Jamie Hirata

Effectiveness of First-Line Management Strategies for Stage I Follicular Lymphoma: Analysis of the National LymphoCare Study

PURPOSE The optimal management of stage I follicular lymphoma, according to consensus guidelines, is based on uncontrolled experiences of select institutions. Diverse treatment approaches are used despite guidelines that recommend radiation therapy (XRT). PATIENTS AND METHODS We analyzed outcomes of patients with stage I follicular lymphoma enrolled onto the National LymphoCare database. RESULTS Of 471 patients with stage I follicular lymphoma, 206 patients underwent rigorous staging as defined by both a bone marrow aspirate and biopsy and an imaging study (a computed tomography [CT] scan of the whole body, a positron emission tomography [PET]/CT scan, or both). Rigorously staged patients had superior progression-free survival (PFS) compared with nonrigorously staged patients (hazard ratio [HR], 0.63). Treatments given to rigorously staged patients were rituximab/chemotherapy (R-chemo; 28%), XRT (27%), observation (17%), systemic therapy + XRT (13%), rituximab monotherapy (12%), and other (3%). With a median follow-up of 57 months for PFS, there were 44 progression events (in 21% of patients) for rigorously staged patients. For these patients, PFS was significantly improved with either R-chemo or systemic therapy + XRT compared with patients receiving XRT alone after adjustment for histology, LDH, and the presence of B symptoms. There were no differences in overall survival. CONCLUSION In this largest, prospectively enrolled group of patients with stage I follicular lymphoma, variable treatment approaches resulted in similar excellent outcomes, which challenges the paradigm that XRT should be standard for this presentation.

Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia

Obinutuzumab is a glycoengineered, type 2 anti-CD20 humanized antibody with single-agent activity in relapsed chronic lymphocytic leukemia (CLL). With other CD20 antibodies, a dose-response relationship has been shown. We therefore performed a randomized phase 2 study in symptomatic, untreated CLL patients to evaluate if an obinutuzumab dose response exists. Obinutuzumab was given at a dose of 1000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 8 and day 15 of cycle 1; 1000 mg day 1 of cycles 2-8) or 2000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 3, 2000 mg day 8 and day 15 of cycle 1; 2000 mg day 1 of cycles 2-8). The primary end point was overall response rate (ORR). Eighty patients were enrolled with similar demographics: median age 67 years, 41% high-risk Rai disease, and 10% del(17p)(13.1). ORR (67% vs 49%, P = .08) and complete response (CR) or CR with incomplete cytopenia response (20% vs 5%) favored 2000 mg obinutuzumab. Overall, therapy was well tolerated, and infusion events were manageable. This study demonstrates significant efficacy of obinutuzumab monotherapy, for 1000 mg as well as for 2000 mg, in untreated CLL patients with acceptable toxicity. Although exploratory, a dose-response relationship may exist, but its relevance to improving progression-free survival is uncertain and will require further follow-up. This trial was registered at www.clinicaltrials.gov as #NCT01414205.

Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial

Obinutuzumab is a type 2, glycoengineered, anti-CD20 antibody recently approved with chlorambucil for the initial therapy of chronic lymphocytic leukemia (CLL). In this nonrandomized, parallel-cohort, phase 1b, multicenter study, we explored the safety and preliminary efficacy of obinutuzumab-bendamustine (G-B) or obinutuzumab fludarabine cyclophosphamide (G-FC) for the therapy of previously untreated fit patients with CLL. Patients received up to 6 cycles of G-B (n = 20) or G-FC (n = 21). The primary end point was safety, with infusion-related reactions (88%, grade 3-4 20%) being the most common adverse event and grade 3-4 neutropenia in 55% on G-B and 48% on G-FC. Mean cycles completed were 5.7 for G-B and 5.1 for G-FC, with 2 and 7 early discontinuations, respectively. The objective response rate (ORR) for G-B was 90% (18/20) with 20% complete response (CR) and 25% CR with incomplete marrow recovery (CRi). The ORR for G-FC was 62% (13/21), with 10% CR and 14% CRi, including 4 patients not evaluable. With a median follow-up of 23.5 months in the G-B cohort and 20.7 months in the G-FC cohort, no patient has relapsed or died. We conclude that obinutuzumab with either B or FC shows manageable toxicity and has promising activity. This study was registered at www.clinicaltrials.gov as #NCT01300247.

Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices

BACKGROUND Because follicular lymphoma (FL) patients have heterogeneous outcomes, the FL international prognostic index (FLIPI) was developed to risk-stratify patients and to predict survival. However, limited data exist regarding the role of FLIPI in the era of routine first-line rituximab (R) and R-chemotherapy regimens and in the setting of community oncology practices. PATIENTS AND METHODS We evaluated the outcome data from the National LymphoCare Study (NLCS), a prospective, observational cohort study, which collects data on patients with FL in the United States (US) community practices. RESULTS Among 1068 male and 1124 female patients with FLIPI data, most were treated in US community practices (79%); 35% were FLIPI good risk, 30% intermediate risk, and 35% poor risk. FLIPI risk groups were significant predictors of overall survival (OS) and progression-free survival (PFS) for patients who undergo watchful waiting (WW), and those who receive non-R-containing regimens, R-alone, and R-chemotherapy combinations. CONCLUSIONS In the setting of contemporary practice with routine R use, stratifying patients into good, intermediate, and poor FLIPI risk groups predicts distinct outcomes in terms of OS and PFS. FLIPI remains an important prognostic index in the R era and should be used in clinical practices to support discussions about prognosis.BACKGROUND Because follicular lymphoma (FL) patients have heterogeneous outcomes, the FL international prognostic index (FLIPI) was developed to risk-stratify patients and to predict survival. However, limited data exist regarding the role of FLIPI in the era of routine first-line rituximab (R) and R-chemotherapy regimens and in the setting of community oncology practices. PATIENTS AND METHODS We evaluated the outcome data from the National LymphoCare Study (NLCS), a prospective, observational cohort study, which collects data on patients with FL in the United States (US) community practices. RESULTS Among 1068 male and 1124 female patients with FLIPI data, most were treated in US community practices (79%); 35% were FLIPI good risk, 30% intermediate risk, and 35% poor risk. FLIPI risk groups were significant predictors of overall survival (OS) and progression-free survival (PFS) for patients who undergo watchful waiting (WW), and those who receive non-R-containing regimens, R-alone, and R-chemotherapy combinations. CONCLUSIONS In the setting of contemporary practice with routine R use, stratifying patients into good, intermediate, and poor FLIPI risk groups predicts distinct outcomes in terms of OS and PFS. FLIPI remains an important prognostic index in the R era and should be used in clinical practices to support discussions about prognosis.

Racial differences in presentation and management of follicular non-Hodgkin lymphoma in the United States: Report from the National LymphoCare Study

Racial differences in follicular lymphoma (FL) in the United States have not been investigated.

Abstract 880: Anti-tubulin antibody drug conjugates potentiate venetoclax activity in non-Hodgkin lymphoma by targeting MCL-1

Venetoclax, a potent, orally bioavailable inhibitor that selectively targets BCL-2 and induces intrinsic apoptosis, is currently approved for the treatment of relapsed/refractory chronic lymphocytic leukemia with 17p deletion (R/R 17p del CLL) and also has profound efficacy in broad R/R CLL as a single agent or in combination with obinutuzumab (anti-CD20 antibody). However, evidence of robust efficacy by venetoclax as a single agent in certain subtypes of non-Hodgkin lymphoma (NHL) has been limited. For example, diffuse large B-Cell lymphoma (DLBCL) is the most common sub-type of NHL, yet the overall response rate of DLBCL patients to venetoclax was 18% in contrast to 61% in other NHL sub-types. It has been proposed that expression of other pro-survival BCL-2 family members may limit single-agent venetoclax efficacy and is thus considered a potential major resistance factor. To this end, we have observed that low sensitivity to venetoclax monotherapy is correlated with MCL-1 expression in NHL cell lines. We have previously reported that anti-tubulin agents promote MCL-1 degradation. Given that polatuzumab vedotin is a novel antibody drug conjugate targeted to CD79b and delivers an auristatin anti-tubulin agent, we hypothesized that combining polatuzumab with venetoclax presents a mechanism-driven combination strategy for maximizing anti-tumor responses in NHL. In NHL patients, both polatuzumab vedotin and venetoclax have acceptable and non-overlapping toxicities and the combination of both drugs may provide an improved therapeutic index relative to conventional chemotherapy. Here, we demonstrate that polatuzumab vedotin synergizes with venetoclax both in vitro and in vivo. Mechanistically, the combination of both drugs promotes apoptosis in NHL cell lines as indicated by caspase 3/7 activation and dependence on BAX/BAK expression, and decreases MCL-1 protein levels. Furthermore, the combination of venetoclax with polatuzumab vedotin is more efficacious in vitro than the combination of venetoclax with a selective MCL-1 small molecule inhibitor (AMG 176). The combination of polatuzumab vedotin with venetoclax results in durable tumor regressions in diffuse large B-cell and mantle cell lymphoma xenograft models at tolerated doses and is more efficacious than the combination of venetoclax plus bendamustine, a standard chemotherapeutic agent. Based on our pre-clinical data and the strong mechanistic rationale, a drug combination regimen of venetoclax with polatuzumab vedotin and obinutuzumab is currently being evaluated in Phase1b clinical trials in R/R FL and DLBCL (ClinicalTrials.gov identifier NCT02611323). Citation Format: Dhara N. Amin, Jason Oeh, Anuradha Zindal, Lisa Musick, Jamie Hirata, Mehrdad Mobasher, Andy Polson, Deepak Sampath, Ingrid E. Wertz. Anti-tubulin antibody drug conjugates potentiate venetoclax activity in non-Hodgkin lymphoma by targeting MCL-1 [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 880.