Possible New Target for Novel Targeting Therapies in the Treatment of Patients with ALK-ALCL

ggi9001By Giorgio Inghirami, MD

Although the role of ALK chimeras is well known in the pathogenesis of ALK + Anaplastic Large Cell Lymphoma (ALCL), the mechanisms underlying the transformation of ALK-ALCL is unknown. In an abstract presented before the 56th Annual Meeting of the American Society of Hematology we provided a comprehensive characterization of the various driving genetic alterations that led to the constitutive activation of STAT3 in ALK-ALCL.

This characterization was reached by combining Whole Exome Sequencing (WES), Copy Number Variation analysis and RNAseq in a discovery panel (5 ALK+ and 18 ALK- ALCL). The frequency of JAK/STAT3 mutations was further tested by Sanger and deep sequencing analyses, in an independent panel of 158 ALCL (88 ALK-, 26 ALK+ ALCL and 44cALCL) AND 67 PTCL. Functional tests were completed by transfection/transduction of different cells lines (STAT3 -/- MEF, HEK-293T, SUPM2 TTA and SUPM2 S3S), in association with Western Blot, and using cells viability analyses, Luciferase Assay, 2D and soft agar colony assays.

From the gathered data we were able to demonstrate that a subset of ALK-ALCL displays the constitutive activation of JAK/STAT3 pathway via multiple mechanisms. These mechanisms could be significantly abrogated by specific inhibitors like JAK1/2 and ROS1. With the central role of STAT3 there is the possibility of using novel targeting strategies to provide new avenues for the treatment of ALK- ALCL patients as suggested in our preclinical ALC PDT model.

ASH 2011: New Treatment for T-Cell Lymphoma

By Jia Ruan, MD

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 Continue reading “ASH 2011: New Treatment for T-Cell Lymphoma”

FDA Approves Brentuximab for Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma

By Rebecca Elstrom, MD

The FDA granted accelerated approval last week to brentuximab vedotin for use in patients with Hodgkin lymphoma (HL) which has relapsed after 2 prior therapies, and patients with anaplastic large T cell lymphoma (ALCL) which has relapsed after one prior treatment. Weill Cornell Medical College participated in the studies that led to the approval.

Brentuximab vedotin is an antibody-drug conjugate (ADC); that is, a chemotherapy drug which has been attached to a monoclonal antibody in order to deliver the drug more specifically to target cells. In this case, the ADC targets CD30, a protein on the surface of the malignant HL cells and ALCL. Two phase 2 clinical studies were recently completed evaluating activity of brentuximab vedotin in HL patients who had had recurrence following autologous stem cell transplant and in ALCL patients that had relapsed after prior therapy. Response in both patient groups was striking. In HL, 73% of patients responded to treatment, with 32% achieving complete remission.  In ALCL, 86% of patients responded, with 57% achieving complete remission.

Major side effects of brentuximab vedotin in both groups of patients consisted of peripheral neuropathy, decreased blood counts, fatigue, nausea, rash and fever.

While long term results are still under investigation, initial response rates indicate that this drug represents an important new tool in the care of patients without other standard treatment options. Further studies are ongoing investigating how best to incorporate brentuximab vedotin into the routine care of patients with these lymphomas.