Refractory Indolent non-Hodgkin Lymphoma Research Articles

Safety and activity of lenalidomide in combination with obinutuzumab in patients with relapsed indolent non-Hodgkin lymphoma: a single group, open-label, phase 1/2 trial

Rituximab and lenalidomide is a preferred option for relapsed indolent B cell non-Hodgkin lymphoma. Obinutuzumab may be a superior combination partner with lenalidomide given enhanced antibody dependent cellular cytotoxicity and phagocytosis compared to rituximab. Our aim was to determine the recommended phase 2 dose, safety, and activity of lenalidomide in combination with fixed dose of obinutuzumab in relapsed and refractory indolent B cell non-Hodgkin lymphoma. In this single-arm, open-label, phase 1/2 trial, we enrolled patients with relapsed or refractory WHO Grade 1-3A follicular lymphoma, marginal zone lymphoma and small lymphocytic lymphoma and adequate performance status (ECOG 0-2) at the MD Anderson Cancer Center. We excluded patients with evidence of ongoing transformation to aggressive lymphoma. During phase 1, 1000mg intravenous obinutuzumab was administered with three predefined levels of oral lenalidomide in a 3+3 dose escalation design to establish lenalidomide 20mg as the recommended phase 2 dose. During phase 2, patients received induction therapy with six 28-day cycles of lenalidomide 20mg with intravenous obinutuzumab 1000mg. In accordance with our prior experience with lenalidomide plus rituximab, patients who were responding to the combination could receive up to 6 additional cycles (up to 12 cycles in total) of combination therapy. Dosing of obinutuzumab was continued in all responding patients after cycle 6 every 2 months for a total of 30 months from the start of therapy. The decision of number of cycles of combination therapy beyond 6 was at discretion of the investigator and was included to allow individualisation of therapy to maximise response while minimising exposure. The co-primary objectives were to evaluate the safety and overall response, defined as the proportion of patients who achieved a complete or partial response in relapsed and refractory indolent non-Hodgkin lymphoma at the end of induction therapy, according to Cheson and colleagues (2007 criteria). The secondary endpoints were complete response after induction therapy and time to event endpoints including time to progression, progression free survival, and overall survival. Analyses were intent to treat in the efficacy cohort and per-treated in the safety population in all patients who received at least one dose of either investigational agent. This trial is registered with ClinicalTrials.gov, NCT01995669. Between June 03, 2014, and 07 March 2019, we completed planned enrolment, and 66 patients started therapy including 9 patients in phase 1 and 57 patients in phase 2. All patients were evaluated for safety and the 60 patients treated at the recommended phase 2 dose of lenalidomide 20mg were evaluable for activity. Grade 3-4 haematological toxicities included neutropenia 21% (14/66) and thrombocytopenia 11% (7/66) with no cases of febrile neutropenia. Grade 3-4 non-haematological toxicities included lung infection 8% (5/66), fatigue 8% (5/66) and rash 6% (4/66). By Cheson 2007 criteria, 90% (54/60, 95% CI: 79-96) achieved an overall response at the end of induction meeting the prespecified activity endpoint. Complete responses were seen in 33% (20/60, 95% CI: 22-47) at the end of induction. Median progression free survival, time to progression and overall survival have not been reached after median follow-up of 41.7 months. Estimated 4-year progression free survival rates were 55% (95% CI: 42-73), time to progression of 56% (95% CI: 43-74) and overall survival of 84% (95% CI: 74-95). Our findings suggest that oral lenalidomide with obinutuzumab is safe and highly active in patients with relapsed and refractory indolent B cell non-Hodgkin lymphoma and is associated with prolonged remission duration. The study is limited by the lack of a control arm leading to cross-trial comparisons to evaluate activity. Future randomised trials comparing this regime to rituximab and lenalidomide are warranted. Genentech and an MD Anderson Core grant.

Phase I safety and preliminary efficacy of IMM0306 in combination with lenalidomide in patients with relapsed or refractory CD20-positive B-cell non-Hodgkin's lymphoma.

e19040 Background: The combination of rituximab (anti-CD20 mAb) and lenalidomide was approved for use in relapsed or refractory (R/R) indolent non-Hodgkin's lymphoma (iNHL). IMM0306 is a fusion protein of CD20 monoclonal antibody with the CD47 binding domain of SIRPα on both heavy chains. It exerts excellent cancer killing efficacy by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement. Here, we report on a Phase I study of 8 patients (pts) with R/R CD20-positive B-cell NHL. Methods: This is an open-label, multicenter phase I study (NCT05771883). The study is designed to use "3+3" scheme for dose escalation exploring in 2 dose levels of IMM0306 (1.6 mg/kg, 2.0 mg/kg), intravenously administered each week in each 28-day cycle; while lenalidomide will be administered as fixed dose of 20 mg for NHL, taken orally once daily for the first 21 days of each 28-day cycle to determinate maximum tolerated dose (MTD). Dose-limiting toxicity (DLT) was evaluated in the first 28 days of the combination therapy. Safety was evaluated per CTCAE 5.0, tumor assessments performed once every 8 weeks by Lugano 2014. Results: As of Jan 5, 2024, 8 pts with R/R follicular lymphoma (FL, n=6) and marginal zone lymphoma (MZL, n=2) were enrolled. The median age was 52.5 years with 7 (87.5%) males. The median prior line of therapy was 1. All pts received previous anti-CD20 therapy. Among 7 efficacy evaluable pts, 1 CR (FL), 4 PR (2 FL, 2 MZL), and 1 SD were seen. The ORR and DCR were 71.4% and 85.7%, respectively. Two DLTs (grade 4 PLT decreased without bleeding) were observed at 2.0 mg/kg IMM0306 + 20 mg Lenalidomide dose level, but none at the dose level of 1.6 mg/kg IMM0306 + 20 mg Lenalidomide. The most common treatment related adverse events (TRAEs) were lymphocyte decreased (62.5%), ANC decreased (62.5%), WBC decreased (50%), anemia (50%), bilirubin increased (50%), PLT decreased (37.5%), infusion-related reactions (37.5%). Grade ≥3 TRAEs occurred in 6 pts, including lymphocyte decreased (62.5%), PLT decreased (25%), WBC decreased (12.5%), ANC decreased (12.5%) and pneumonia (12.5%). One pt experienced treatment related serious adverse event. 5 patients experienced TRAEs, leading to the study drug interruption, while no patients experienced TRAEs leading to the study drug discontinuation or death. 2 pts had a dose reduction of IMM0306 (2.0 mg/kg dose level), 3 pts had dose reductions of lenalidomide due to TRAEs. Pharmacodynamics analysis demonstrated IMM0306 combine lenalidomide effectively depleted B cell in peripheral blood within 24 hours. Conclusions: 1.6 mg/kg IMM0306 in combination with 20 mg lenalidomide was well-tolerated and with a robust preliminary anti-tumor activity in pts with R/R FL and MZL. The phase I study is ongoing. Clinical trial information: NCT05771883 .

Five-Year Results and Overall Survival Update from the Phase 3 Randomized Study Augment: Lenalidomide Plus Rituximab (R2) Vs Rituximab Plus Placebo in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Background: The combination of lenalidomide + rituximab (R2) showed superior efficacy vs rituximab + placebo (R-placebo) in patients (pts) with relapsed refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) (Leonard et al. J Clin Oncol 2019). Based on these AUGMENT study results, R2 was approved for the treatment of adult pts with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL) in the US, Japan, and Brazil, and for FL in Europe. Reported here are updated long-term follow-up results from AUGMENT. Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase 3 study of R2 vs R-placebo (control) in pts with FL grade 1-3a or MZL who were previously treated with ≥ 1 prior systemic therapy with documented relapsed or refractory disease but not refractory to rituximab (refractory was defined as < partial response to rituximab or rituximab-chemotherapy OR disease progression < 6 mo after last rituximab dose). Pts were stratified by prior rituximab treatment (yes vs no), time since last antilymphoma therapy (≤ 2 vs > 2 y), and histology (FL vs MZL), and then randomized 1:1 to R2 or control for up to 1 y. R2 pts received oral lenalidomide 20 mg/d, d1-21/28 for 12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2-5. Control pts received rituximab and placebo on the same schedule. Dose modifications were prespecified in the protocol to manage toxicities. The primary endpoint was progression-free survival (PFS) per 2007 IWG criteria without PET as assessed by Independent Review Committee (IRC; central review). During the follow-up period, pts were followed every 6 mo to assess endpoints, including overall survival (OS), time-to-next antilymphoma treatment (TTNLT), progression, second primary malignancies (SPMs), and histological transformation. Results: A total of 358 pts were randomized (n = 178 R2; n = 180 control); baseline characteristics were similar in both groups. As of January 26, 2022 at a median follow-up of 65.9 mo, median PFS per 2007 IWG criteria as assessed by Investigator was 27.6 mo for R2 vs 14.3 mo for control, with HR = 0.50 (95% CI, 0.38-0.66; P < 0.0001). Although median OS was not reached for either group, there was an improvement in OS for R2 (HR = 0.59, 95% CI, 0.37-0.95, P = 0.0285; Figure). 5-y OS rates for the R2 vs control groups were 83.2% (95% CI, 76.3-88.3) vs 77.3% (95% CI, 70.1-83.1). Median TTNLT (after 12 cycles of time-limited therapy) was 73.1 mo for R2 vs 31.8 mo for control with HR = 0.53 (95% CI, 0.39-0.71; P < 0.0001). In the R2 group, 73 pts (41%) received ≥ 1 subsequent antilymphoma treatment compared with 109 (61%) in the control group, most commonly rituximab in both groups (25% and 34%). 3 (2%) and 5 (3%) pts received lenalidomide as part of any subsequent anti-lymphoma treatment in the R2 and control groups, respectively. The updated overall safety profile of both groups was consistent with the 1st analysis. SPMs occurred in 13 (7%) R2-treated and 21 (12%) control pts, an increase from 6 (3%) and 10 (6%), respectively, in the previous analysis. 9 pts died of SPM (n = 3 R2, n = 6 R-placebo), an increase from 2 pts (both R-placebo) in the previous analysis. The incidence rate of SPMs per 100 y was 1.62 (95% CI, 0.94-2.78) in the R2 group vs 2.66 (95% CI, 1.73-4.07) in the control group. Fewer histological transformations occurred in the R2 arm than in the control group (n = 10 vs n = 15, respectively). The updated incidence rate of histological transformation in the overall population was 1.24% (95% CI, 0.66-2.3) in the R2 arm and 1.85% (95% CI, 1.12-3.07) in the control arm. Conclusions: R2 continues to demonstrate superior efficacy over rituximab monotherapy (plus placebo) as measured by the primary endpoint of PFS (as assessed by Investigator in long-term follow up). The updated results for OS are consistent with the improvement observed in PFS. The OS KM curve separation after 5 y continues to favor R2, providing evidence for a survival benefit. The updated TTNLT KM curves continue to demonstrate that fewer R2-treated patients needed subsequent antilymphoma treatment to date, well beyond the 1-y treatment period. The safety profile of R2 and R-placebo remain consistent with the primary analysis, with continued lower rates of SPM and rates of histologic transformation comparable to historical experience. These updated results, including OS data, provide further support for the use of the R2 regimen as a standard of care for pts with R/R iNHL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.

The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.

A phase I pharmacokinetic study of copanlisib in Chinese patients with relapsed indolent non-Hodgkin lymphoma

Copanlisib, a pan-PI3K inhibitor, has previously shown clinical efficacy and a tolerable safety profile in patients with indolent non-Hodgkin lymphoma. However, the pharmacokinetics, safety, tolerability, and efficacy of copanlisib in Chinese patients have not been reported. This was a single-arm, open-label, phase I study of copanlisib in Chinese patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL). Patients received a single intravenous 60mg infusion of copanlisib over 1h on days 1, 8, and 15 of a 28-day cycle, with 1week of rest. Safety was monitored throughout the study, and plasma copanlisib levels were measured for pharmacokinetic analysis. Tumor response was determined by independent central radiologic review. Sixteen patients were enrolled and 13 were treated with 60mg of copanlisib for a median of 15.0weeks. With a Cmax of 566μg/L and a AUC (0-24) of 1880μg·h/L following single intravenous infusion, the pharmacokinetic parameters of copanlisib were consistent with that in previous studies, and no accumulation in plasma was observed. Treatment-emergent adverse events were reported for all 13 patients, the most common of which were hyperglycemia (100.0%), hypertension (76.9%), decreased neutrophil count (76.9%), and decreased white blood cell count (69.2%). Seven out of 12 evaluated patients achieved partial response, resulting in an overall response rate of 58.3% CONCLUSIONS: Copanlisib was well tolerated in Chinese patients with relapsed or refractory iNHL at the dose of 60mg and demonstrated encouraging disease control, thus warranting further clinical investigation. NCT03498430 (April 13, 2018).

CAR T-cell therapy for indolent lymphoma: a new treatment paradigm?

Comprised of heterogeneous, chronic lymphomas that generally have a lingering, protracted course, indolent non-Hodgkin lymphoma remains difficult to cure. In those with early disease progression and recurrent relapse when responses to second-line and third-line therapies are suboptimal, and a high risk of transformation to more aggressive lymphomas is seen, novel approaches are needed. In The Lancet Oncology, Caron A Jacobson and colleagues1 report the results of the ZUMA-5 trial, a multicentre, single-arm, phase 2 study of axicabtagene ciloleucel for treatment of relapsed or refractory indolent non-Hodgkin lymphoma.

INDUCTION R2 FOLLOWED BY MAINTENANCE IN PATIENTS WITH RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA: INTERIM ANALYSIS FROM THE PHASE 3B MAGNIFY STUDY

The combination of lenalidomide + rituximab (R 2 ) has shown complementary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (NHL), as well as mantle cell lymphoma (MCL), an uncommon but aggressive form of NHL. The MAGNIFY phase 3 trial previously reported an ORR of 54% in patients with R/R MCL (Sharman J, et al. Hematol Oncol . 2019). Presented here are updated analyses from this trial. MAGNIFY is a multicenter, phase 3b trial (NCT01996865) in patients with R/R follicular lymphoma (FL) grades 1–3b, transformed FL, marginal zone lymphoma, and MCL. Lenalidomide 20 mg on d 1–21 of a 28-d cycle + rituximab 375 mg/m 2 /wk cycle 1 and then every 8 wk starting with cycle 3 (R 2 ) is given for 12 cycles followed by 1:1 randomization in patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R 2 vs rituximab maintenance for 18 mo. The primary end point is progression-free survival (PFS) by 1999 International Working Group (IWG) criteria. Secondary end points include safety, CR rate, duration of response (DOR), duration of CR (DOCR), time-to-response (TTR), time-to-next antilymphoma therapy, and overall survival. This analysis evaluates the interim primary endpoint of overall response rate (ORR) by 1999 IWG criteria and safety of R 2 induction in patients with MCL in the induction intention-to-treat population. As of August 28, 2020, 73 patients with MCL were enrolled (median age, 70.0 y [range, 51–88]); 89% had stage III/IV disease, and 41% had bulky disease (> 7 cm or > 3 cm ×3 lymph nodes). All patients had received prior rituximab-containing therapy, with 25 (34%) rituximab refractory (progression ≤ 6 mo after last rituximab dose). Seven patients (10%) had received prior ibrutinib. Median follow-up was 31.7 mo for patients still alive. ORR was 51%, with 34% CR rate (CR + CRu). Response rates were similar in patients refractory to rituximab (ORR = 48%, CR/CRu = 32%) and patients not refractory to rituximab (ORR = 52%, CR/CRu = 35%). Median DOR was 31.6 mo; median DOCR was not reached; median TTR was 2.8 mo, and median PFS was 28.0 mo, with 1-year PFS rate of 57%. The most common treatment emergent adverse events (TEAEs) of any grade were neutropenia (51%), fatigue (44%), diarrhea (32%), constipation (28%), cough (28%), dyspnea (26%), and nausea (26%). Grade 3/4 neutropenia was 46%; all other grade 3/4 TEAEs were ≤ 11%. R 2 is an active and tolerated regimen with durable responses among patients with R/R MCL and mostly naive to Bruton tyrosine kinase inhibitor therapy. These results suggest that R 2 should be considered as a therapeutic option for patients with R/R MCL.

IBCL-203: Umbralisib, a PI3Kδ/CK1ε Dual Inhibitor Demonstrates Marked Clinical Activity in Patients with Relapsed or Refractory Indolent Non-Hodgkin Lymphoma (iNHL): Results from the Phase 2 Global UNITY-NHL Trial

Background Umbralisib is an oral, once-daily inhibitor of PI3Kδ and CK1e that is highly selective for the delta isoform. The UNITY-NHL trial (NCT02793583) is a multicenter, open-label, Phase 2b study evaluating umbralisib in previously treated NHL patients. Herein, we present results from the UNITY-NHL study. Methods 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, SLL) unresponsive to prior treatments (≥1 MZL; ≥2 FL/SLL), including ≥1 anti-CD20–based therapy, were administered umbralisib 800mg orally once-daily until disease progression, unacceptable toxicity, or study withdrawal. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee, according to the revised IWG criteria. Results At a median follow up of 27.8 months, MZL patients (n=69) had an ORR of 49.3% (95% CI 37.0% - 61.6%) with 15.9% achieving a complete response (CR), and a Disease Control Rate (DCR: CR+PR+SD) of 82.6%. Median time-to-response (TTR): 2.8 months (95% CI 2.7 - 2.9). No patient who achieved CR has progressed to date. At a median follow up of 27.5 months, FL patients (n=117) had an ORR of 45.3% (95% CI 36.1% - 54.8%) with 5.1% achieving a CR, and a DCR of 79.5%. Median TTR: 4.6 months (95% CI 3.0 - 5.6). At a median follow up of 29.3 months, SLL patients (n=22) had an ORR of 50.0% (95% CI 28.2 - 71.8) with 4.5% achieving a CR, and a DCR of 86.4%. Median TTR: 2.7 months (95% CI 2.4 - 2.8). At least one grade ≥3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). Grade ≥3 TEAEs reported in ≥10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥3) occurred in 6.7%/7.2% of patients. Conclusions Umbralisib achieved meaningful clinical activity in a heavily pretreated iNHL population. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and AE-related discontinuations. These results suggest umbralisib has a favorable benefit-risk profile in this patient population and have supported the Accelerated Approval of umbralisib in previously treated MZL and FL patients.

Efficacy and safety assessment of prolonged maintenance with subcutaneous rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma: results of the phase III MabCute study.

Rituximab plus chemotherapy induction followed by rituximab maintenance for up to 2 years confers a long-term benefit in terms of progression-free survival in patients with indolent non-Hodgkin lymphoma. It is not known whether further prolonged maintenance with rituximab provides additional benefit. The phase III MabCute study enrolled 692 patients with relapsed or refractory indolent non-Hodgkin lymphoma. Patients who responded to induction with rituximab plus chemotherapy and were still responding after up to 2 years’ initial maintenance with subcutaneous rituximab were randomized to extended maintenance with subcutaneous rituximab (n=138) or observation only (n=138). The primary endpoint of investigator-assessed progression-free survival in the randomized population was un-addressed by the end of study because of an insufficient number of events (129 events were needed for 80% power at 5% significance if approximately 330 patients were randomized). In total, there were 46 progression-free survival events, 19 and 27 in the rituximab and observation arms, respectively (P=0.410 by stratified log-rank test; hazard ratio 0.76 [95% confidence interval: 0.37– 1.53]). The median progression-free survival was not reached in either randomized arm. There were no new safety signals; however, adverse events were seen slightly more frequently with rituximab than with observation during extended maintenance. Maintenance for up to 2 years with rituximab after response to initial induction therefore remains the standard of care in patients with relapsed or refractory indolent non- Hodgkin lymphoma. (Clinicaltrials.gov identifier: NCT01461928)

Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial

Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4-28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8-33·0) versus 13·8 months (10·2-17·5; hazard ratio 0·52 [95% CI 0·39-0·69]; p<0·0001). The most common grade 3-4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group. Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma. Bayer.

PI3Kδ-CK1ε Inhibitor Umbralisib Shows Promise in R/R Indolent NHL.

Umbralisib showed efficacy and in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (NHL).

Lenalidomide: A Review in Previously Treated Follicular Lymphoma.

Lenalidomide (Revlimid®) is a targeted immunomodulatory drug with multiple mechanisms of action. In the USA and the EU, oral lenalidomide is indicated in combination with rituximab or a rituximab product for the treatment of patients with previously treated follicular lymphoma. In the pivotal, phaseIII AUGMENT trial, lenalidomide + rituximab significantly prolonged progression-free survival (PFS; primary endpoint) relative to placebo + rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma, with the PFS benefit appearing to be specific to patients with follicular lymphoma and extending to elderly patients with this subtype. Lenalidomide + rituximab also demonstrated activity in an interim analysis of the phaseIII MAGNIFY trial in patients with relapsed or refractory indolent non-Hodgkin lymphoma, including those with rituximab-refractory disease. Lenalidomide had an acceptable tolerability profile. Although grade3 or 4 neutropenia occurred more frequently with lenalidomide + rituximab than with placebo + rituximab, this was generally well managed with dosage adjustments and growth factor support. In conclusion, lenalidomide in combination with rituximab represents an important new treatment option for previously treated follicular lymphoma, including patients whose disease has become refractory to rituximab.

PI3K Inhibitors and Their Role as Novel Agents for Targeted Therapy in Lymphoma.

Phosphatidylinositol 3-kinase (PI3K) inhibitors represent a novel class of agents targeting the key cellular regulatory PI3K/AKT/mTOR pathway involved in crucial functions such as cellular proliferation, cell cycle regulation, protein synthesis, and cell motility. This review starts with an overview of the PI3K pathway and the rationale for its targeting in lymphoma and potential on-target side effects of PI3K inhibition. With three agents now FDA approved for the treatment of relapsed and refractory (R/R) indolent non-Hodgkin lymphoma (iNHL), idelalisib, copanlisib, and duvelisib, we aim to review the pivotal trials leading to their approval as well as their clinical applications according to lymphoma subtypes. Important treatment-related adverse events are also reviewed and a perspective on the clinical role of these agents is provided, as well as some practical guidance on how to prevent, monitor, and manage potential adverse events in the clinic. PI3K inhibitors have an established role in the management of R/R iNHL, but their use and development are hampered by adverse events, particularly when used in combination with other anti-lymphoma therapies. Finally, this review highlights areas in need of more research in order to optimally use these agents in the care of patients with lymphoma.

Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy &gt;180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy &gt;180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy &gt;180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy &gt;180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT &gt;180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

Survival Outcomes Following Idelalisib Interruption in the Treatment of Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Survival Outcomes Following Idelalisib Interruption in the Treatment of Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Matching Adjusted Indirect Comparison to Assess the Relative Efficacy of Idelalisib in Double-Refractory Follicular Lymphoma

BackgroundIdelalisib, an oral, first-in-class, selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, is approved in the US and Europe as monotherapy for relapsed/refractory follicular lymphoma (FL). Its safety and efficacy were primarily established from a Phase 2 study in patients with double-refractory FL, which carries a poor prognosis and has no current standard of care. As this was a single-arm trial, data regarding the relative efficacy of idelalisib compared to other regimens used in this population are limited. Therefore, we conducted a Matching-Adjusted Indirect Comparison (MAIC) to derive measures of relative efficacy of idelalisib versus other therapies in double-refractory FL using a well-established registry.MethodsStudy 101-09 was a Phase 2, multi-centre, single-arm, open-label trial of 125 patients with relapsed or refractory indolent non-Hodgkin's lymphoma (iNHL) treated with idelalisib monotherapy which included 72 patients (58%) with FL. Summary data from this Phase 2 trial were compared with individual level patient data from the HMRN (Haematological Malignancy Research Network). HMRN is an ongoing population-based cohort registry in the Northern UK that includes a population of 3.8 million and collects information on all haematological malignancies in the region.This analysis included all patients newly diagnosed with FL from 1st Sep 2004 to 31st Aug 2013. Outcomes in patients who had received ≥ 2 prior lines of chemo/immuno-chemotherapy and were refractory to both rituximab and an alkylating agent, or had a relapse within 6 months after receipt of those therapies and were subsequently treated, were examined. MAICs were conducted in order to match to the characteristics reported of the trial population using previously described methodology.ResultsIn total, 1,007 patients were newly diagnosed with FL during the index period, of whom 675 received treatment either from time of diagnosis (n=556) or after a period of ‘watch and wait’ (n=119); the majority of patients were treated with chemotherapy (n=520), with 155 receiving radiotherapy. The most common regimen at first line was R-CVP (n=304) followed by R-CHOP (n=135). Number of patients receiving second line therapy was 185 either due to relapse (n=136) or being refractory to first line therapy (n=49), the most common regimens were R-CVP, R-CHOP and other agents such as DHAP or bendamustine. Overall, 68 patients received third line treatment, the most common being chlorambucil-based (19.1%), fludarabine-based (6.8%) and DHAP (20.6%); the overall response rate was 58.8%. In the 675 patients treated with therapy, survival diminished by treatment line with respective 5-year OS being 74.7% in first line, 50.6% in second line and 39.3% in third line.Twenty-six patients had received two or more prior regimens, were refractory to both rituximab and an alkylating agent, or had a relapse within 6 months of those therapies and were subsequently treated with chemotherapy - this cohort was used for MAIC against the 101-09 study population. Demographically, both populations were relatively similar. Since HMRN included patients as soon as they reached the eligibility criteria, differences were seen in time since diagnosis and the median prior therapies, suggesting that patients with higher risk disease and a poorer prognosis may have been identified. Accordingly, HMRN patients had a poorer 2-year OS than trial patients (46.2% vs 69.8%). The variables included were: age (62 < or ≥62), sex, stage III/IV disease, bulky disease and time from diagnosis (< or ≥4.7y). The results of the MAIC analyses pre and post matching were as follows: 2 year OS decreased from 46.2% to 19.8% after matching and 1-year PFS decreased from 57.7% to 24.7%; the respective 2-year OS of the trial population was 69.8% and 1-year PFS of 43.0% demonstrating favourable efficacy of idelalisib in this population.ConclusionThis MAIC analysis using real-world data suggests that idelalisib provides superior efficacy relative to the other therapies used for the treatment of patients with FL who are refractory to two prior lines. The small effective sample size is a potential limitation of this analysis, along with the possible converse effect on prognosis associated with time since diagnosis between the two studies. However, the favourable efficacy of idelalisib remained when the analysis was repeated excluding time from diagnosis (2-year OS 39.9%). DisclosuresRajakumaraswamy:Gilead Sciences: Employment. Lovato:Gilead Sciences: Employment. Smith:Gilead Sciences: Employment. Bagguley:Gilead Sciences: Consultancy. Smith:Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Research Funding; Novartis: Research Funding; Gilead Sciences: Consultancy. Patmore:Roche: Consultancy; Gilead Sciences: Consultancy. Marcus:Gilead Sciences: Consultancy; Roche/ Genentech: Consultancy, Honoraria.

Abstract CT146: First-in-human phase I combination of the IL-15 receptor super agonist complex ALT-803 with a therapeutic (anti-CD20) monoclonal antibody (mAb) for patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL)

Abstract Immunotherapy is an effective modality for cancer treatment. IL-15 is a cytokine that stimulates CD8+ T cell and NK cell survival, metabolism, and anti-tumor immunity. We hypothesized that IL-15 therapy will augment anti-cancer immune responses in concert with tumor-targeting therapeutic mAbs. Pre-clinical studies have shown that the IL-15 receptor super agonist complex, ALT-803, enhanced the anti-tumor effects of anti-CD20 mAb against iNHL in vitro and in vivo (Rosario M et al., Clin Ca Res, 2016). Here, we conducted the first clinical study combining ALT-803 with a tumor-targeting mAb, in patients with rel/ref iNHL. A total of 21 iNHL patients [N=16 FL (FLIPI low: 4, int: 4, high: 8), N=4 MZL, N=1 SLL] were treated. Median age was 64 years (range 54-81), median number of prior therapies was 2 (range 1-18), and 5 patients were refractory to prior anti-CD20 mAb therapy. Treatment included an induction cycle of 4 weekly doses of rituximab (375 mg/m2 intravenously, IV) and ALT-803. The ALT-803 dose levels were 1, 3, and 6 mcg/kg IV followed by 6, 10, 15, and 20 mcg/kg subcutaneously (SC, N=3 per dose level). In patients with SD, PR or CR, consolidation therapy with ALT-803 (at the same dose level) and rituximab was then administered every 8 weeks for 4 cycles. No dose limiting toxicities were observed, and the recommended phase 2 dose was 20 mcg/kg SC. Overall ALT-803 was well tolerated with no grade 4 or 5 adverse events. Grade 3 AEs (regardless of attribution to ALT-803) included transient hypertension (14%), anemia (5%), nausea (5%), chills (5%), fever (5%), neutropenia (5%), and hyperglycemia (5%). Patients who received ALT-803 SC had a self-limited injection site reaction. To date, best ORR was 10/21 (48%), with 7 CR, 3 PR, 8 SD (all with decreased tumor volume), and 3 PD. Of the 12 patients treated with SC ALT-803, only 1 patient had PD, with the remainder receiving ongoing consolidation. In the 5 rituximab-refractory patients we observed 1 CR, 2 SD (45% and 36% tumor volume decrease), and 2 PD. PK analysis showed that SC ALT-803 administration resulted in a lower Cmax and prolonged blood levels compared to IV. At the 15 and 20 mcg/kg SC dose levels of ALT-803, NK cells were significantly increased by percentage (mean peak 30+5%, 6-fold, P&amp;lt;0.001) and number (mean peak 687+347/uL, 10-fold, P&amp;lt;0.001). This was accompanied by a marked increase in proliferation (Ki67, 97+0.5%, P&amp;lt;0.001) and activation (CD69, 10-fold, P&amp;lt;0.01) in vivo. CD8+ T cell number (2-fold, P&amp;lt;0.01) and proliferation (Ki67, 56+6%, P&amp;lt;0.001) were also significantly increased, without increases in CD4+ or regulatory T cell numbers. Patient NK cells exhibited enhanced functional responses (degranulation and IFN-γ production) against anti-CD20 mAb coated NHL targets after ALT-803 administration, compared to pre-ALT-803 samples. NK cells (P&amp;lt;0.05) and CD8 T cells (P&amp;lt;0.05) were also increased at the 6 and 10 mcg/kg SC ALT-803 levels. Thus, the immunostimulatory IL-15-based agent ALT-803 may be safely combined with a therapeutic mAb to significantly enhance NK and CD8+ T cell number and function in patients with iNHL. Phase 2 testing is underway in iNHL. Clinical investigations combining ALT-803 with additional therapeutic mAbs, complementary types of immunotherapy, and in additional malignancies are warranted. Citation Format: Todd A. Fehniger, Brian T. Hess, Veronika Bachanova, Michelle Becker-Hapak, Ethan McClain, Melissa Berrien-Elliott, Julia Wagner, Nancy L. Bartlett, Brad Kahl, Neha Mehta-Shah, Amanda F. Cashen, Feng Gao, Kyle Conradi, Amy D. Rock, Emily K. Jeng, Liza Hernandez, Jack O. Egan, Peter R. Rhode, Hing C. Wong. First-in-human phase I combination of the IL-15 receptor super agonist complex ALT-803 with a therapeutic (anti-CD20) monoclonal antibody (mAb) for patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT146.

Long-term outcomes, secondary malignancies and stem cell collection following bendamustine in patients with previously treated non-Hodgkin lymphoma.

Despite the long history of bendamustine as treatment for indolent non-Hodgkin lymphoma, long-term efficacy and toxicity data are minimal. We reviewed long-term data from three clinical trials to characterize the toxicity and efficacy of patients receiving bendamustine. Data were available for 149 subjects at 21 sites. The median age was 60years at the start of bendamustine (range 39-84), and patients had received a median of 3 prior therapies. The histologies included grades 1-2 follicular lymphoma (FL; n=73), grade 3 FL (n=23), small lymphocytic lymphoma (n=20), marginal zone lymphoma (n=15), mantle cell lymphoma (n=9), transformed lymphomas (n=5), lymphoplasmacytic lymphoma (n=2) and not reported (n=2). The median event-free survival was 14·1months. Nine of 12 attempted stem cell collections were successful. With a median follow-up of 8·9years, 23 patients developed 25 cancers, including 8 patients with myelodysplastic syndrome/acute myeloid leukaemia. These data provide important information regarding the long-term toxicity of bendamustine in previously treated patients. A small but meaningful number of patients achieved durable remissions following bendamustine. These rigorously collected, patient-level, long-term follow-up data provide reassurance that bendamustine or bendamustine plus rituximab is associated with efficacy and safety for patients with relapsed or refractory indolent non-Hodgkin lymphoma.

Obinutuzumab plus Bendamustine Followed by Obinutuzumab Maintenance Prolongs Overall Survival Compared with Bendamustine Alone in Patients with Rituximab-Refractory Indolent Non-Hodgkin Lymphoma: Updated Results of the GADOLIN Study

Obinutuzumab plus Bendamustine Followed by Obinutuzumab Maintenance Prolongs Overall Survival Compared with Bendamustine Alone in Patients with Rituximab-Refractory Indolent Non-Hodgkin Lymphoma: Updated Results of the GADOLIN Study

Bendamustine and rituximab for the treatment of relapsed indolent and mantle cell lymphoma: when timing of a study matters

In a recent issue of The Lancet Oncology , Rummel and colleagues reported the mature results of StiL NHL 2-2003, a multicenter, randomized, open-label, non-inferiority phase 3 trial comparing bendamustine plus rituximab (BR) with fludarabine plus rituximab (FR) in patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) or mantle-cell lymphoma (MCL) (1). When this study was conceived, fludarabine-containing regimens were widely used, and rituximab was rapidly being integrated into the chemotherapy regimens for CD20-positive lymphomas ( Table 1 ) (12). This study and others reintroduced bendamustine for the treatment of lymphoid neoplasms after its long clinical abeyance. In fact, the authors reported the results of a simultaneous trial, the StiL NHL 1-2003, demonstrating the superiority of BR as compared to rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) in patients with newly diagnosed iNHL or MCL (13).