The peripheral T-cell lymphomas (PTCL) are uncommon lymphoid diseases that account for 5-10% of all non-Hodgkin lymphomas in adults in North America. Compared to B-cell non-Hodgkin lymphomas, the PTCLs are generally aggressive and less responsive to current treatment options. Relapsed and refractory diseases are common. Novel and target therapies are in much need to improve quality and duration of response. At the 2012 American Society of Hematology (ASH) meeting in Atlanta, several research groups reported encouraging study results with the antibody-drug conjugate Brentuximab vedotin for T-cell lymphomas. Brentuximab vedotin (BV) is an anti-CD30 chimeric antibody conjugated by a protease-cleavable linker to the microtubule-disrupting agent monomethyl auristatin E. BV received accelerated FDA approval in 2011 for relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), 2 diseases that express abundant CD30. Several new studies have looked at the treatment outcome of BV in patients with systemic or cutaneous T-cell lymphomas that express variable amount of CD30.
Studies in Systemic T-cell Lymphomas
Dr. Jacobsen from Dana Farber Cancer Institute reported an interim analysis of a phase II multicenter study which evaluated the antitumor activity of BV in patients with relapsed or refractory CD30-positive NHL. BV was administered at 1.8 mg/kg every 3 weeks by IV infusion. The study also explored the correlation between antitumor activity and quantitative CD30 expression. Fifty-three patients with various CD30-positive NHLs have been enrolled, including 18 patients with mature T-/NK-cell lymphomas. Of the T-cell lymphoma patients enrolled, 9 have angioimmunoblastic T-cell lymphoma (AITL), 8 have PTCL-NOS, and 1 has cutaneous T-cell lymphoma. The ORR was 27% (3/11) for mature T-/NK-cell NHLs. Thus far, response was particularly noteworthy in in AITL where 3 of 5 patients (60%) have responded (2 CR, 1 PR). Treatment-emergent adverse events were generally mild and moderate (grade 1/2), and expected including peripheral neuropathy and cytopenias, which was consistent with the safety profile of BV. CD30 expression levels for patients with a CR or PR were widely variable and ranged from <1% to 90%. Preliminary data seems to suggest that BV may be beneficial for patients with T-cell lymphomas that have low CD30 expression. Dr. Fanale from MD Anderson Cancer Center reported a phase I study with BV administered concurrently with multi-agent chemotherapy as frontline treatment of systemic ALCL and other CD30 positive T-cell lymphomas. The study was originally composed of 3 arms. Data were presented for 26 patients treated with combination of BV and CHP (CHOP without vincristine, to minimize overlapping neural toxicity). Patients received treatment with up to 6 cycles of 1.8 mg/kg BV in combination with standard-dose CHP chemotherapy administered every 3 weeks. Responders received subsequent single-agent brentuximab vedotin therapy for additional 8–10 cycles. Nineteen of 26 patients had a diagnosis of systemic ALCL and 7 patients had a diagnosis of another mature T- or NK-cell lymphoma, which included 2 peripheral T-cell lymphoma-NOS, 2 angioimmunoblastic T-cell lymphoma, 2 adult T-cell leukemia/lymphoma, and 1 enteropathy-associated T-cell lymphoma. All patients (100%) achieved an objective response, with 23 patients (88%) achieving a CR. All 7 non-sALCL patients achieved a CR with combination therapy. The treatment-related toxicities were generally tolerable, and in line as expected with CHOP therapy for the BV + CHP combination. Given these encouraging efficacy and safety data, a phase 3 study comparing CHOP to BV + CHP in the frontline treatment of mature T-cell lymphoma is planned and expected to enroll patients in US and globally in 2013.
Studies in Cutaneous T-cell Lymphomas
Dr. Youn Kim’s group from Stanford University reported a phase II study of BV in patients with relapsed and refractory mycosis fungoides / Sezary syndrome, a common form of cutaneous T-cell lymphoma. The study participants were treated with up to 8 cycles of brentuximab vedotin (1.8 mg/kg) administered every 3 weeks. CD30 expression levels in the skin were evaluated by routine immunohistochemistry to correlate response to the expression levels. A total of 19 subjects were enrolled and all received at least one dose of BV. The overall response rate was significant at 68%, and responses were observed in all clinical stages. Clinical responses were observed in those with all levels of CD30 expression. At a median study follow-up time of 36 weeks, 73% of responders were progression-free. The treatment-related side effects were expected and mostly mild and moderate, which included peripheral neuropathy, fatigue, decreased appetite, and nausea. CD30 expression levels in the skin biopsies did not correlate with clinical response as assessed by routine IHC or image analysis. Dr. Duvic from MD Anderson Cancer Center reported a phase II study of BV in primary cutaneous CD30+ lymphoproliferative disorders (including lymphomatoid papulosis (LyP) or primary cutaneous pc-ALCL) and CD30+ mycosis fungoides (MF) with or without large cell transformation. BV was administered at 1.8 mg/kg every 21 days up to 8 doses with an option of up to 8 more doses for responders. 38 patients were evaluable for responses. The overall response rate is 63% with CR of 32%. Response rate was 100% in LyP/pc-ALCL. In MF, although highest response rates correlated with highest CD30+ expression, low expression patch/plaque MF responded as well following additional treatment cycles.