Selected Abstracts From the 2016 ASH Annual Meeting

High-Grade, Aggressive Non-Hodgkin Lymphomas: Part 1


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Syed Abutalib, MD

Syed Abutalib, MD

Here are several abstracts selected from the proceedings of this year’s American Society of Hematology (ASH) Annual Meeting & Exposition, highlighting newer therapeutics in high-grade, aggressive B-cell non-Hodgkin lymphomas (NHLs), including newly diagnosed as well as relapsed or refractory diffuse large B-cell lymphomas (DLBCLs) and primary B-cell lymphoma. For the full details of these study abstracts, visit http://www.bloodjournal.org/content/128/22.

Diffuse Large B-Cell Lymphoma

Abstract 469: Phase III randomized study of R-CHOP vs DA-EPOCH-R and molecular analysis of untreated diffuse large B-cell lymphoma: CALGB/Alliance 503031

Study Endpoints: The primary study endpoints were event-free survival of rituximab (Rituxan)-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP; arm A) vs dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin-rituximab (DA-EPOCH-R; arm B) and to develop a molecular predictor of outcome based on germinal center B-cell–like (GCB) and activated B-cell DLBCL.

Abstract Conclusion: Efficacy analysis includes R-CHOP (n = 233) and R-EPOCH (n = 231) assigned patients with confirmed eligibility who received any treatment. Therapy was completed per protocol (total of 6 cycles) in 89% and 83%, respectively, for arms A and B, and disease progression on therapy was 2.6% and 1.7%.

Adverse side effects leading to treatment discontinuation were 1.7% and 5.6%, respectively, for arms A and B. Arm B vs arm A was associated with more grade 4 neutropenia (90%; 56%), grade 4 thrombocytopenia (35%; 6%), grade 3/4 febrile neutropenia (37%; 19%) and grade 3 neuropathy (motor: 8%; 1% and sensory: 15%; 3%). Grade 5 events on study were the same in both arms.

Preliminary analysis of event-free survival in confirmed eligible subjects showed no difference between arms A and B, with a hazard ratio of 1.02 and P = .89 at a median follow-up of 4.9 years. Overall survival is also similar, with a hazard ratio of 1.19 and P = .40 at a median follow-up of 5.0 years.

Clinical Implications: DLBCL comprises multiple diseases with different outcomes, cell of origin, and molecular pathogenesis. Subset analyses of outcomes by age (< 60 years and ≥ 60 years), National Comprehensive Cancer Network® (NCCN®) International Prognostic Index, central nervous system (CNS) relapse, and GCB vs activated B-cell DLBCL are necessary before these results can be generalized to all comers with DLBCL. Additionally, these data do not address the efficacy of R-CHOP in primary mediastinal B-cell lymphoma or MYC-positive DLBCL due to low frequency of such diseases and where more dose-intense regimens appear to be important for superior outcomes.

Abstract 471: International double-blind randomized phase III study of lenalidomide maintenance in elderly (aged 60 to 80 years) patients with DLBCL, follicular lymphoma grade 3b, or transformed lymphoma treated with R-CHOP (6–8 cycles) in first line, the REMARC study from Lysa2

Study Endpoints: The primary endpoint of the study was progression-free survival. Secondary endpoints were safety, partial remission to complete remission conversion rate, and overall survival.

Abstract Conclusion: At the end of R-CHOP therapy, 650 patients were randomized to receive maintenance, either in complete remission (n = 495) or in partial remission (n = 152). With a median follow-up of 40 months, median progression-free survival was not reached in the lenalidomide (Revlimid) group vs 68 months in the placebo group (hazard ratio favoring the lenalidomide group, 0.708 [95% confidence interval (CI): 0.537–0.932; P = .0135]). In the lenalidomide group, 18 patients (21%) converted from partial remission to complete remission during maintenance compared with 13 patients (14%) in the placebo group. During maintenance, the most common observed grade 3 or 4 adverse effects were neutropenia (56% vs 22%), rash (5% vs 1%), infections (8% vs 6%), and thrombocytopenia (2.5% vs 0.6%) in the lenalidomide and placebo arms, respectively.

Clinical Implications: The ­REMARC study showed that 2 years of lenalidomide maintenance in patients responding to R-CHOP significantly improved progression-free survival without an early significant impact on overall survival. Cell of origin analyses are ongoing for both the Hans algorithm and NanoString technology.

Abstract 474: Lenalidomide maintenance significantly improves survival in patients (n = 46) with relapsed ­DLBCL who are not eligible for autologous hematopoietic cell transplantation (AHCT): Final results of a multicenter phase II trial3

Study Endpoint: The primary study endpoint was 1-year progression-free survival.

Abstract Conclusion: All patients were previously treated with anthracycline- and rituximab-based combination therapy, plus AHCT in six patients. Median time to progression after the prior therapy was 16 months. Relapsed disease was responsive to rituximab in all enrolled patients, and salvage therapy contained high doses of cytarabine or ifosfamide in two-thirds of cases. Patients received maintenance lenalidomide at 25 mg/d for 21 days out of 28, until lymphoma progression or unacceptable toxicity. At 1 year from trial registration, 28 patients were still progression-free, which was significantly higher than the predetermined efficacy threshold (n ≥ 19). The benefit of lenalidomide maintenance was observed in both patients with de novo and those with transformed DLBCL. According to the Hans algorithm, the 1-year progression-free survival was 64 ± 11% for GCB DLBCL and 67 ± 11% for non-GCB DLBCL (P = .67). Overall, 33 patients (72%) are alive, with 1- and 3-year overall survival of 81 ± 6% and 71 ± 8%, respectively.

Clinical Implications: With the limitations of a nonrandomized design and small numbers, this trial promotes the use of lenalidomide maintenance in patients with chemosensitive relapse of DLBCL not eligible for AHCT or experiencing relapse after AHCT. Lenalidomide was well tolerated, with a survival benefit in patients with de novo or transformed DLBCL and in patients with GCB or non-GCB DLBCL.

Abstract 1115: A multi-institutional outcomes analysis of patients with relapsed or refractory DLBCL treated with ibrutinib4

Study Background: This retrospective analysis focused on outcomes in patients with relapsed or refractory ­DLBCL treated with ibrutinib (Imbruvica) at a number of large academic medical centers. A total of 27 patients had de novo DLBCL and 8 patients had transformed DLBCL from indolent lymphoma. There were 21 cases of non-GCB, 9 cases of GCB, and 5 unknown using the Hans criteria.

Abstract Conclusion: The overall response rate to ibrutinib was 29%, with 4 patients achieving a complete remission and 6 patients achieving a partial remission. The median progression-free survival was comparable for patients with the GCB, non-GCB, and unknown subtypes (3.9, 2.2, and 4.1 months, respectively, P = .382). The median overall survival was longer for patients with the GCB subtype (10.5 months) than for those with the non-GCB subtype (5.5 months); it was 9.7 months for those with an unknown subtype, but this difference was not statistically significant (P = .564).

Clinical Implications: Response rates to single-agent ibrutinib in the GCB and non-GCB subtypes of relapsed or refractory DLBCL do not seem to differ when using the Hans algorithm to assign subtypes or between de novo or transformed lymphoma. The progression-free survival and overall survival were modest in both groups and not statistically different.

Primary Mediastinal B-Cell Lymphoma

Abstract 1116: DA-EPOCH-R in primary mediastinal B-cell lymphoma: Analysis of end of therapy 18F-fluorodeoxyglucose–positron-emission tomography (FDG-PET) and outcome5

Study Goals: To investigate the predictive value of the end of therapy FDG-PET following DA-EPOCH-R and provide updated results from the National Cancer Institute and Stanford University Hospital publication of primary mediastinal B-cell lymphoma6

Abstract Conclusion: DA-EPOCH-R (without radiation) is highly effective in primary mediastinal B-cell lymphoma and is associated with an event-free survival of 90% with long-term follow-up. A negative FDG-PET at the end of therapy has a negative predictive value of 98%. Even among patients with a positive FDG-PET at the end of therapy, 80% are cured of disease and achieve long-term remission.

Clinical Implications: These results demonstrate that end-of-therapy Deauville 4–5 FDG-PET scans following DA-EPOCH-R do not accurately identify patients with residual disease in most cases and should not be used to justify mediastinal radiation. In the absence of disease progression on computed tomography scans, patients with positive FDG-PET scans at the end of therapy should be carefully monitored with a short interval (eg, 4–6 weeks); before instituting further therapy, FDG-PET scans should be repeated to assess progressive changes in standardized uptake values and the need for biopsy. ■

Disclosure: Dr. Abutalib reported no potential conflicts of interest.

References

1. Wilson WH, Ho JS, Pitcher BN, et al: Phase III randomized study of R-CHOP versus DA-EPOCH-R and molecular analysis of untreated diffuse large B-cell lymphoma: CALGB/Alliance 50303. 2016 ASH Annual Meeting. Abstract 469.

2. Thieblemont C, Tilly H, da Silva MG, et al: First analysis of an international double-blind randomized phase III study of lenalidomide maintenance in elderly patients with DLBCL treated with R-CHOP in first line, the Remarc Study from Lysa. 2016 ASH Annual Meeting. Abstract 471.

3. Ferreri AJM, Sassone M, Zaja F, et al: Lenalidomide maintenance significantly improves survival figures in patients with relapsed (DLBCL) who are not eligible for autologous stem cell transplantation (ASCT): Final results of a multicentre phase II trial. 2016 ASH Annual Meeting. Abstract 474.

4. Winter AM, Landsburg DJ, Hernandez-Ilizaliturri FJ, et al: A multi-institutional outcomes analysis of patients with relapsed or refractory diffuse large B-cell lymphoma treated with ibrutinib. 2016 ASH Annual Meeting. Abstract 1115.

5. Melani CJ, Advani R, Chen CC, et al: DA-EPOCH-R in primary mediastinal B-cell lymphoma: Analysis of end of therapy FDG-PET and outcome. 2016 ASH Annual Meeting. Abstract 1116.

6. Dunleavy K, Pittaluga S, Maeda LS, et al: Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368:1408-1416, 2013.



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