Triplet Combination With Vorinostat Shows High Response Rate in Frontline MCL

Stephen E. Spurgeon, MD

Stephen E. Spurgeon, MD

A combination of vorinostat (Zolinza), cladribine, and rituximab (Rituxan) demonstrated high, durable rates of complete response (CR) in patients with previously untreated mantle cell lymphoma (MCL), according to the results of a phase I/II trial of the triplet regimen in patients with non-Hodgkin lymphoma (NHL).

Among patients with newly diagnosed MCL, the objective response rate (ORR) was 97% and the CR rate was 80%.

The study authors, led by Stephen E. Spurgeon, MD, of the Center for Hematologic Malignancies at the Knight Cancer Institute of Oregon Health & Science University in Portland, said that “the response rates and [progression-free survival (PFS)] seen with the [vorinostat, cladribine, and rituximab] regimen compare favorably with other less intensive induction regimens.”

The study was an open-label, non-blinded, investigator-initiated, single-arm phase I/II trial to assess the safety, efficacy, and potential synergy of the addition of vorinostat to cladribine and rituximab for patients with NHL.

The phase I portion enrolled 10 patients with relapsed or refractory CD20-positive small lymphocytic lymphoma, chronic lymphocytic leukemia (CLL), follicular lymphoma, MCL, and diffuse large B-cell lymphoma (DLBCL). All patients had an ECOG performance status of 0 to 2 and adequate hepatic and renal function. Those who were receiving other HDAC inhibitors or concurrent immunotherapy, chemotherapy, or radiation were ineligible for enrollment, as well as those who had HIV, active hepatitis B, or other malignancies.

Patients in the phase I portion were treated in a 3+3 dose-escalation design with 200, 300, or 400 mg of oral vorinostat once daily for days 1 to 14 as well as intravenous cladribine 5 mg/m²for days 1 to 5 and intravenous rituximab 375 mg/m²administered weekly for the first cycle then once a month for up to 6 cycles of 28 days. Dose reductions of rituximab were not allowed and all patients who were intolerant of rituximab were removed from the study.

Pneumocystis(PJP) prophylaxis was mandated after 1 patient developedPJP.Anti-CD20 maintenance therapy was also allowed after completion of the protocol-specified therapy.

Of the 10 patients in phase I, 6 were male and 4 were female, and the median age was 64.5 years (range, 45-84). The majority had CLL (n = 5) followed by DLBCL (n = 3) and MCL (n = 2). The median number of prior therapies received was 2.4 (range, 1-6).

The ORR was 40%, which consisted of 1 CR in a patient with MCL and 3 partial responses in 2 patients with CLL and 1 with MCL; none of the patients with DLBCL responded to the triplet.

No dose-limiting toxicities were observed across the 3 doses of vorinostat. The most common hematologic grade ≥3 treatment-emergent adverse events were neutropenia (80%), thrombocytopenia (60%), and anemia (50%). Common non-hematologic grade ≥3 toxicities included fatigue (30%), infection (30%), hypokalemia (40%), and hypophosphatemia (30%).

The phase II dose of vorinostat was determined to be 400 mg, as it is the FDA-approved dose when administered to patients with cutaneous T-cell lymphoma.

The phase II portion consisted of 2 cohorts: one of patients with relapsed NHL minus those with DLBCL (n = 18), and a second for patients with newly diagnosed MCL (n = 39). Patients with DLBCL were excluded due to the lack of activity seen in phase I. Of the previously treated NHL cohort, 10 had relapsed MCL, 3 had relapsed CLL, 2 had relapsed follicular lymphoma, and 3 had relapsed marginal zone lymphoma. In the untreated MCL cohort, 95% of patients had stage IV disease. Overall, the median age across the 2 cohorts was 61.5 years (range, 35-87) and the majority of patients were male (86%).

The primary endpoint across phase II was ORR, and 39% (95% CI, 17%-64%) of patients in the relapsed NHL cohort responded to treatment, including 30% of patients with relapsed MCL. Of note in the previously untreated MCL cohort, 92% of patients with non-blastoid variant achieved a CR.

Median follow-up was 42.0 months (95% CI, 39.0-52.0), which was extended to 43.0 months (95% CI, 37.0-59.0) in the previously untreated MCL cohort.

In the relapsed NHL cohort, the median PFS was 19.5 months (95% CI, 2.0-33.0) and the median overall survival (OS) was 25.0 months (95% CI, 12.0-45.0). At 4 years, the PFS rate was 20.8% (95% CI, 5.8%-42.1%). Among the patients with relapsed MCL specifically, the median PFS was 5.5 months (95% CI, 0.0-24.0) and the median OS was 14.5 months (95% CI, 0.0-33.0).

In the previously untreated MCL cohort, the median PFS was 84.0 months (95% CI, 30.0-not reached) and the median OS could not be estimated. The PFS rate at 4 years was 61.5% (95% CI, 43.5%-75.3%). Eleven patients in the cohort have relapsed and 3 have died.

Grade ≥3 adverse events were similar between the 2 cohorts. The most common hematologic malignancies in phase II were neutropenia (67%), thrombocytopenia (42%), and anemia (14%). One patient with relapsed MCL and extensive pulmonary involvement died due to pulmonary hemorrhage during cycle 1.

Patients who achieved a CR were tested for minimal residual disease (MRD) on the peripheral blood by reverse transcription polymerase chain reaction for both cyclin D1 andSOX11. Fourteen patients were considered MRD negative.

The study authors concluded that epigenetic therapy, such as with the triplet regimen, is worthy of further study in MCL.

Reference:Spurgeon SE, Sharma K, Claxton DF, et al. Phase 1-2 study of vorinostat (SAHA), cladribine and rituximab (SCR) in relapsed B-cell non-Hodgkin lymphoma and previously untreated mantle cell lymphoma [published online June 9, 2019].Br J Haematol.doi: 10.1111/bjh.16008.