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Wednesday, April 24, 2013

ONLINE FIRST: Phase II Mantle Cell Lymphoma Study Shows 100% Response with Epigenetic Therapy




WASHINGTON -- Hematologic malignancies set the precedent for conventional therapies of cancer many years ago in terms of combination chemotherapy, and they continue to do so with some exciting new trends in therapy.


In one report here at the American Association for Cancer Research an epigenetic/immunotherapy regimen of cladribine, rituximab, and vorinostat produced a 100 percent response rate with 86 percent complete remissions in newly diagnosed mantle cell lymphoma.

No photo available.In presenting a late-breaker session on clinical trials of agents for hematologic and other malignancies, Kamal Sharma, DO, a hematologist/oncologist at Penn State Hershey Cancer Institute, said the synergistic effects of cladribine, a purine analogue and hypomethylating agent with known epigenetic activity, and the monoclonal antibody rituximab, prompted researchers to add the histone deacetylase inhibitor vorinostat (Abstract LB-140).


The starting dose for the Phase II study (first author was Zainul S. Hasanali, a student in the MD/PhD Program there) was oral vorinostat at 400 mg on Days 1-14, combined with cladribine at 5 mg/m2 IV on Days 1-5, and rituximab at 375 mg/m2 IV weekly for four weeks for cycle 1. The regimen was then repeated every 28 days for up to six cycles.


Sharma reported that among 37 patients who had more than two treatment cycles, all had a response, 32 patients (86%) had a complete remission, and five (14%) had a partial remission. She said the majority of complete responders have received maintenance rituximab, adding that median progression-free survival had not been reached.


The patients’ median age was 64, and 95 percent  had Stage IV disease. On the Mantle Cell International Prognostic Index (MIPI), 52 percent were categorized as low risk, 19 percent as intermediate-risk, and 29 percent as high-risk.


Side Effects Mostly Reversible

Sharma said the majority of observed adverse events were hematologic and reversible:

·        32 percent had Grade 3 neutropenia, and 11 percent had grade 4;

·        20 percent had Grade 3 thrombocytopenia, and five percent had Grade 3;

·        The most common nonhematologic adverse event was fatigue, which also was reversible.


There was one death on study -- a patient with relapsed, refractory mantle cell lymphoma with extensive pulmonary involvement, who died of pulmonary hemorrhage.


Sharma said that in vivo epigenetic changes have been observed and correlative studies are ongoing, including analysis of changes in CD20 expression, cyclin D1-A vs G polymorphism, and methylation, but that so far there does not appear to be a correlation between CD20 expression and response.


She said that based on the results, vorinostat-cladribine-rituximab can be considered a safe and effective regimen for patients with previously untreated mantle cell lymphoma, warrants further study in that group of patients as well as those with other B-cell malignancies.


The moderator of the session where the results were reported, Kenneth B. Anderson, MD, Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, said he was enthusiastic about this new regimen, which illustrates a “potentially novel treatment paradigm -- albeit with a small number of patients, but it is nonetheless proof of principle.”


“There is much work to be done to determine the precise mechanism [of immunotherapy with epigenetic therapy], whether that’s additive or synergistic activity, but that’s where the excitement is going to be,” he said.


In addition, he continued, while vorinostat is a broad-acting and “remarkably effective agent,” it is possible that a more selective histone deacetylase (HDAC) inhibitor might be able to achieve similar responses with fewer side effects.


Sharma said the researchers are, in fact, considering romidepsin, another HDAC inhibitor, for the regimen.



Epnergenetic Therapy’

The senior author of the report, Eliot Epner MD, PhD, Professor of Medicine at Penn State Medical Center, is shown here (left) with a nurse (center) and a patient (right). “Epnergenetic therapy” is derived from Dr. Epner’s name and epigenetic therapy. “Current versions of epigenetic therapy including inhibitors of DNA methylation combined with histone deacetylase (HDAC) inhibitors have not lived up to their promise to date,” he explained in an email message. “We have modified that, using the addition of a cryptic epigenetic agent, cladribine, an HDAC inhibitor (vorinostat), and a monoclonal antibody. Preliminary results are quite impressive, justifying the name.”