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 various types of high-grade, aggressive non-Hodgkin lymphomas (NHLs), including peripheral T-cell lymphomas, central nervous system lymphomas, and Richter’s transformation. For full details of these study abstracts, visit http://www.bloodjournal.org/content/128/22.

Peripheral T-Cell Lymphoma

Abstract 2989: GDPT vs CHOP in newly diagnosed peripheral T-cell lymphoma: A prospective randomized controlled, open-label study¹

Study Endpoints: The efficacy and safety of gemcitabine, cisplatin, prednisone, and thalidomide (Thalomid; GDPT; n = 52) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; n = 51) regimens for patients with newly diagnosed peripheral T-cell lymphoma (PTCL)

Abstract Conclusion: The complete response rate and overall response rate of the GDPT group were higher than those in the CHOP group (52% vs 33%, P = .044 for complete response rate; 67% vs 49%, P = .046 for overall response rate). The 2-year progression-free and overall survival rates were better in the GDPT group than in the CHOP group (57% vs 35% for progression-free survival, P = .0035; 71% vs 50% for overall survival, P = .0001). Acute toxicity was comparable and tolerable in both arms.

Clinical Implications: GDPT chemotherapy resulted in significant improvement in progression-free and overall survival compared with CHOP chemotherapy, and the side effects of chemotherapy were well tolerated. GDPT is a promising new regimen in the first-line setting.

Abstract 2993: Four-year survival and durability results of brentuximab vedotin in combination with CHP in the front-line treatment of patients with CD30-­expressing PTCL [including ALCL]²

Study Outcomes: Four-year survival and durability results plus updated results on peripheral neuropathy resolution

Abstract Conclusion: Of the 26 patients who achieved remission with combination treatment (brentuximab vedotin [Adcetris] and cyclophosphamide, doxorubicin, and prednisone [CHP]), 21 went on to receive single-agent brentuximab vedotin. The estimated 4-year progression-free survival and overall survival rates were 52% (95% confidence interval [CI] = 31%–69%) and 80% (95% CI = 59%–91%), respectively. The median progression-free survival has not been reached. Five patients (19%) received subsequent treatment with single-agent brentuximab vedotin in long-term follow-up, and three patients received transplants (one autologous and two allogeneic) for relapsed disease. There were no patients who underwent a consolidative hematopoietic cell transplant (HCT).

Of the 26 patients treated with combination therapy, 19 patients (73%) experienced peripheral neuropathy. Of these patients, 95% (18 of 19 patients) experienced complete resolution (8 patients) or some resolution or improvement (defined as a decrease by at least 1 grade from the worst grade, 10 patients). The median time to resolution of symptoms of peripheral neuropathy was 5.7 months. At the last follow-up, 11 patients had ongoing neuropathy.

Clinical Implications: This therapeutic strategy can induce long-term remissions with a tolerable safety profile. A phase II randomized trial comparing brentuximab vedotin plus CHP with CHOP for the front-line treatment of CD30-expressing PTCL is ongoing (NCT01777152).

Central Nervous System Lymphoma

Abstract 783: Ibrutinib in recurrent/refractory, primary and secondary central nervous system (CNS) lymphomas³

Study Endpoints: The efficacy and toxicity of ibrutinib (Imbruvica) in CNS lymphomas. In patients with secondary CNS lymphomas, systemic disease needed to be absent.

Abstract Conclusion: A total of 20 patients were enrolled (3 at 560 mg; 17 at 840 mg); 65% had primary CNS lymphoma, and 35% had secondary CNS lymphoma; 70% had recurrent disease. A total of 11 patients had parenchymal disease, 3 had isolated cerebrospinal fluid involvement, and 6 had both. Five grade 4 adverse events were observed in 4 patients (lymphopenia [2], sepsis [1], neutropenia [2]). The most common toxicities were hyperglycemia, anemia, and thrombocytopenia. After a median follow-up of 193 days, 19 of 20 patients were evaluated for response: 8 had complete remission, 7 had partial remission, 1 had stable disease and 3 had progressive disease; the overall response rate was 75% (15 of 20 patients). The median progression-free survival was 7.29 months (95% CI = 3.80–15.43 months ([longest: 15.3 months]).

Clinical Implications: Clinical response was seen in 75% of patients with CNS lymphomas. An additional treatment arm has been added to the trial, which will evaluate the adverse events of the combination of ibrutinib and high-dose methotrexate chemotherapy.

Abstract 785: Rituximab/lenalidomide in relapsed or primary CNS lymphoma or vitreoretinal lymphoma: Results of a ‘proof of concept’ phase II study of the French LOC Network⁴

Study Endpoint: The primary endpoint was the overall response rate at the end of the induction phase, according to the International Primary CNS Lymphoma Collaborative Group (IPCG) criteria.

Abstract Conclusion: A total of 45 patients were evaluable for response after the first cycle of treatment. At the end of the induction phase, 43 patients were evaluable for the primary objective.

The overall response rate was 39% (17 of 43 patients), including 13 complete remissions (30%). A response has been observed in patients included for a primary CNS lymphoma (n = 13, 32%) and an intraocular relapse or vitreoretinal lymphoma (n = 4, 44%). Seventeen patients started the maintenance phase. With a median follow-up of 9 months (range, 1.1–15.4 month), median overall survival and progression-free survival of the whole population were 15.3 months (95% CI = 9.6 to not reached) and 8.1 months (95% CI = 4.2 to not reached), respectively. The median duration of response in the responding patients was 8.9 months (95% CI = 7.6 to not reached).

Clinical Implications: This phase II study demonstrates a significant activity of the rituximab (Rituxan)/lenalidomide (Revlimid) regimen in relapsed or refractory primary CNS lymphoma or vitreoretinal lymphoma. Updated results with a longer follow-up are awaited to better evaluate the progression-free survival and the median duration of response.

Richter’s Transformation

Abstract 4392: PD-1 blockade with pembrolizumab in relapsed chronic lymphocytic leukemia (CLL) including Richter’s transformation (n = 9): An updated report from a phase II trial (MC1485).⁵ Patients with prior allogeneic HCT were excluded. Pembrolizumab (Keytruda) at 200 mg was administered intravenously every 3 weeks.

Study Background: Approximately 7% to 15% of patients with relapsed CLL treated with ibrutinib or venetoclax (Venclexta) developed Richter’s syndrome, an aggressive high-grade lymphoma transformation. Standard chemotherapy has limited efficacy in Richter’s syndrome. Investigators hypothesized that checkpoint blockade would reestablish antitumor immune response in progressive CLL/Richter’s syndrome, and here we aim to update the clinical data and correlative analysis of MC1485. The primary endpoint of this study was overall response rate.

Abstract Conclusion: Among the nine patients with Richter’s syndrome, one complete remission (11%), three partial remissions (33%), three cases of stable disease (33%), and two cases of progressive disease (22%) were observed. The overall response rate in those with Richter’s syndrome was 44%. No patient with CLL (n = 16) achieved a complete remission/partial remission, three had stable disease, and nine had progressive disease. The overall response rate of all patients (n = 25) was 16%. In particular, six patients with Richter’s syndrome who had prior ibrutinib experienced complete or partial remission or stable disease with nodal responses. Drug-related grade 3 or above adverse events occurred in nine patients (38%), with the most common being thrombocytopenia, dyspnea, and fatigue. The most common immune-related adverse event was liver enzyme elevation, and it was reversible with therapy interruption or steroid therapy.

Clinical Implications: Early efficacy was observed in heavily pretreated patients with Richter’s syndrome, including those whose disease progressed on both anthracycline-based treatment and ibrutinib. These results indicate that programmed cell death protein 1 (PD-1) inhibition is a promising novel approach in patients with Richter’s syndrome.

T-Cell Lymphoma

Abstract 2991: Phase Ib/IIa trial of the combination of romidepsin, lenalidomide, and carfilzomib shows complete responses in relapsed or refractory T-cell lymphomas⁶

Study Goals: To evaluate the safety and toxicity of romidepsin (Istodax) and lenalidomide in combination with carfilzomib (Kyprolis) in patients with relapsed or refractory lymphomas. Romidepsin and carfilzomib were given intravenously on days 1 and 8, and lenalidomide was given orally on days 1 to 14 of a 21-day cycle.

Abstract Conclusion: Of the 16 patients with T-cell lymphoma evaluable for response, the overall response rate was 50% (8/16, 95% CI = 25%–75%). The complete remission rate was 31% (5 of 16, 95% CI = 11%–59%), and the partial response rate was 19% (3 of 16, 95% CI = 4%–46%). The complete remissions were seen in patients with angioimmunoblastic T-cell lymphoma (four of five) and PTCL–not otherwise specified (one of eight), with three patients in complete remission proceeding to allogeneic HCT. A partial response was seen in PTCL–not otherwise specified, angioimmunoblastic T-cell lymphoma, and transformed myelofibrosis. In T-cell lymphoma, the median event-free survival for all patients was 9.7 weeks (95% CI = 6.0 to not reached) and for responders, it was not reached (95% CI = 15.0 weeks to not reported). The median duration of response was 9.6 weeks (95% CI = 8.0 to not reported). The maximum tolerated doses for phase II study were identified as 8 mg/m² of romidepsin, 15 mg of lenalidomide, and 36 mg/m² of carfilzomib.

Clinical Implications: No unexpected toxicities have emerged. The preliminary overall and complete response rates of this regimen are promising in T-cell lymphoma, particularly in patients with angioimmunoblastic T-cell lymphoma, and it warrants further study. ■

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

References

1. Li L, Duan W, Young KH, et al: GDPT versus CHOP in newly diagnosed peripheral T-cell lymphoma: A prospective randomized controlled, open-label study. 2016 ASH Annual Meeting. ­Abstract 2989.

2. Fanale MA, Horwitz SM, Forero-Torres A, et al: Four-year survival and durability results of brentuximab vedotin in combination with CHP in the frontline treatment of patients with CD30-expressing peripheral T-cell lymphomas. 2016 ASH Annual Meeting. Abstract 2993.

3. Grommes C, Pastore A, Gavrilovic I, et al: Single-agent ibrutinib in recurrent/refractory central nervous system lymphoma. 2016 ASH Annual Meeting. Abstract 783.

4. Ghesquieres H, Houillier C, Chinot O, et al: Rituximab-lenalidomide in relapse or refractory primary central nervous system or vitreo retinal lymphoma: Results of a ‘proof of concept’ phase II study of the French LOC Network. 2016 ASH Annual Meeting. Abstract 785.

5. Ding W, Le-Rademacher J, Call TB, et al: PD-1 blockade with pembrolizumab in relapsed CLL including Richter’s transformation: An updated report from a phase 2 trial (MC1485). 2016 ASH Annual Meeting. Abstract 4392.

6. Mehta-Shah N, Moskowitz AJ, Lunning M, et al: A phase Ib/IIa trial of the combination of romidepsin, lenalidomide and carfilzomib in patients with relapsed/refractory lymphoma shows complete responses in relapsed and refractory T-cell lymphomas. 2016 ASH Annual Meeting. Abstract 2991.