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Polatuzumab vedotin plus rituximab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study

Abrisqueta, Pau; González-Barca, Eva; Panizo, Carlos; Pérez, José María Arguiñano; Miall, Fiona; Bastos-Oreiro, Mariana; Triguero, Ana; Banerjee, Lalita; McMillan, Andrew; Seymour, Erlene; Hirata, Jamie; de Guzman, Jayson; Sharma, Sunil; Jin, Hyun Yong; Musick, Lisa; Diefenbach, Catherine
BACKGROUND:Diffuse large B-cell lymphoma comprises nearly 30% of non-Hodgkin lymphoma cases and patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for stem-cell transplantation have few treatment options and poor prognoses. We aimed to determine whether the novel combination of polatuzumab vedotin in combination with rituximab and lenalidomide (Pola+R+Len) would provide a tolerable treatment option with enhanced antitumour response in patients with relapsed or refractory diffuse large B-cell lymphoma. METHODS:on day 1 and lenalidomide 10 mg/day on days 1-21 of each 28-day cycle for a maximum of 6 cycles. The primary safety objective of the dose-escalation phase was identification of the maximum tolerated dose through incidence of dose-limiting toxic effects. The primary efficacy outcome of the dose-expansion phase was Independent Review Committee-assessed complete response rate at end of induction, based on PET-CT. Analyses were conducted in the safety population, which included all patients who received at least one dose of any study drug, and the efficacy population, which included all patients who received at least one dose of any study drug at the recommended phase 2 dose. This study is registered with, number NCT02600897. FINDINGS/RESULTS:Between July 11, 2017 and Feb 3, 2020, 57 patients were enrolled (median age 71 years [IQR 60-75]; 38 [67%] were male and 19 (33%) were female; 47 [82%] were not Hispanic or Latino; and the median previous lines of therapy was 2 [IQR 1-3]). 18 participants were included in phase 1b and 39 were included in phase 2. Phase 1b confirmed a 20 mg recommended phase 2 dose for lenalidomide. After a median follow-up of 11·8 months (IQR 4·7-25·8), the complete response rate, as assessed by the Independent Review Committee, was 31% (90% CI 20-43). The most common grade 3-4 adverse events were neutropenia (35 [61%] of 57) and thrombocytopenia (eight [14%] of 57). Serious adverse events were reported in 23 (40%) of 57 patients and one patient died due to a treatment-related adverse event (neutropenic sepsis). INTERPRETATION/CONCLUSIONS:Although the combination of Pola+R+Len did not meet the prespecified activity threshold, some patients derived clinical benefit and the regimen had a tolerable safety profile in patients with relapsed or refractory diffuse large B-cell lymphoma. FUNDING/BACKGROUND:Genentech/F Hoffmann-La Roche.
PMID: 38190832
ISSN: 2352-3026
CID: 5628572

Mosunetuzumab Safety Profile in Patients With Relapsed/Refractory B-cell Non-Hodgkin Lymphoma: Clinical Management Experience From a Pivotal Phase I/II Trial

Matasar, Matthew; Bartlett, Nancy L.; Shadman, Mazyar; Budde, Lihua E.; Flinn, Ian; Gregory, Gareth P.; Kim, Won Seog; Hess, Georg; El-Sharkawi, Dima; Diefenbach, Catherine S.; Huang, Huang; To, Iris; Parreira, Joana; Wu, Mei; Kwan, Antonia; Assouline, Sarit
Background: Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody approved in Europe and the United States for relapsed/refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior therapies. Materials and Methods: We present interim safety data from the mosunetuzumab GO29781 (NCT02500407) phase I/II dose-escalation study in R/R non-Hodgkin lymphoma (NHL), focusing on FL. Results: Overall, 218 patients with R/R NHL, including 90 with R/R FL, received a median of eight 21-day cycles of intravenous mosunetuzumab with step-up dosing in Cycle (C) 1 (C1 Day [D] 1, 1 mg; C1D8, 2 mg; C1D15/C2D1, 60 mg; C3D1 and onwards, 30 mg). Cytokine release syndrome (CRS) was the most common adverse event (AE), occurring in 39.4% (NHL) and 44.4% (FL) of patients. Events occurred predominantly during C1 at the first loading dose; the majority were grade 1/2. CRS events were managed at the investigator's discretion with supportive care, steroids, and tocilizumab, based on protocol management guidelines. Immune effector cell-associated neurotoxicity syndrome was uncommon, reported in 0.9% (NHL) and 1.1% (FL) of patients. Neutropenia occurred in 27.5% (NHL) and 28.9% (FL) of patients (mostly grade 3/4) and could be effectively managed using granulocyte colony-stimulating factor. Tumor lysis syndrome occurred in 0.9% (NHL) and 1.1% (FL) of patients (all grade 3/4 with CRS; all resolved). Conclusion: Mosunetuzumab monotherapy as treatment for R/R B-cell NHL, including FL, was associated with low rates of severe AEs (including CRS) and is suitable for outpatient administration in the community setting. Adapted protocol guidance for the management of select AEs during mosunetuzumab treatment is included.
ISSN: 2152-2650
CID: 5630042

Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial

Budde, Lihua E; Olszewski, Adam J; Assouline, Sarit; Lossos, Izidore S; Diefenbach, Catherine; Kamdar, Manali; Ghosh, Nilanjan; Modi, Dipenkumar; Sabry, Waleed; Naik, Seema; Mehta, Amitkumar; Nakhoda, Shazia K; Smith, Stephen D; Dorritie, Kathleen; Jia, Ting; Pham, Song; Huw, Ling-Yuh; Jing, Jing; Wu, Hao; Ead, Wahib S; To, Iris; Batlevi, Connie Lee; Wei, Michael C; Chavez, Julio C
Relapsed/refractory aggressive large B cell lymphoma (LBCL) remains an area of unmet need. Here we report the primary analysis of a phase 1b/2 trial of outpatient mosunetuzumab (a CD20xCD3 T-cell-engaging bispecific antibody) plus polatuzumab vedotin (an anti-CD79B antibody-drug conjugate) in relapsed/refractory LBCL. The phase 2 component is a single arm of an ongoing multi-arm trial. The primary endpoint during dose expansion was independent review committee (IRC)-assessed best overall response rate. Secondary endpoints included investigator-assessed overall response rate, complete response, duration of response, progression-free survival and overall survival. At data cutoff, 120 patients were enrolled (22 dose escalation, 98 dose expansion). The primary endpoint was met during dose expansion, with IRC-assessed best overall response rate and complete response rates of 59.2% (58/98; 95% confidence interval (CI): 48.8-69.0) and 45.9% (45/98; 95% CI: 35.8-56.3), respectively (median follow-up, 23.9 months). Median duration of complete was not reached (95% CI: 20.5-not estimable (NE)). Median progression-free survival was 11.4 months (95% CI: 6.2-18.7). Median overall survival was 23.3 months (95% CI: 14.8-NE). Across dose escalation and expansion, the most common grade 3 or higher adverse events were neutropenia (25.0%, 30/120) and fatigue (6.7%, 8/120). Any-grade cytokine release syndrome occurred in 16.7% of patients. These data demonstrate that mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy in transplant-ineligible relapsed/refractory LBCL. identifier: NCT03671018 .
PMID: 38072960
ISSN: 1546-170x
CID: 5589472

Overall survival of patients with cHL who progress after autologous stem cell transplant: results in the novel agent era

Desai, Sanjal H; Spinner, Michael A; Evens, Andrew M; Sykorova, Alice; Bachanova, Veronika; Goyal, Gaurav; Kahl, Brad; Dorritie, Kathleen; Azzi, Jacues; Kenkre, Vaishalee P; Chang, Cheryl; Michalka, Jozef; Ansell, Stephen M; Fusco, Brendon; Sumransub, Nuttavut; Hatic, Haris; Saba, Raya; Ibrahim, Uroosa; Harris, Elyse I; Shah, Harsh; Wagner-Johnston, Nina; Arai, Sally; Nowakowski, Grzegorz S; Mocikova, Heidi; Jagadeesh, Deepa; Blum, Kristie A; Diefenbach, Catherine; Iyengar, Siddharth; Rappazzo, K C; Baidoun, Firas; Choi, Yun; Prochazka, Vit; Advani, Ranjana H; Micallef, Ivana
In the pre-novel agent era, the median postprogression overall survival (PPS) of patients with classic Hodgkin lymphoma (cHL) who progress after autologous stem cell transplant (ASCT) was 2 to 3 years. Recently, checkpoint inhibitors (CPI) and brentuximab vedotin (BV) have improved the depth and durability of response in this population. Here, we report the estimate of PPS in patients with relapsed cHL after ASCT in the era of CPI and BV. In this multicenter retrospective study of 15 participating institutions, adult patients with relapsed cHL after ASCT were included. Study objective was postprogression overall survival (PPS), defined as the time from posttransplant progression to death or last follow-up. Of 1158 patients who underwent ASCT, 367 had progressive disease. Median age was 34 years (range, 27-46) and 192 were male. Median PPS was 114.57 months (95% confidence interval [CI], 91-not achieved) or 9.5 years. In multivariate analysis, increasing age, progression within 6 months, and pre-ASCT positive positron emission tomography scan were associated with inferior PPS. When adjusted for these features, patients who received CPI, but not BV, as first treatment for post-ASCT progression had significantly higher PPS than the no CPI/no BV group (hazard ratio, 3.5; 95% CI, 1.6-7.8; P = .001). Receipt of allogeneic SCT (Allo-SCT) did not improve PPS. In the era of novel agents, progressive cHL after ASCT had long survival that compares favorably with previous reports. Patients who receive CPI as first treatment for progression had higher PPS. Receipt to Allo-SCT was not associated with PPS in this population.
PMID: 37729621
ISSN: 2473-9537
CID: 5589902

On the Precipice of a "Rituximab-Like" Era for T-Cell Lymphomas? [Comment]

Varma, Gaurav; Diefenbach, Catherine S
To date, mAbs have had limited success in improving outcomes for patients with T-cell lymphomas. Preclinical data suggest that anti-T-cell receptor Vβ-segment mAbs are a novel therapeutic strategy for patients with T-cell lymphomas that avoid several limitations of current therapies. See related article by Lucero et al., p. 4230.
PMID: 37581573
ISSN: 1557-3265
CID: 5614012

Safety and efficacy of atezolizumab with rituximab and CHOP in previously untreated diffuse large B-cell lymphoma

Younes, Anas; Burke, John M; Cheson, Bruce D; Diefenbach, Catherine; Ferrari, Silvia; Hahn, Uwe; Hawkes, Eliza A; Khan, Cyrus; Lossos, Izidore S; Musuraca, Gerardo; Tani, Monica; Vitolo, Umberto; Yuen, Sam L S; Raval, Aparna; Shivhare, Mahesh; Nielsen, Tina G; Sellam, Gila; Sharman, Jeff P
Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is the current standard therapy for patients with diffuse large B-cell lymphoma (DLBCL) and is curative in ∼60% of patients. Atezolizumab is a humanized immunoglobulin G1 monoclonal antibody that targets programmed death-ligand 1 and has previously shown anti-tumor activity in several tumor types. In a phase 1b/2 trial (NCT02596971) we evaluated the safety and efficacy of atezolizumab in combination with R-CHOP (atezo-R-CHOP; for 6 to 8 cycles) in patients with previously untreated DLBCL. Patients achieving a complete response at the end of induction received consolidation therapy with atezolizumab on Day 1 of each 21-day cycle for an additional 17 cycles. Overall, 42 patients with DLBCL were included in this analysis. The primary endpoint, complete response rate at end of induction, as assessed by an independent review committee (IRC; modified Lugano 2014) was 77.5% (95% confidence interval [CI], 64.0-87.7; n = 40). Investigator-assessed progression-free survival and overall survival at 3 years were 77.4% (95% CI, 59.7-88.0) and 87.2% (95% CI, 71.9-94.5), respectively. All treated patients experienced ≥1 adverse event (AE; 32 patients [76.2%] had a Grade 3-4 AE). One patient had a fatal AE (unconfirmed progressive multifocal leukoencephalopathy), that was considered related to atezolizumab and rituximab, and 17 (40.5%) patients experienced atezolizumab-related AEs of special interest. In previously untreated patients with DLBCL, atezo-R-CHOP demonstrated encouraging clinical efficacy and a safety profile consistent with the known toxicities of the individual drugs.
PMID: 36287231
ISSN: 2473-9537
CID: 5359462

Checkpoint inhibitor-based salvage regimens prior to autologous stem cell transplant improve event-free survival in relapsed/refractory classic Hodgkin lymphoma

Desai, Sanjal H; Spinner, Michael A; David, Kevin; Bachanova, Veronika; Goyal, Gaurav; Kahl, Brad; Dorritie, Kathleen; Azzi, Jacques; Kenkre, Vaishalee P; Arai, Sally; Chang, Cheryl; Fusco, Brendon; Sumransub, Nuttavut; Hatic, Haris; Saba, Raya; Ibrahim, Uroosa; Harris, Elyse I; Shah, Harsh; Murphy, Jacob; Ansell, Stephen; Jagadish, Deepa; Orellana-Noia, Victor; Diefenbach, Catherine; Iyenger, Siddharth; Rappazzo, K C; Mishra, Rahul; Choi, Yun; Nowakowski, Grzegorz S; Advani, Ranjana H; Micallef, Ivana N
Clinical trials of novel salvage therapies have encouraging outcomes for relapsed/refractory transplant-eligible classic Hodgkin lymphoma (R/R cHL) but comparison with conventional chemotherapy is lacking. Herein, we report the final analysis of a multicenter retrospective cohort of R/R cHL assessing outcomes by type of salvage therapy before autologous stem cell transplant (ASCT). R/R cHL patients who underwent ASCT at 14 institutions across the United States were included. Outcomes were compared among patients receiving conventional chemotherapy, brentuximab vedotin (BV) + chemotherapy, BV alone, and a checkpoint inhibitor (CPI)-based regimens before ASCT. Study endpoints included event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). All endpoints are defined from relapse. Of 936 patients, 728 received conventional chemotherapy, 73 received BV + chemotherapy, 70 received BV alone, and 65 received CPI-based regimens prior to ASCT. When adjusted for time to relapse, pre-ASCT response and use of BV maintenance, patients receiving CPI-based regimens had superior 2-year EFS compared to conventional chemotherapy, BV + chemotherapy, and BV alone (79.7, 49.6, 62.3, and 36.9%, respectively, p < .0001). Among 649 patients transplanted after 1 line of salvage therapy, CPI-based regimens were associated with superior 2-year PFS compared to conventional chemotherapy (98% vs. 68.8%, hazard ratio: 0.1, 95% confidence interval: 0.03-0.5, p < .0001). OS did not differ by pre-ASCT salvage regimen. In this large multicenter retrospective study, CPI-based regimens improved EFS and PFS compared to other salvage regimens independent of pre-ASCT response. These data support earlier sequencing of CPI-based regimens in R/R cHL in the pre-ASCT setting.
PMID: 36629030
ISSN: 1096-8652
CID: 5410432

Safety and efficacy of atezolizumab with obinutuzumab and bendamustine in previously untreated follicular lymphoma

Younes, Anas; Burke, John M; Diefenbach, Catherine; Ferrari, Silvia; Khan, Cyrus; Sharman, Jeff P; Tani, Monica; Ujjani, Chaitra; Vitolo, Umberto; Yuen, Sam; Raval, Aparna; Shivhare, Mahesh; Nielsen, Tina G; Sellam, Gila; Gilbertson, Michael
Obinutuzumab (G) chemoimmunotherapy demonstrated improved progression-free survival (PFS) vs rituximab-based chemoimmunotherapy in patients with previously untreated follicular lymphoma (FL) in the GALLIUM trial. Atezolizumab (atezo) is a programmed death-ligand 1 inhibitor with a complementary mechanism of action to G by restoring cytotoxic T-cell function. We evaluated the safety and efficacy of atezo-G-bendamustine in patients with previously untreated FL in a phase Ib/II trial (#NCT02596971). A safety run-in phase was followed by an expansion phase with atezo-G-bendamustine induction and atezo-G maintenance for ≤24 months. Forty patients with previously untreated FL were enrolled and treated with atezo-G-bendamustine. The primary endpoint, complete response (CR) rate, assessed by an independent review committee (IRC; modified Lugano 2014 criteria) was 75.0% (95% confidence interval [CI], 61.3% to 85.8%). Three-year investigator-assessed PFS and overall survival rates were 80.9% (95% CI, 63.9% to 90.5%) and 89.3% (95% CI, 73.9% to 95.9%), respectively. At baseline, 21/40 patients had circulating lymphoma-specific clonotypes and underwent repeat testing at end of induction; all were minimal residual disease negative (10-5 sensitivity), with 16 (76.2%) CRs, 3 (14.3%) partial responses, and 2 (9.5%) with stable disease (IRC assessed). Grade 5 (fatal) adverse events (AEs) were reported in 5 patients. The efficacy of atezo-G-bendamustine in previously untreated FL did not appear superior to G-bendamustine efficacy as seen in the GALLIUM trial, and the addition of atezo to G-bendamustine was associated with an increased risk of AEs. Particularly due to the unfavorable safety profile, this regimen cannot be recommended in patients with previously untreated FL. This trial was registered at as #NCT02596971.
PMID: 35359000
ISSN: 2473-9537
CID: 5357802

Polatuzumab vedotin in relapsed / refractory aggressive B-cell lymphoma

Varma, Gaurav; Wang, Jacqueline; Diefenbach, Catherine
INTRODUCTION/UNASSIGNED:Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma histology. Outcomes for patients with relapsed or refractory (R/R) disease remain suboptimal. Polatuzumab vedotin (polatuzumab) is a recently approved antibody drug conjugate that targets CD79b, with a tubulin toxin payload, that has demonstrated significant clinical activity and an acceptable toxicity profile when administered with both anti-CD20 monoclonal antibodies and chemotherapy in clinical trials. AREAS COVERED/UNASSIGNED:In this article, we discuss the early-phase trials supporting the accelerated FDA approval of polatuzumab for patients with R/R DLBCL and review the status of and data from ongoing trials combining polatuzumab with other agents. EXPERT OPINION/UNASSIGNED:Polatuzumab is an important new tool for the management of patients with R/R DLBCL who are ineligible for or who relapse following standard second-line therapies. Combinations of polatuzumab with other agents may represent an opportunity to improve outcomes for this difficult to treat population. The recent publication of the POLARIX trial (NCT03274492) incorporating polatuzumab in the frontline treatment of DLBCL may impact the future role of this agent in the R/R setting.
PMID: 35726803
ISSN: 1744-8328
CID: 5281912

Anti-CD79B Antibody-Drug Conjugate DCDS0780A in Patients with B-Cell Non-Hodgkin Lymphoma: Phase 1 Dose-Escalation Study

Herrera, Alex F; Patel, Manish R; Burke, John M; Advani, Ranjana; Cheson, Bruce D; Sharman, Jeff P; Penuel, Elicia; Polson, Andrew G; Liao, Chen Di; Li, Chunze; Schuth, Eva; Vaze, Anjali; Samineni, Divya; Elstrom, Rebecca; Cooper, James; Diefenbach, Catherine
PURPOSE/OBJECTIVE:Targeting CD79B using antibody-drug conjugates (ADC) is an effective therapeutic strategy in B-cell non-Hodgkin lymphoma (B-NHL). We investigated DCDS0780A, an anti-CD79B ADC with THIOMAB{trade mark, serif} technology (TDC) that consistently conjugates two anti-neoplastic molecules per antibody, in contrast to ADCs with heterogeneous loads. PATIENTS AND METHODS/METHODS:This phase 1 study enrolled 60 patients with histologically confirmed B-NHL that had relapsed/failed to respond following {greater than or equal to}1 prior treatment regimens; 41 (68%) had diffuse large B-cell lymphoma (DLBCL). Fifty-one patients received DCDS0780A monotherapy once every 3 weeks (0.3-4.8 mg/kg); 9 received combination therapy (3.6-4.8 mg/kg) with rituximab. RESULTS:=20). CONCLUSIONS:DCDS0780A as the TDC format for CD79B was tested at higher doses than its ADC counterpart investigated earlier, leading to deep responses. However, dose intensity was limited by ocular toxicities seen at the higher doses indicating that the TDC format was unable, in the current study, to expand the therapeutic index for the CD79B target. The encouraging anti-tumor activity advocates continuation of investigations into novel ADC technologies.
PMID: 34980599
ISSN: 1557-3265
CID: 5106922