diarrhea and neutropenia, each of which occurred in approximately 10% of patients. Grade 3/4 elevated liver enzymes occurred in approximately 7%, a lower rate than that seen with other drugs from this family. There were a few cases of grade 3/4 opportunistic infection (3.4%), rash (1.9%), and pneumonitis (1.0%). Discontinuations owing to AEs were limited. Approximately 3% of patients discontinued treatment after developing transaminase elevations, and 3% discontinued owing to diarrhea.
Among patients with follicular lymphoma, the overall response rate was 45.3%, with 5% achieving a complete response.3 These outcomes are similar to the other PI3K inhibitors.5-7 The median time to response was 4.6 months. The median duration of response was 11.1 months. Subgroup analysis showed that response was not impacted by clinical characteristics such as the number of prior lines of therapy, chemoresistance, or resistance to anti-CD20 antibodies. These important data confirm that umbralisib is effective in follicular lymphoma, with an acceptable tolerability profile.
Dr Ryan Lynch presented results of the CITADEL-203 study, which evaluated the PI3K inhibitor parsaclisib.8 This drug is administered in a unique schedule compared with the other PI3K inhibitors. The CITADEL-203 study evaluated 2 regimens: a weekly schedule, in which parsaclisib was administered at 20 mg once daily for 8 weeks, followed by 20 mg once weekly; and a daily schedule, which consisted of the same loading dose for 8 weeks, followed by 2.5 mg once daily continuously.
The study recruited 125 patients with relapsed/refractory follicular lymphoma. Most patients received the daily regimen. The patients’ characteristics were typical for those with this disease. All had received prior chemotherapy and anti-CD20 agents. Approximately 1 out of 5 patients had undergone prior transplant. Approximately half of patients were refractory to their previous line of therapy. The median duration of treatment with parsaclisib was approximately 7 months. The primary reason for discontinuation was disease progression. Among all patients in the study evaluable for efficacy (n=118), the overall response rate was 73%, which is higher than that typically reported for these types of agents. Approximately 14% of patients achieved a complete response. Many patients had good disease control. The median duration of response was 15.9 months, and the median progression-free survival (PFS) was 15.8 months, confirming the efficacy of this drug.
Approximately half of the patients developed a treatment-emergent AE of grade 3 or higher, most commonly, diarrhea and neutropenia. Elevations in transaminase levels occurred in approximately one-quarter of the patients, but most events were grade 1 or 2. Approximately half of patients required dose modification. Overall, this selective PI3Kδ inhibitor had promising efficacy in this setting, with an expected safety profile. Further research is needed for parsaclisib, as well as for other agents in this class.
Bispecific Antibodies
The ASH meeting provided data for bispecific antibodies, a promising intervention for patients with follicular lymphoma. Many bispecific antibodies are currently in development. At the ASH meeting, updates were given for several of these compounds in lymphoma.9-12 In these studies, the overall response rates ranged from 67% to 90% in patients with relapsed/refractory follicular lymphoma, and the complete response rates ranged from 50% to 70%. The number of patients in these studies remains small, and these data are preliminary. Some of the agents have not reached their optimal dosing and schedule. Side effects, such as cytokine release syndrome, can occur during the first infusion. Cytokine release syndrome should be managed with hospitalization for a day or more, which can represent a burden for patients in this setting.
Dr Sarit Assouline presented results from a phase 1 dose-escalation trial of mosunetuzumab, an anti-CD20 and anti-CD3 bispecific antibody.13 The study recruited 62 patients with relapsed/refractory follicular lymphoma with classic characteristics. Approximately 60% of patients were double refractory, and the median number of prior systemic therapies was 3.
The escalated dose schedule ranged from 0.4 mg to 13.5 mg, administered every 3 weeks. The overall response rate was 67.7%, with a complete response in 51.6%. Interestingly, responses, including complete responses, were reported among patients with an adverse prognosis, such as those who were refractory to the last prior therapy and those who were double refractory. There was a high response rate in patients who were refractory to PI3K inhibitors. Among the 4 patients treated after chimeric antigen receptor (CAR) T-cell therapy, all responded, including 2 patients with a complete response.
The median duration of response was 20 months, suggesting a prolonged efficacy for these patients. The AE profile was similar to that described for other antibodies, but also included neutropenia, infections, and hypophosphatemia. Cytokine release syndrome occurred in 17.7% of patients, with only a few serious cases. The median duration of hospitalization for cytokine release syndrome was 2 days.
CAR T-Cell Therapy
Another category of immunotherapy agents in development for follicular lymphoma are the CAR T-cell therapies. At the ASH meeting, Dr Caron Jacobson presented updated results of the ZUMA-5 study, which evaluated axicabtagene ciloleucel in patients with relapsed/refractory indolent non-Hodgkin lymphoma.14 Results were previously presented at the European Hematology Association congress in June.15 The updated analysis reported results for 124 patients with follicular lymphoma and 22 patients with marginal zone lymphoma. These patients were heavily pretreated, with almost two-thirds having received more than 3 lines of prior therapy. In the cohort of patients with follicular lymphoma, the overall response rate was extremely high, at 94%, with 80% of patients achieving a complete response. Among all patients, the median time to a first response was a rapid 1 month. Among the patients with follicular lymphoma who initially had only a partial response, half later converted to a complete response. Responses were seen regardless of the patients’ tumor burden, number of prior therapies, and exposure to different agents. The median follow-up was 17.5 months. The median duration of response had not been reached. Among the follicular lymphoma patients with a complete response, 78% were still responding at the time of the analysis. The median PFS had not been reached.
The AEs were typical for CAR T-cell therapies, and included cytopenia, cytokine release syndrome, and neurotoxicity. Frequency and severity were somewhat lower than those seen in patients with diffuse large B-cell lymphoma.16 Axicabtagene ciloleucel is therefore a promising intervention for patients with follicular lymphoma.
Dr Nathan Fowler presented preliminary results of another CAR T-cell therapy, tisagenlecleucel.17 The phase 2 ELARA trial enrolled patients with follicular lymphoma from 12 countries. The patients’ characteristics were similar to those enrolled in other studies. The trial recruited 97 patients, but results were reported for 52 patients evaluable for efficacy. The overall response rate was 83%, with 65% of patients achieving a complete response. The median duration of response was not reached.
There was a high rate of conversion from partial remissions to complete remissions, which was also observed frequently in patients treated with 4-1BB CAR T cells. The safety profile was as expected. These results are promising, and longer follow-up is needed.
Antibody-Drug Conjugates
The antibody-drug conjugates in development for follicular lymphoma include polatuzumab vedotin and loncastuximab tesirine. At the ASH meeting, Dr Francisco Hernandez-Ilizaliturri presented data from a phase 1 study of TRPH-222, an antibody-drug conjugate that targets the antigen CD22 with a payload known as maytansine.18 TRPH-222 incorporates a new type of biochemical linker between the payload and the antibody that allows a stable antibody-drug ratio.
Among the 10 patients with follicular lymphoma, the overall response rate was 50%, with a complete response rate of 40%. In some patients with a complete response, the response was maintained after several cycles. TRPH-222 had a similar safety profile as the other antibody-drug conjugates. There were a few infusion-related reactions. The most common grade 3/4 events included thrombocytopenia and neutropenia. Peripheral neuropathy was infrequent and mostly low grade. As with other antibodies that use maytansine, there were some ocular symptoms, an AE that should be considered in future research.
Tazemetostat
There were several presentations about tazemetostat, which is the first EZH2 inhibitor approved by the US Food and Drug Administration for patients with relapsed or refractory follicular lymphoma.19 Approval was based on a phase 2 study that recruited 99 patients with follicular lymphoma, either with or without the EZH2 mutation.20 This mutation occurs in approximately one-quarter of patients with follicular lymphoma.
The recently published results from the phase 2 trial of tazemetostat demonstrated an overall response rate of 69% for patients with the EZH2 mutation and 35% for patients with wild-type disease.20 The median duration of response was 10.9 months in the EZH2-mutated cohort and 13.0 months in the EZH2–wild-type cohort. At the ASH meeting, I presented results of an analysis of the phase 2 trial that aimed to better understand the efficacy of tazemetostat in patients with relapsed follicular lymphoma, when the status of the mutation is not known.21 This analysis of pooled data examined variables that might influence the overall response rate or the duration of response. The analysis found that the overall response rate was similar in patients with normal or high levels of lactate dehydrogenase (LDH) and was not markedly different for patients who were or were not refractory to rituximab. A significantly lower overall response rate was seen in patients who had received more than 2 lines of therapy; this response rate still remained at 40%. Patients who developed progressive disease within 24 months had an overall response rate of 39% vs 60% for the other patients. The variables that predicted duration of response included refractoriness to rituximab and a high LDH level. The median PFS was 19 months among patients who were not refractory to rituximab vs 8 months in those who were. Among patients with normal LDH levels, the median PFS was 16 months vs 7 months in those with high levels. This analysis confirmed that tazemetostat provides good control of follicular lymphoma, which is prolonged for more than 1 year in the majority of patients. Furthermore, patients with or without the EZH2 mutation can benefit from treatment.
David Proudman presented data from a matched, indirect comparison of tazemetostat vs PI3K inhibitors.22 The analysis showed that the response rate did not significantly differ between tazemetostat and the other compounds. The safety of tazemetostat was satisfactory, with less than 20% of patients experiencing mild side effects, such as fatigue or cytopenia, and less than 3% experiencing grade 3/4 events.
Several ongoing studies are evaluating tazemetostat. Dr Krish Patel presented the design of a new study evaluating the combination of tazemetostat plus rituximab for the treatment of relapsed or refractory follicular lymphoma.23 Dr Connie Batlevi presented the design of a large, ongoing randomized trial that is combining tazemetostat with the recently approved regimen of lenalidomide plus rituximab (known as R2).24 The study consists of different stages. The first stage will identify the recommended phase 3 doses of tazemetostat in combination with R2. This stage has almost been completed. The second stage will determine the safety of this combination in a larger number of patients. The randomization with allow patients to receive tazemetostat plus R2, and to continue with tazemetostat as a single agent for a 24-month maintenance phase. Therefore, the investigative arm will consist of 6 cycles of the combination followed by 2 years of maintenance, while the control arm will consist of the usual R2 regimen. This important study will combine epigenetic modulation with immunotherapy. An interesting recent observation is that tazemetostat is able to enhance the expression of several immunomodulatory molecules on the surface of B cells. Tazemetostat may increase and enhance the activity of the R2 regimen. This new study will be a registration trial for this regimen in relapsed/refractory follicular lymphoma.
Rituximab-Based Regimens
Dr Paolo Strati presented a study regarding the efficacy of second-line regimens in patients treated with the R2 regimen in the first line.25 The study showed that immunochemotherapy, rather than biologic therapy, was optimal for this patient group.
A study in newly diagnosed follicular lymphoma compared rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) vs rituximab plus bendamustine with or without rituximab maintenance among patients with high maximum standardized uptake value (SUVmax) on positron emission tomography/computed tomography at diagnosis.26 Dr Patrizia Mondello from our institute presented the results. R-CHOP might reduce the risk of early transformation, although this improvement was not statistically significant. Interestingly, in patients with progressive disease at 2 years, the rate of overall survival was approximately 80%, indicating that we have made progress with new treatments in controlling this disease when early progression occurs.
Treatment During the COVID-19 Pandemic
A current concern for patients with follicular lymphoma is how they will respond to vaccinations against COVID-19. Unfortunately, patients with hematologic malignancies treated with an anti-CD20 antibody had a low immune response to the virus in a study by Dr Alessandra Sottini.27 It will be necessary to mitigate the risk of lymphoma progression vs treatment with anti-CD20 antibodies, especially among patients who will be candidates to receive the vaccine.
Disclosure
In the past 12 months, Dr Salles has received financial compensation for participating in advisory boards or consulting fees from AbbVie, BeiGene, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Janssen, Miltenyi, MorphoSys, Novartis, Roche, and VelosBio. Dr Salles has received financial compensation for participation in educational events from BMS/Celgene, Kite/Gilead, MorphoSys, Novartis, and Roche.
References
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24. Leonard JP, Batlevi CL, Gabrail N, et al. A phase 1b/3 randomized, double-blind, 3-stage study of tazemetostat or placebo plus lenalidomide and rituximab in patients with relapsed/refractory follicular lymphoma [ASH abstract 2052]. Blood. 2020;136(suppl 1).
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26. Mondello P, Strati P, Merryman RW, et al. R-CHOP versus R-bendamustine with or without rituximab maintenance in newly diagnosed follicular lymphoma patients with high SUV at baseline PET [ASH abstract 2041]. Blood. 2020;136(suppl 1).
27. Sottini AS, Imberti L, Paghera S, et al. Impaired Sars-Cov-2 specific antibody responses in patients treated with anti-CD20 antibodies [ASH abstract 2040]. Blood. 2020;136(suppl 1).