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New agents may change standards of care for non-Hodgkin’s lymphoma histologies
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There were a number of studies on very exciting new drugs for non-Hodgkin’s lymphoma presented at the ASH Annual Meeting and Exposition that may ultimately change our standards of care.
One series of new therapies are cellular immunotherapies with chimeric antigen receptor (CAR)-modified T lymphocytes directed to the anti-CD19 antigen on the surface of non-Hodgkin’s lymphoma cells. Two important ongoing studies had updated data presented at this meeting.
One of these includes data from University of Pennsylvania, presented by Schuster and colleagues. These data looked at both diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma in heavily relapsed and refractory patients. They showed a 47% response rate in patients with relapsed DLBCL and a remarkable 73% response rate in patients with follicular lymphoma. Most of the complete remissions in both of those populations seemed sustained.
In a second study, Turtle and colleagues from Fred Hutchinson Cancer Center made several modifications to their approach. What the researchers found early on was that lymphocyte-depleting therapy with fludarabine and cyclophosphamide proved beneficial at preserving the CAR T cells and enhancing response. In patients who received lymphocyte-depleting therapy, 72% of heavily relapsed patients with DLBCL achieved remission, many of which were sustained.
Overall, these are very exciting data in highly refractory diseases, and these approaches are moving briskly forward through commercial enterprises.
We also presented data using a BET (bromodomain and extra-terminal) inhibitor called CPI-0610 (Constellation Pharmaceuticals). BET bromodomains enable the reading of DNA and, thus, they can facilitate the transcription or disrupt the transcription of potential oncogenes. We found that use of BET bromodomain inhibitor in patients with relapsed/refractory lymphoma knocks down MYC expression and may, thus, ultimately prove beneficial in patients with DLBCL, among others.
Although the data thus far are preliminary, we found the drug to be well tolerated with only modest thrombocytopenia and gastrointestinal upset. At doses above 200 mg, we found that we are indeed hitting our target by knocking down target genes of BET bromodomain transcription. We are seeing responses thus far, with three responses in DLBCL, a response in follicular lymphoma and, additionally, several extended stable diseases in those histologies, as well as in marginal zone lymphoma.
We also saw exciting data using a novel histone deacetylase (HDAC) inhibitor called abexinostat (Pharmacyclics). Those data — presented by Ribrag and colleagues — showed an overall response rate of 28%, including 31% in DLBCL, about 50% in follicular lymphoma and 40% in peripheral T-cell lymphoma.
Further, a novel targeted inhibitor against HDAC, as well as pan PI3-kinase, presented by Anas Younes, MD, showed an improved response in DLBCL of up to 55%, making that a very promising dual targeting treatment strategy.
There also were very exciting data using EZH2 inhibition from the company Epizyme. Their lead compound, tazemetostat (EPZ-6438) — which is a first-in-class EZH2 inhibitor — showed a remarkable response rate in multiple histologies, and the drug was well tolerated. Among 13 patients with DLBCL, there were five responses, and that included responses in both the germinal center and nongerminal center phenotypes of DLBCL. Of five patients with follicular lymphoma who were treated, three achieved a response. One patient with marginal zone lymphoma also was treated, and that patient did achieve a response. To date, there has been no correlation with EZH2 mutations and response but, rather, there have been responses in wild-type patients.
From these data in cellular immunotherapy, across multiple small, novel, targeted agents, it is clear this is a very exciting time for new drug development in DLBCL, follicular lymphoma and other non-Hodgkin’s lymphoma histologies.
References:
Abramson JS, et al. Abstract 1491.
Ribrag V, et al. Abstract 256.
Ribrag V, et al. Abstract 473.
Schuster SJ, et al. Abstract 183.
Turtle CJ, et al. Abstract 184.
Younes A, et al. Abstract 257.
For more information:
Jeremy S. Abramson, MD, is clinical director of the Center for Lymphoma at Massachusetts General Hospital Cancer Center and assistant professor of medicine at Harvard Medical School. He can be reached at jabramson@partners.org.
Disclosure: Abramson reports no relevant financial disclosures.