Vorinostat Triplet Elicits High Responses in Newly Diagnosed MCL

Stephen E. Spurgeon, MD

The triplet regimen of vorinostat (Zolinza), cladribine, and rituximab (Rituxan) demonstrated an objective response rate (ORR) of 97% and a complete response (CR) rate of 80% in newly diagnosed patients with mantle cell lymphoma (MCL), according to results of a phase I/II study.

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

The open-label, non-blinded, investigator-initiated, single-arm phase I/II trial assessed 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/m² for days 1 to 5 and intravenous rituximab at 375 mg/m² administered 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 developed PJP. 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).

Results showed that 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: relapsed NHL minus those with DLBCL (n = 18), and newly diagnosed MCL (n = 39). Patients with DLBCL were excluded due to the lack of activity seen in the phase I portion. Of the previously treated NHL cohort, 10 patients 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 the phase II portion 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.

Regaridng safety, 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 and SOX11;14 patients were considered MRD negative.

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.