Update: The below mentioned trials are closed to enrollment.
The peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphoid diseases that constitute less than 15 percent of all non-Hodgkin lymphomas in adults in North America. The most common subtypes are 1) Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS); 2) Anaplastic large cell lymphoma, primary systemic type (ALCL); and 3) Angioimmunoblastic T-cell lymphoma (AITL). The PTCLs are generally aggressive, and tend to run a more relapsing and less favorable clinical course compared to B-cell NHLs. Relapsed and refractory diseases are common. Novel and target therapies are in much need.
At the recent Annual Society of Hematology (ASH) meeting, Dr. Friedberg of the University of Rochester reported the result of a phase 2 trial of Alisertib (MLN8237), a potent inhibitor of aurora A kinase, in patients with relapsed aggressive non-Hodgkin’s lymphoma (NHL). Aurora kinases regulate mitosis during cell division. Inhibition of aurora A kinase can lead to mitotic errors and premature cell death. Alisertib is taken orally twice daily for 7 days on 21-day cycles. This phase 2 study enrolled a total of 48 patients, including 8 patients with peripheral T-cell lymphoma. The overall response rate was 32%. Response in T-cell NHL was the most impressive at 57%: four out of eight patients responded, and the some of the responses were durable. The response rates in DLBCL and MCL were modest around 20%. Treatment-related side effects were generally tolerable and included low blood counts, fever, fatigue and inflammation in mouth. Based on these results, additional clinical trials (phase II sponsored by SWOG / NCI and phase III sponsored by Millennium) with this orally available compound are moving forward in T-cell lymphoma. Both of these studies will be available soon at Weill Cornell Medical College (click here to read about the SWOG/NCI trial and click here to read about the Millennium trial on clinicaltrials.gov).
Dr. Advani of Stanford University discussed the updated results of an international phase 2 study of Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large cell lymphoma (Click here to read about this study, which is also being conducted at Weill Cornell, on clinicaltrials.gov). Anaplastic large cell lymphoma (ALCL) is a T-cell NHL characterized by the uniform expression of CD30. Brentuximab vedotin is composed of an anti-CD30 antibody conjugated with a potent anti-microtubule agent, monomethyl auristatin E (MMAE). When bound to a CD30-expressing target, Brentuximab vedotin releases the MMAE compound to interfere with microtubule functions, leading to targeted cell death. Brentuximab vedotin is given as an infusion every 3 weeks for up to 16 cycles of treatment.
This study enrolled 58 patients: 72% had ALK-negative disease, 62% had primary refractory disease, and 26% failed a prior autologous stem cell transplant. The overall response rate was 86%, including a complete response rate of 57%. The median duration of response was 13 months for all patients, and 17 months for patients achieving CR. The median progression-free survival with brentuximab vedotin (20 months) was significantly longer than the median PFS achieved with the most recent prior therapy (5.9 months) by investigator assessment. A significant portion of patients (28%) was able to move on to receive hematopoietic stem cell transplant after Brentuximab vedotin due to improved disease control. The most common treatment-related adverse events were peripheral neuropathy, fatigue, gastrointestinal symptoms, skin rash and low white blood count, and were generally mild and moderate. Brentuximab vedotin received FDA approval in 8/2011 for the treatment of relapsed ALCL.
Currently Brentuximab vedotin is being evaluated in combination with chemotherapy in frontline setting for patients with previously untreated ALCL.