Selected Abstracts From the 2016 ASH Annual Meeting

Indolent 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 follicular lymphoma. For full details of these study abstracts, visit http://www.bloodjournal.org/content/128/22.

Follicular Lymphoma

Abstract 6: Obinutuzumab-based induction and maintenance prolongs progression-free survival in patients with previously untreated follicular lymphoma: Primary results of the randomized phase III GALLIUM study1

Question Asked: What are the efficacy and safety of rituximab (Rituxan) and obinutuzumab (Gazyva) with a variety of different chemotherapy regimens (cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP]; cyclophosphamide, vincristine, prednisone [CVP]; or bendamustine) followed by maintenance as first-line treatment in follicular lymphoma (grades 1–3A)?

Abstract Conclusion: The current data are from a planned interim efficacy analysis done when 67% of the 370 progression-free survival events had occurred (cutoff date: January 31, 2016), after which the study was unblinded on independent data-monitoring committee recommendation. In patients with previously untreated follicular lymphoma, obinutuzumab-based chemotherapy (n = 601) and maintenance resulted in a clinically meaningful improvement in progression-free survival, with a 34% reduction in the risk of a progression-free survival event relative to rituximab-based therapy (n = 601). The frequency of some adverse events (eg, infusion-related reactions, cytopenias, and infections) was higher with obinutuzumab.

Clinical Implications: These data support obinutuzumab-based chemotherapy becoming a new standard of care in previously untreated patients with follicular lymphoma.

Abstract 1099: Rituximab plus lenalidomide (n = 77) vs rituximab monotherapy (n = 77) in untreated follicular lymphoma patients in need of therapy: First analysis of survival endpoints of the randomized phase II trial SAKK 35/102

Question Asked: How did the combination therapy affect the secondary endpoints of progression-free survival, time to next antilymphoma treatment, duration of complete remission, and complete remission rate at 30 months?

Abstract Conclusion: The results of the primary endpoint (complete remission at week 23) previously showed that the addition of lenalidomide (Revlimid) to rituximab significantly increased the complete remission rate at the expected cost of increased but manageable toxicity. The increased complete remission rate and was maintained throughout 30 months (42% vs 19%, P = .001). Although the trial was not powered to detect survival differences (secondary endpoints), a significantly better time to next antilymphoma treatment (median not reached vs 2.1 years, P = .02) and a trend toward prolonged progression-free survival (median not reached vs. 2.3 years) and duration of complete remission (median not reached vs 2.3 years) were seen with the combination arm. Adverse events of grade ≥ 3 were more common in the combination arm (56% vs 22%), including neutropenia (23% vs 7%).

Clinical Implications: The excellent overall survival in both arms suggests that chemotherapy-free strategies should be further explored in patients with follicular lymphoma in need of therapy.

Abstract 1104: Vitamin D insufficiency is associated with an increased risk of early clinical failure in follicular lymphoma3

Question Asked: Is vitamin D insufficiency predictive of early clinical failure, overall survival, and lymphoma-specific survival among patients with follicular lymphoma?

Abstract Conclusion: The study tested the hypothesis that vitamin D insufficiency is predictive of early clinical failure (failure to achieve event-free survival at 12 months), overall survival, and lymphoma-specific survival among patients with follicular lymphoma overall and in subgroups who were initially observed or treated with immunochemotherapy, rituximab monotherapy, or other therapies. Vitamin D insufficiency was defined as serum total 25-hydroxyvitamin D [25(OH)D] < 20 ng/mL (per Institute of Medicine criteria) determined within 120 days of diagnosis.

The prospective cohort included 642 newly diagnosed patients with grades 1–3A follicular lymphoma enrolled from 2002- to 2012 in the Molecular Epidemiology Resource of the Iowa/Mayo Lymphoma SPORE. Overall, 19% of patients had vitamin D insufficiency.

In the full cohort (n = 642), vitamin D insufficiency was associated with inferior event-free survival at 12 months (odds ratio = 2.05; 95% confidence interval [CI]: 1.18–3.54), overall survival (hazard ratio [HR] = 2.35; 95% CI: 1.37–4.02), and lymphoma-specific survival (HR = 2.97; 95% CI: 1.52–5.80).

Clinical Implications: The study confirmed previous findings that vitamin D insufficiency is associated with adverse long-term prognosis among patients with follicular lymphoma treated with chemoimmunotherapy and extend these findings to patients who are initially observed or treated with other therapies.

Abstract 1103: Longer term efficacy and safety of subcutaneous compared with intravenous rituximab: Updated results of the phase III SABRINA Study.4 The study investigated induction intravenous or subcutaneous rituximab plus chemotherapy followed by maintenance intravenous or subcutaneous rituximab in patients with follicular lymphoma.

Question Asked: How does subcutaneous rituximab measure up with intravenous rituximab in terms of efficacy?

Abstract Conclusion: Pharmacokinetic noninferiority was previously reported for subcutaneous rituximab (1,400 mg) compared with intravenous rituximab (375 mg/m2) as well as comparable efficacy and safety. The study reported updated results including objective response rate at the end of maintenance and time-to-event data (progression-free, overall, and event-free survival), with a median follow-up of 37 months.

Overall, there were no new clinically relevant safety signals observed with subcutaneous rituximab, and the safety profile was comparable to that of intravenous rituximab. Response rates as well as progression-free and overall survival data for subcutaneous rituximab (n = 205) were comparable to those for intravenous rituximab (n = 205), indicating that the antilymphoma activity of rituximab is not impaired when given subcutaneously.

Clinical Implications: The availability of subcutaneous administration over approximately 6 minutes seems to have positive implications for patient and health-care professional convenience, as well as health-care resource savings, without compromising efficacy or safety.

Abstract 614: Sequential rituximab plus CHOP (R-CHOP) x 6 cycles, radioimmunotherapy followed by rituximab maintenance every 3 months for up to 4 years improves early outcomes in advanced stage follicular lymphoma: 5 year outcomes from SWOG 08015

Question Asked: Is consolidative radioimmunotherapy and sequential maintenance rituximab useful in patients with advanced-stage follicular lymphoma after chemoimmunotherapy induction?

Abstract Conclusion: Of the 84 evaluable patients, 73 completed R-CHOP and iodine-131 tositumomab (Bexxar). Following induction and radioimmunotherapy, 59 complete responses and 23 partial responses were observed, for an objective response rate of 99% (95% CI: 93.5%–99.9%). A total of 69 eligible patients registered to maintenance therapy, with 42 completing the 4-year treatment plan.

Four additional secondary malignancies were reported following completion of therapy, including solid tumors (n = 3) and acute myeloid leukemia (n = 1). After median follow-up of 5.6 years (range, 3–7 years), 17 events have occurred, including 9 patients experiencing progressive follicular lymphoma. Progression-free survival rates reported were 90% (95% CI: 81.9%–95.1%) at 3 years and 84% (95% CI: 74.5%–90.6%) at 5 years. Three-year overall survival is 96% (95% CI: 89.3%–98.8%), and 5-year overall survival is 94% (95% CI: 86.2%–97.5%).

Clinical Implications: This sequential therapeutic strategy appears to improve early outcomes, as 94% of patients are without disease progression at 2 years; these findings are consistent with the best results ever demonstrated for follicular lymphoma in the National Clinical Trials Network. Given these promising outcomes, future studies investigating precision strategies in high-risk follicular lymphoma may consider an aggressive chemoimmunotherapy induction and radioimmunotherapy consolidation platform to overcome early progression of follicular lymphoma.

Abstract 1100: Chimeric antigen receptor–modified T cells directed against CD19 (CTL019) in patients (n = 14) with a poor prognosis, relapsed or refractory CD19-positive follicular lymphoma: Prolonged remissions relative to antecedent therapy6

Question Asked: Is CTL019 safe and effective in the treatment of patients with relapsed or refractory follicular lymphoma?

Abstract Conclusion: Nine patients with follicular lymphoma grades 1 to 2 and five patients with follicular lymphoma grade 3A were enrolled in this ongoing phase IIa clinical trial. The median number of prior therapies was 5 (range, 2–10), and the number of patients with a prior transplant was 3 (autologous transplant = 2, allogeneic transplant = 1).

The objective response rate at 3 months was 79%, with a complete remission rate of 50%. At 6 months, two of three patients with partial remission converted to complete remission. Best response was complete remission in 64% of patients. One patient with partial remission at 3 months, who remained in partial remission at 6 and 9 months, ultimately had disease progression at 13 months. At the median follow-up of 11.4 months from a single infusion of CTL019, the proportion of patients who were progression-free was 77% (95% CI: 45%–92%), and the median time to next antilymphoma treatment had not yet been reached compared with 7.2 months (95% CI: 4.4–13.8 months) for antecedent therapy (P < .001, log rank).

Cytokine-release syndrome occurred in six patients (four, grade 2; one, grade 3, one, grade 4) and did not predict response. Other toxicities included one episode of grade V encephalitis, possibly related to therapy; this patient remained in complete remission at the time of death.

Clinical Implications: The study suggests that a single treatment with CTL019 cells has efficacy in patients with relapsed or refractory follicular lymphoma. ■

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

References

1. Marcus RE, Davies AJ, Ando K, et al: Obinutuzumab-based induction and maintenance prolongs progression-free survival in patients with previously untreated follicular lymphoma: Primary results of the randomized phase 3 GALLIUM study. 2016 ASH Annual Meeting. Abstract 6. Presented December 4, 2016.

2. Kimby E, Rondeau S, Vanazz A, et al: Rituximab plus lenalidomide versus rituximab monotherapy in untreated follicular lymphoma patients in need of therapy: First analysis of survival endpoints of the randomized phase-2 trial SAKK 35/10. 2016 ASH Annual Meeting. Abstract 1099. Presented December 5, 2016.

3. Tracy SI, Maurer MJ, Witzig TE, et al: Vitamin D insufficiency is associated with an increased risk of early clinical failure in follicular lymphoma. 2016 ASH Annual Meeting. Abstract 1104. Presented December 5, 2016.

4. Davies AJ, Mihaljevic B, Mercadal S, et al: Longer term efficacy and safety of subcutaneous compared with intravenous rituximab: Updated results of the phase 3 SABRINA study. 2016 ASH Annual Meeting. Abstract 1103. Presented December 5, 2016.

5. Barr PM, Li H, Burack R, et al: Sequential RCHOP, radioimmunotherapy and rituximab maintenance improves early outcomes in advanced stage follicular lymphoma: 5 year outcomes from SWOG 0801. 2016 ASH Annual Meeting. Abstract 614. Presented December 5, 2016.

6. Chong EA, Svoboda J, Dwivedy Nasta S, et al: Chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with poor prognosis, relapsed or refractory CD19+ follicular lymphoma: Prolonged remissions relative to antecedent therapy. 20 16 ASH Annual Meeting. Abstract 1100. Presented December 5, 2016.



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