Selected Abstracts From the 2016 ASH Annual Meeting

Indolent Lymphomas: Part 2


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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 several different types of non-Hodgkin lymphomas (NHLs), including mantle cell lymphoma and marginal zone lymphoma. For full details of these study abstracts, visit http://www.bloodjournal.org/content/128/22.

Abstract 145: Rituximab maintenance after autologous hematopoietic cell transplantation (AHCT) prolongs survival in younger patients with mantle cell lymphoma: Final results of the randomized phase III LyMa trial of the Lysa/Goelams group.1

Question Asked: Does rituximab (Rituxan) maintenance (one infusion of rituximab [375 mg/m2] every 2 months for 3 years) improve outcomes in young, previously untreated patients with mantle cell lymphoma?

Abstract Conclusion: The LyMa trial demonstrates for the first time that rituximab maintenance after AHCT prolongs event-free, progression-free, and overall survival. The event-free survival duration was significantly superior in the rituximab maintenance arm, with a 54.3% reduction in the risk of event (hazard ratio [HR] = 0.457; 95% confidence interval [CI]: 0.28–0.74; P = .0016). The median progression-free and overall survival from randomization were not reached in both arms. The 4-year progression-free and overall survival from randomization were superior with rituximab maintenance than without: 82.2% (95% CI: 73.2%–88.4%) vs 64.6% (95% CI: 54.6%–73%; P = .0005) and 88.7% (95% CI: 80.7%–93.5%) vs 81.4% (95% CI: 72.3%–87.7%; P = .0413), respectively. Patients in the rituximab maintenance arm had a 60% reduction in the risk of disease progression (HR = 0.4; 95% CI: 0.23–0.68; P = .0007) and a 50% reduction in the risk of death (HR = 0.5; 95% CI: 0.25–0.98;
P = .0454).

Clinical Implications: These data demonstrate for the first time that extended rituximab therapy after AHCT prolongs event-free, progression-free, and overall survival.

Abstract 146: Molecular monitoring and tailored strategy with preemptive rituximab treatment for molecular relapse: Results from the Nordic MCL studies (MCL2 and MCL3) with median follow-up of 8.5 years.2

Questions Asked: What is the value of minimal residual disease monitoring in guiding preemptive treatment with rituximab? What is its value in predicting clinical relapse in mantle cell lymphoma following AHCT in two prospective trials with long-term follow-up conducted by the Nordic Lymphoma Group?

Abstract Conclusion: Patients who were minimal residual disease–negative after AHCT had significantly longer relapse-free and overall survival compared with those who were minimal residual disease–positive (P < .001). A total of 58 patients with minimal residual disease relapse received preemptive treatment on one or more occasions. Conversion back to a minimal residual disease–negative state was achieved in the majority of cases (82%) after rituximab treatment. The median time from molecular relapse to clinical relapse in patients who received preemptive rituximab was 55 months.

In a multivariate analysis, significant predictors of molecular relapse were Mantle Cell International Prognostic Index (MIPI) high risk category at diagnosis (HR = 1.91; 95% CI: 1.37–2.66; P = .0001) and detection of minimal residual disease prior to AHCT (HR = 2.47; 95% CI: 1.49–4.09; P = .0005). Late minimal residual disease relapses continued to occur 5 to 10 years after AHCT, even in lower-risk groups.

Clinical Implications: Such findings argue in favor of minimal residual disease monitoring after AHCT in mantle cell lymphoma as a useful approach to select the minimal residual disease–positive patients for novel strategies in future trials and as an alternative to maintenance therapy for all patients with mantle cell lymphoma.

Abstract 1213: Single-agent ibrutinib demonstrates efficacy and safety in patients with relapsed and refractory marginal zone lymphoma: A multicenter, open-label, phase II study3

Question Asked: Is single-agent ibrutinib ­(Imbruvica) safe and effective in the treatment of patients with relapsed and refractory marginal zone lymphoma?

Abstract Conclusion: The median time on study was 16.6 months, and the median duration of therapy was 11.7 months. A total of 63 patients were enrolled. The overall response rate was 51% (6 complete responses and 26 partial responses). A total of 38% of all patients had stable disease, and the clinical benefit rate (complete remission, partial remission, and stable disease) was 89%, with 87% having some tumor reduction. The overall median duration of response was 19 months (95% CI: 8.0 to not reached). The median time to initial response was 4.2 months, and the median progression-free survival was 18 months (95% CI: 12.2 to not reached).

Grade ≥ 3 adverse effects occurred in 40 patients (63%). The most common events were anemia (14%), pneumonia (8%), and fatigue (6%). Serious adverse effects of any grade occurred in 28 patients (44%), with grade 3/4 pneumonia being the most common adverse effect (5 patients [8%]). Atrial fibrillation occurred in four patients (6%; all grade 1/2). Any-grade bleeding events occurred in 57% of patients, with a single grade III event of hematemesis and a single grade 5 cerebral hemorrhage. At least two patients appeared to have experienced pseudoprogression at weeks 9 and 13, which was confirmed by further follow-up; pseudoprogression phenomena associated with the use of ibrutinib were also reported at the 2016 ASH Annual Meeting in the phase II Dawn study.4

Clinical Implications: These data support the potential role of single-agent ibrutinib as an effective, chemotherapy-free strategy for relapsed and refractory marginal zone lymphoma.

Abstract 615: Obinutuzumab plus bendamustine followed by obinutuzumab maintenance prolongs overall survival compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma: Updated results of the GADOLIN study5

Question Asked: How does the combination of obinutuzumab ­(Gazyva) and bendamustine followed by obinutuzumab maintenance measure up with bendamustine induction alone in the treatment of rituximab-refractory indolent NHL?

Abstract Conclusion: In the primary analysis, which involved 396 patients enrolled as of September 1, 2014 (including 321 [81%] with follicular lymphoma), median progression-free survival was longer with the combination of obinutuzumab and bendamustine (n = 194; median not reached) than with bendamustine alone (n = 202; 14.9 months), with a 45% reduction in the risk of disease progression or death (HR = 0.55; 95% CI: 0.40–0.74; P = .0001). Now, updated time-to-event and safety results from a planned analysis of all 413 patients (including 335 with follicular lymphoma) using a data cutoff of April 1, 2016, have been reported. Findings demonstrated a significant improvement in overall survival with the combination of obinutuzumab and bendamustine over bendamustine alone. No new safety signals were detected.

After 31.8 months’ of median follow-up, median progression-free survival was 25.8 months in the combination therapy arm vs 14.1 months in the bendamustine arm; the hazard ratio was 0.57 (95% CI: 0.44–0.73; P < .0001)—representing a 43% reduction in the risk of disease progression or death with obinutuzumab and bendamustine. Fewer patients died in the combination therapy arm (25.5%) than in the bendamustine arm (34.9%), with a hazard ratio for overall survival of 0.67 (95% CI: 0.47–0.96; P = .0269; risk reduction, 33%); median overall survival was not reached for either arm.

Clinical Implications: These updated data confirm significant improvement of outcomes with the addition of obinutuzumab to bendamustine backbone over bendamustine alone in patients with rituximab-refractory indolent NHL.

Abstract 756: Molecular basis of ibrutinib resistance in Waldenström’s macroglobulinemia6

Question Asked: What are the molecular mechanisms associated with ibrutinib resistance in Waldenström’s macroglobulinemia?

Abstract Conclusion: Among eight patients with Waldenström’s macroglobulinemia who progressed on ibrutinib, five had Bruton’s tyrosine kinase (BTK) Cys481 mutations: three were positive for Cys481SerG>C and two were positive for all three mutations (Cys481SerG>C, Cys481SerT>A, and Cys481ArgT>C). Furthermore, targeted deep sequencing (> 300x coverage) confirmed all BTK Cys481 mutations and identified an additional mutation at Cys481 (Cys481TyrG>A) in both patients who were positive for Cys481SerG>C, Cys481SerT>A, and Cys481ArgT>C. In contrast, no BTK Cys481 mutations were identified in 100 ibrutinib-naive patients with Waldenström’s macroglobulinemia using the nested allele-specific–polymerase chain reaction assays. Among the eight patients with Waldenström’s macroglobulinemia included in this study, all had activating MYD88 mutations and four had CXCR4WHIM mutations. All four patients with CXCR4WHIM mutations had BTK Cys481 mutations.

The investigators next utilized targeted deep sequencing to expand the mutation analysis to the entire coding regions of the BTK, as well as select genes relevant to BCR and MYD88 signaling. A missense mutation in CARD11 (L878F) was identified in one patient who lacked any BTK Cys481 mutations, whereas a missense mutation in PLCG2 (Y495H) was found in another patient with a Cys481SerG>C mutation.

Clinical Implications: These study findings provide the first reported insights into the molecular mechanisms associated with ibrutinib resistance in Waldenström’s macroglobulinemia and highlight the emergence of multiple BTK-mutated clones within individual patients who progress on ibrutinib. ■

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

References

1. Le Gouill S, Thieblemont C, Oberic L, et al: Rituximab maintenance after autologous stem cell transplantation prolongs survival in younger patients with mantle cell lymphoma: Final results of the randomized phase 3 LyMa trial of the Lysa/Goelams group. 2016 ASH Annual Meeting. Abstract 145. Presented December 3, 2016.

2. Kolstad A, Pedersen LB, Winther Eskelund C, et al: Molecular monitoring and tailored strategy with pre-emptive rituximab treatment for molecular relapse: Results from the Nordic Mantle Cell Lymphoma studies (MCL2 and MCL3) with median follow-up of 8.5 years. 2016 ASH Annual Meeting. Abstract 146. Presented December 3, 2016.

3. Noy A, de Vos S, Thieblemont C, et al: Single-agent ibrutinib demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: A multicenter, open-label, phase 2 study. 2016 ASH Annual Meeting. Abstract 1213. Presented December 5, 2016.

4. Salles GA, Trotman J, Lill M, et al: Pseudo-progression among patients with follicular lymphoma treated with ibrutinib in the phase 2 DAWN study. 2016 ASH Annual Meeting. Abstract 2980. Presented December 4, 2016.

5. Cheson BD, Trněný M, Bouabdallah K, et al: Obinutuzumab plus bendamustine followed by obinutuzumab maintenance prolongs overall survival compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma: Updated results of the GADOLIN study. 2016 ASH Annual Meeting. Abstract 615. Presented December 5, 2016.

6. Xu L, Tsakmaklis N, Yang G, et al: Molecular basis of ibrutinib resistance in Waldenström’s macroglobulinemia. 2016 ASH Annual Meeting. Abstract 756. Presented December 5, 2016.



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