Friedberg, Jonathan W.

Purpose SWOG S0016 was a phase III randomized study that compared the safety and efficacy of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) with CHOP-RIT (CHOP followed by consolidation with iodine-133–tositumomab radioimmunotherapy) for previously untreated patients with follicular lymphoma. Understanding the long-term outcome of patients provides a benchmark for novel treatment regimens for FL. Patients and Methods Between 2001 and 2008, 531 previously untreated patients with FL were randomly assigned to receive either six cycles of R-CHOP or six cycles of CHOP-RIT. Patients with advanced-stage disease (bulky stage II, III, or IV) of any pathologic grade (1, 2, or 3) were eligible. Results After a median follow-up of 10.3 years, 10-year estimates of progression-free and overall survival were 49% and 78% among all patients, respectively. Patients in the CHOP-RIT arm had significantly better 10-year progression-free survival compared with patients in the R-CHOP arm (56% v 42%; P = .01), but 10-year overall survival was not different between the two arms (75% v 81%; P = .13). There was no significant difference between the CHOP-RIT and R-CHOP arms in regard to incidence of second malignancies (15.1% v 16.1%; P = .81) or myelodysplastic syndrome or acute myeloid leukemia (4.9% v 1.8%; P = .058). The estimated 10-year cumulative incidences of death resulting from second malignancies were not different (7.1% v 3.2%; P = .16), but cumulative incidence of death resulting from myelodysplastic syndrome or acute myeloid leukemia was higher in the CHOP-RIT arm compared with the R-CHOP arm (4% v 0.9%; P = .02). Conclusion Given these outstanding outcomes, immunochemotherapy should remain the standard induction approach for patients with high-risk FL until long-term follow-up of alternative approaches demonstrates superiority.

AbstractLoss of major histocompatibility Class II expression (MHCII) in diffuse large B‐cell lymphoma (DLBCL) correlates with decreased survival. MHCII transcription is in part regulated by histone acetylation. We tested the hypothesis that combination of histone deacetylase inhibitor (HDACI) with standard chemotherapy would improve outcomes in DLBCL in part through increased MHCII expression. S0806 was a single arm phase I/II trial of vorinostat given at 400 mg po daily on days 1‐9 (subsequently amended to days 1‐5 due to toxicity), combined with R‐CHOP given on day 3 of a 21‐day cycle for 8 cycles, with primary phase II endpoint of 2‐year progression free survival (PFS). With 72 evaluable patients, at median follow up of 3 years, 2‐year PFS estimate was 73%, and OS estimate was 86%. Considering that the regimen fell short of predefined efficacy improvement and was associated with high rates of febrile neutropenia (38%) and sepsis (19%), it cannot be recommended for general use. Consistent with our hypothesis, patients with low MCHII expression on S0806 had numerically superior outcomes compared to those from trial S0433 which did not use an HDACI, but the difference was not statistically significant. Current studies are focused on finding biomarkers of response to HDACI.

Abstract Introduction: Outcomes for pts with refractory aggressive NHL are poor with current therapies (Crump, ASCO 2016). Results from the interim analysis of (n=62) of ZUMA-1, the 1st multicenter trial of an anti-CD19 chimeric antigen receptor (CAR) T cell, axi-cel, in refractory aggressive NHL, showed an objective response rate (ORR) of 79% (complete response [CR] 52%; Blood 2016;128:LBA-6). Here we present results from the primary analysis of ZUMA-1. Methods: Pts received a target dose of 2 × 106 anti-CD19 CAR T cells/kg after lowdose conditioning with cy/flu. Eligible pts (≥18 y) had diffuse large B cell lymphoma (DLBCL), primary mediastinal B cell lymphoma (PMBCL) or transformed follicular lymphoma (TFL); an ECOG performance status (PS) 0-1; and refractory disease (progressive or stable disease as best response to last prior therapy, or relapsed ≤12 m of autologous stem cell transplant [ASCT]). The primary endpoint for this analysis was ORR in the combined DLBCL, PMBCL, and TFL population. Key secondary endpoints were duration of response (DOR), overall survival (OS), and frequency of adverse events (AEs). The primary analysis was triggered when 92 pts had at least 6 m of follow-up. Results: As of January 27, 2017, 111 pts from 22 institutions were enrolled; 101 pts (91%) received axi-cel. Median age was 58 y (range, 23-76), 67% male, 85% stage IIIIV, 47% IPI 3-4, 77% refractory to ≥2nd line of therapy, and 21% relapsed ≤12 m of ASCT. Axi-cel was successfully manufactured in 110/111 (99%) pts with an average turnaround time from apheresis to the clinical site of 17 d. With an ORR of 82% (n = 92; P<.0001) the study met the primary endpoint. The ORR in the mITT analysis set of 101 pts was 82% (CR 54%, PR 28%), and was consistent across key covariates including disease subtype, refractory status, stage, and IPI score. At a median follow up of 8.7 m, 44% of pts were in response and 39% were in CR. The median DOR was 8.2 m overall and not reached for pts who achieved a CR. Median OS was not reached; 80% of pts remained alive at 6 m. The most common Gr ≥3 treatmentemergent AEs were neutropenia (66%), leukopenia (44%), anemia (43%), febrile neutropenia (31%), and encephalopathy (21%). Gr ≥3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 13% and 28% of pts, respectively. All CRS and all NE resolved except 1 Gr 1 memory impairment. As previously reported, there were 3 Gr 5 AEs (3%). Peak and cumulative CAR T levels post-axi-cel were associated with durable responses. Conclusions: Axi-cel significantly improved ORR in patients with refractory aggressive NHL. The CR rate was 7-fold higher compared to historical controls (Crump, ASCO 2016) and nearly half the patients have an ongoing response. Axi-cel demonstrated significant clinical benefit with a manageable safety profile in pts lacking curative treatment options.[F.L.L. and S.S.N. contributed equally to this study.] Funding source: Kite Pharma and in part by funding from the Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program treatment options. Citation Format: Frederick L. Locke, Sattva S. Neelapu, Nancy L. Bartlett, Lazaros J. Lekakis, David Miklos, Caron A. Jacobson, Ira Braunschweig, Olalekan Oluwole, Tanya Siddiqi, Yi Lin, John Timmerman, Jonathan W. Friedberg, Adrian Bot, John Rossi, Lynn Navale, Yizhou Jiang, Jeff Aycock, Meg Elias, Jeff Wiezorek, William Y. Go. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axicel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT019. doi:10.1158/1538-7445.AM2017-CT019

SummaryAggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto‐HCT) is effective for younger patients with mantle cell lymphoma (MCL). However, the optimal induction regimen is widely debated. The Southwestern Oncology Group S1106 trial was designed to assess rituximab plus hyperCVAD/MTX/ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) (RH) versus rituximab plus bendamustine (RB) in a randomized phase II trial to select a pre‐transplant induction regimen for future development. Patients had previously untreated stage III, IV, or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB, followed by auto‐HCT. Fifty‐three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2‐year progression‐free survival (PFS) was 81% vs. 82% and overall survival (OS) was 87% vs. 88% for RB and RH, respectively. RH is not an ideal platform for future multi‐centre transplant trials in MCL. RB achieved a 2‐year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL.

Key Points The posttreatment end point progression of FL within 24 months (POD24) is strongly associated with OS. A pretreatment clinicogenetic risk model (m7-FLIPI) predicts POD24 and OS and identifies the smallest subgroup with highest unmet need.

We aimed to comprehensively study sex differences in disease and patients' characteristics, treatment and outcomes in patients with follicular lymphoma (FL) in the United States (USA) utilizing the National LymphoCare Study registry (2004–2014). Among evaluable males (n = 1277) and females (n = 1375) with FL, females less commonly received anthracyclines and were more likely to receive rituximab monotherapy. Overall response rates were comparable between sex groups. With a median follow‐up of 8.1 years, male sex emerged as an adverse factor for PFS (HR, 0.84, 95% CI, 0.72–0.97). Lymphoma‐related mortality (HR, 0.46; 0.23–0.93) and overall survival (HR, 0.63; 0.41–0.97) favored females aged ≤60 years. There are subtle differences in outcomes between male and female FL patients diagnosed and treated in the contemporary era. These data represent the largest prospective analysis of FL patients in the USA based on sex and can aid design of clinical trials for this disease. Am. J. Hematol. 91:770–775, 2016. © 2016 Wiley Periodicals, Inc.

SummaryTo examine the effectiveness of an initial management strategy of watchful waiting for follicular lymphoma (FL) in clinical practice, we compared outcomes for patients diagnosed 2004–2007 in the United States initially managed with watchful waiting with outcomes following initial rituximab monotherapy and chemoimmunotherapy. In total, 1754 stage II–IV patients in the National LymphoCare Study underwent watchful waiting (n = 386), rituximab monotherapy (n = 296) or rituximab plus chemotherapy (n = 1072) as initial management strategy. Female patients and those who received treatment in the Northeast or in an academic setting more commonly underwent watchful waiting versus initial chemoimmunotherapy; whereas patients with grade 3 histology, anaemia, elevated lactate dehydrogenase, extranodal involvement, B symptoms or performance status ≥1 more commonly received chemoimmunotherapy. Although time to new treatment and progression‐free survival following first‐ and second‐line therapy were improved with chemoimmunotherapy, and time to chemotherapy was improved with rituximab monotherapy, there were no differences in overall survival between watchful waiting and chemoimmunotherapy or rituximab monotherapy. With 8‐year overall survival estimates of 74%, initial management with watchful waiting in the context of sequential therapy remains a viable option for FL patients in the modern era. This trial was registered at www.clinicaltrials.gov (NCT00097565).