L. Nastoupil

Factors influencing outcome in advanced stage, low-grade follicular lymphoma treated at MD Anderson Cancer Center in the rituximab era

BACKGROUND The optimal initial therapy of follicular lymphoma (FL) remains unclear. The aims of this study were to compare primary treatment strategies and assess the impact of maintenance rituximab and patterns of treatment failure. PATIENTS AND METHODS We retrospectively analyzed patients with treatment-naive advanced stage, grade 1-2 FL treated at our center from 2004 to 2014. We included 356 patients treated on clinical trials or standard of care with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP, n = 119); R-CHOP with maintenance (R-CHOP + M, n = 65); bendamustine/rituximab (BR, n = 45); BR with maintenance (BR + M, n = 35); R(2) (n = 94). We compared baseline characteristics, progression-free survival (PFS), overall survival (OS) and analyzed prognostic factors using univariate and multivariate analysis adjusted for treatment. RESULTS After a median follow-up of 4 years (range 0.2-15.0), the 3-year PFS was 60% [95% confidence interval (CI) 51% to 69%] for R-CHOP, 72% (59% to 82%) for R-CHOP + M, 63% (42% to 78%) for BR, 97% (80% to 100%) for BR + M and 87% (78% to 93%) for R(2). Patients treated with R-chemotherapy had more high-risk features than patients treated with R(2) but, by adjusted multivariate analysis, treatment with R(2) [hazard ratio (HR) 0.39 (0.17-0.89), P = 0.02] was associated with a superior PFS. Eastern Cooperative Oncology Group Performance status of one or more predicted inferior OS. Among patients treated with R-chemotherapy, maintenance was associated with the superior PFS [HR 0.38 (95% CI 0.21-0.68)]. By adjusted multivariate analysis, disease progression within 2 years [HR 5.1 (95% CI 1.57-16.83)] and histologic transformation (HT) [HR 11.05 (95% CI 2.84-42.93)] increased risk of death. CONCLUSION Induction therapy with R(2) may result in disease control which is comparable with R-chemotherapy. Early disease progression and HT are predictive of inferior survival.

Patients with classical Hodgkin lymphoma experiencing disease progression after treatment with brentuximab vedotin have poor outcomes

BACKGROUND Brentuximab vedotin (BV) is a key therapeutic agent for patients with relapsed/refractory classical Hodgkin lymphoma (cHL). The outcomes of patients experiencing disease progression after BV are poorly described. PATIENTS AND METHODS We reviewed our institutional database to identify patients with cHL treated with BV who were either refractory to treatment or experienced disease relapse. We collected clinicopathologic features, treatment details at progression and outcome. RESULTS One hundred patients met inclusion criteria, with a median age of 32 years (range 18-84) at progression after BV. The median number of treatments before BV was 3 (range 0-9); 71 had prior autologous stem cell transplant. The overall response rate (ORR) to BV was 57%, and the median duration of BV therapy was 3 months (range 1-25). After disease progression post-BV, the most common treatment strategies were investigational agents (n = 30), gemcitabine (n = 15) and bendamustine (n = 12). The cumulative ORR to therapy was 33% (complete response 15%). After a median follow-up of 25 months (range 1-74), the median progression-free (PFS) and overall survival (OS) were 3.5 and 25.2 months, respectively. In multivariate analysis, no factors analyzed were predictive of PFS; age at progression >45 years and serum albumin <40 g/l at disease progression were associated with increased risk of death. Among patients who achieved response to therapy, allogeneic stem cell transplantation was associated with a non-significant trend toward superior OS (P = 0.11). CONCLUSIONS Patients with BV-resistant cHL have poor outcomes. These data serve as a reference for newer agents active in BV-resistant disease.

Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/refractory mantle cell lymphoma (MCL).

Ibrutinib has shown significant activity in patients with relapsed or refractory mantle cell lymphoma (RR‐MCL). We report the long‐term outcome and safety profile of a single‐centre, single arm, open‐label, phase 2 study of RR‐MCL treated with IR. Overall, the median follow‐up time was 47 months (range 1–52 months), median duration on treatment was 16 months (range 1–53 months) and median number of treatment cycles was 17 (range 1–56). Twenty‐nine patients (58%) achieved complete remission and of these, 12 patients continue on study. Thirty‐eight patients discontinued treatment, 14 due to disease progression (2 transformed). Patients with blastoid morphology, high risk MCL International Prognostic Index score and high Ki67% had inferior survival. The commonest grade 1–2 toxicities were fatigue, diarrhoea, nausea, arthralgias and myalgias. None had long term toxicities. Median progression‐free survival was 43 months. Eighteen patients (36%) died (14 deaths were MCL‐related). The median overall survival has not been reached. Treatment with IR can provide durable remissions in a subset of patients with RR‐MCL, especially those with low Ki67%. The possible benefit of adding other therapies in combination with IR in RR‐MCL is under exploration.

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study

Abstract Background Venetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine–rituximab (BR) in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL). Patients and methods BR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50–1200 mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy. Results Sixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n = 4) or respiratory failure (n = 1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800 mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 38.3 months [95% confidence interval (CI) 10.4–NR], not yet reached, and 10.7 months (95% CI 4.3–21.0), respectively. Conclusions This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL. Trial registered Clinicaltrials.gov, NCT01594229.

HIGH RESPONSE RATES WITH PEMBROLIZUMAB IN COMBINATION WITH RITUXIMAB IN PATIENTS WITH RELAPSED FOLLICULAR LYMPHOMA: INTERIM RESULTS OF AN ON OPEN‐LABEL, PHASE II STUDY

primary efficacy endpoint was objective tumor response rate (ORR) per independent radiologic review (Cheson et al. 2007). Archival tumor tissues were used for mRNA extraction and gene expression profiling. Results: The full analysis set comprised 142 treated patients. At the time of analysis, median duration of treatment was 22 weeks (range 1‐105); 46 patients remained on treatment. The ORR was 59.2%, including 12.0% complete response (CR) and 47.2% partial response (PR), with 29.6% stable disease and 2.1% progressive disease. In the FL subset (n = 104), the ORR was 58.7%, (14.4% CR and 44.2% PR). In the MZL subset (n = 23), the ORR was 69.6%, (8.7% CR and 60.9% PR). Tumor shrinkage as best response was observed in 91% of evaluable patients (Figure). The estimated Kaplan‐Meier (KM) median duration of response was 687 days (range 0‐687). The KM‐ estimate of median PFS was 340 days (range 0‐736). Gene expression analysis based on evaluable archival samples from 71 patients indicated that high expression of PI3K and B‐cell receptor gene signatures was associated with response (p = 0.02 and p = 0.04, respectively). The most common treatment‐related AEs (all grade/grade 3+) were transient hyperglycemia (49%/40%) and hypertension (29%/23%). Other AEs included neutropenia (25%/19%), diarrhea (18%/4%), lung infection (14%/11%), pneumonitis (7%/1.4%), and colitis (0.7%/0.7%). There were two non‐fatal opportunistic infections. Laboratory toxicities of interest were principally grade‐1, including elevated ALT (23% all‐grade/19% grade‐1) and AST (28%/25%). There were 6 deaths, with 3 attributed to copanlisib: lung infection, respiratory failure, and a thromboembolic event. Conclusions: Administration of copanlisib resulted in responses in the majority of patients, with a median duration of response exceeding 22 months. The rate of fatal drug‐related events was low; 3 of 142 patients (2.1%). In general the safety profile was distinct and manageable, with low rates of severe hepatic enzymopathy, diarrhea or inflammatory events, and opportunistic infections.

THE IMMUNOLOGIC DOUBLET OF LENALIDOMIDE PLUS OBINUTUZUMAB IS HIGHLY ACTIVE IN RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA, RESULTS OF A PHASE I/II STUDY

279 ONGOING PHASE 1/2 STUDY OF INCB050465, A SELECTIVE PI3Kδ INHIBITOR, FOR THE TREATMENT OF PATIENTS (PTS) WITH RELAPSED/ REFRACTORY (R/R) B‐CELL MALIGNANCIES (CITADEL‐101) P. Caimi* | R. Ramchandren | T.J. Phillips | M.S. Wertheim | M.E. Gutierrez | W.J. Edenfield | L.P. Akard | J.A. Call | D.O. Persky | D.J. DeMarini | L. Zhou | S. Yeleswaram | A. Forero‐Torres Department of Medicine‐Gastroenterology, University Hospitals Seidman Cancer Center, Cleveland, OH, USA; Hematology/Oncology, Karmanos Cancer Center, Detroit, MI, USA; Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA; Hematology/Oncology, Hematology/ Oncology Associates of Treasure Coast, Port St Lucie, FL, USA; Drug Discovery and Phase I Unit, Hackensack University Medical Center, Hackensack, NJ, USA; Hematology, Greenville Health System Cancer Institute, Greenville, SC, USA; Hematology, Indiana Blood & Marrow Transplantation, LLC, Indianapolis, IN, USA; Hematology/Oncology, Utah Cancer Specialists‐Network, Salt Lake City, UT, USA; Hematology/ Oncology, University of Arizona Cancer Center, Tucson, AZ, USA; Clinical Development, Incyte Corporation, Wilmington, USA; Hematology/Oncology, University of Alabama Birmingham, Birmingham, AL, USA

Dose adjusted-EPOCH-R and mediastinal disease may improve outcomes for patients with gray-zone lymphoma.

in 7 5% of cells, del(13q) in 45% of cells and was negative for t(11;14). The patient received a single dose of bendamustine and rituximab, however B-cell lymphocytosis persisted. Upon completion of the 28-d cycle, patient was started on ibrutinib 420 mg/d. The treatment course was complicated by an episode of atrial fibrillation which required a brief interruption of ibrutinib therapy. Upon restarting ibrutinib, his constitutional symptoms resolved with therapy, accompanied by normalization of the absolute lymphocyte count, haemoglobin and platelet count (Fig 1). The patient remains on therapy at 12 months of follow-up with ongoing response. To date, effective treatments for patients with B-PLL have been lacking. Here we demonstrate that ibrutinib induces disease control in B-PLL. Importantly, both patients in this report demonstrated complex cytogenetic abnormalities with aberrations in TP53, both recognized as unfavourable prognostic indicators. Although the second patient had a small aberrant TP53 clone (<10%), recent data indicates that such subclones, even very minor, are an important driver of subsequent disease in CLL (Rossi et al, 2014). Interestingly, we have not observed an increase in lymphocytosis following administration of ibrutinib in patients with B-PLL, contrary to CLL. Given the poor prognosis of B-PLL and lack of effective established treatment modalities, ibrutinib should be considered for upfront therapy of B-PLL. Author contributions

LENALIDOMIDE AND OBINUTUZUMAB WITH CHOP FOR NEWLY DIAGNOSED DIFFUSE LARGE B-CELL LYMPHOMA: PHASE I/II RESULTS

CD20 antigen. Bendamustine (Benda) is an active chemotherapy agent in pts with lymphoma. The combination of UTX + TGR‐ 1202 is tolerable and active in pts with rel/ref hematologic malignancies and is under Phase 3 testing for pts with CLL and under Phase 2b testing for pts with DLBCL. This Phase 1 trial evaluates the safety and efficacy of UTX + TGR‐1202 + Benda in pts with advanced diffuse large B‐cell lymphoma (DLBCL) and Follicular Lymphoma (FL). Methods: Eligible pts had rel/ref DLBCL or FL with an ECOG PS ≤ 2 w/ o limit to number of prior therapies. ANC of ≥750 and Platelets ≥50,000 was permitted. Pts refractory to prior PI3Kδ, Benda, or anti‐ CD20 therapy were eligible. UTX was dosed on Days 1, 8, 15 of Cycle 1, Day 1 of Cycle 2–6, followed by Cycle 9 and 12. TGR‐1202 was started at 800 mg QD with a −1 dose reduction cohort at 600 mg if not tolerated in ≥2/6 pts. Benda was dosed at 90 mg/m on Days 1 and 2 of Cycles 1–6 only. Primary endpoints included safety and efficacy (Cheson 2007). Results: Twenty‐three pts were evaluable for safety: 15 diffuse large B‐cell (DLBCL) and 8 follicular (FL). Med age 68 yo (range 31‐81); 12 M/11 F; median prior treatment regimens = 2 (range 1–6); 12 pts (52%) were refractory to their immediate prior treatment and to prior CD20 therapy, and 7 pts had progressed post‐ transplant. ECOG PS 0/1/2 (3/18/2). Initially, 2/4 pts at 800 mg TGR‐1202 experienced AEs in Cycle 1 that led to treatment interruption (rash, neutropenia); thus, the 600 mg dose of TGR‐1202 was explored. No additional Cycle 1 treatment delays were reported at the 600‐mg dose level, which was later expanded, and the 800‐mg TGR‐1202 dose is now being evaluated with stricter eligibility criteria to require an ANC of ≥1.0, and the use of growth factor support in cycle 1 is now encouraged. The most common AEs included diarrhea (39%; G3/4 4%), decreased appetite (35%; G3/4 4%), nausea (30%; G3/4 4%), asthenia (26%; G3/4 4%) and neutropenia (22%). The only Grade 3/4 AE reported in >10% of pts was neutropenia (22%). Two pts had a TGR‐1202 dose reduction. Nineteen pts (11 DLBCL/8 FL) were evaluable for efficacy: ORR amongst all pts was 79% (15/19) with 42% (8/19) achieving a complete response (CR), of which 5 were DLBCL and 3 FL. ORR in the respective groups is as follows: