While ibrutinib represents undeniable progress in the treatment of mantle cell lymphoma, the outcomes and ideal management of patients that experience ibrutinib failure are unclear. In a study recently published in Blood, Dr. Peter Martin discusses findings from a recent observational study from 15 sites on patients who experienced lymphoma progression while receiving ibrutinib.
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In a study published in February 2016 in Blood, researchers from Leandro Cerchietti’s lab at Weill Cornell Medicine in collaboration with the University of Montreal identified a potential new strategy for the treatment of aggressive diffuse large B-cell lymphomas (DLBCL) called double and triple hit lymphomas.
What are double and triple hit lymphomas and why they are they so difficult to treat?
Double and triple hit lymphomas have chromosomal changes in two or three genes (MYC, BCL2, and/or BCL6) which encode for proteins that have a primary role in cell growth and contribute to the development of cancer. Chemotherapy does not work well to kill these types of lymphomas. Further, patients with double and triple hit lymphomas are often older and have difficulty tolerating aggressive chemotherapy. Therefore it is essential for new, targeted therapies to be developed that are less toxic for these patients.
What did researchers find?
The researchers found that the combination of an FDA-approved antiviral medication called ribavirin and a new targeted medication called an Hsp90 inhibitor work together to kill double and triple hit lymphomas in preclinical models. Ribavirin blocks the function of a protein called eIF4E. With the inhibition of Hsp90 and eIF4E, the proteins MYC, BCL2, and BCL6 are less effective in promoting growth of lymphoma cells. The addition of ribavirin also may prevent developing resistance to treatment with the Hsp90 inhibitor.
What do these findings mean for patients?
The lymphoma group at Weill Cornell Medicine is developing a phase I clinical trial to determine the optimal dose of an Hsp90 inhibitor and ribavirin for patients with aggressive DLBCLs that do not respond or return after initial therapy. We will evaluate tumor and blood samples before and after treatment with this combination to confirm that it negatively impacts MYC, BCL2, and BCL6 as expected. This is a promising treatment strategy in these patients and expected to be much better tolerated than chemotherapy.
Stay tuned for future updates regarding treatments for double and triple hit lymphomas at Weill Cornell.
The Weill Cornell Lymphoma Program has recently opened a new research study for men and women with previously-treated chronic lymphocytic leukemia (CLL) who are intolerant to ibrutinib. The study is sponsored by the Acerta Pharma BV and the principal investigator is John Allan, MD. For more information about the study, please call Amelyn Rodriguez at 212-746-1362 or email her at amr2017@med.cornell.edu.
Key Eligibility
Men and women age 18 and older.
Diagnosis of CLL.
At least one prior therapy for CLL.
Intolerant to ibrutinib.
Detailed eligibility reviewed when you contact the study team.
Study Summary
Btk inhibition is an established therapeutic intervention for the treatment of CLL. In February 2014, ibrutinib (IMBRUVICA®) monotherapy, the first Btk inhibitor developed for clinical use, was approved in the United States for the treatment of patients with CLL who have had ≥ 1 prior therapy or 17p deletion based on high response rates with few drug-related toxicities. However, ibrutinib is not without its adverse reactions. This study will evaluate the safety and efficacy of the second-generation Btk inhibitor, ACP-196, in subjects who have previously discontinued ibrutinib therapy due to adverse reactions. Preliminary data to date suggests that ACP-196 is very well tolerated and has robust activity as a single agent in the treatment of subjects with relapsed/refractory CLL. Additionally, PK/PD results show the 100-mg BID regimen produces optimal target coverage over 24 hours, which may provide greater clinical benefit than the QD regimen of ibrutinib. This study will explore whether ACP-196, as an alternative Btk inhibitor, with a potentially distinct safety profile, may fill an unmet need in therapeutic options for patients who are intolerant to ibrutinib.
Subjects will receive ACP-196 orally twice daily continuously throughout the study as long as they are responding to therapy and not experiencing unacceptable side effects. Subjects who are continuing to tolerate and derive clinical benefit from treatment at the end of the trial may continue to receive their study treatment after discussion with the medical monitor. After discontinuing treatment, subjects will remain in long-term follow-up until loss to follow-up, consent withdrawal, or study closure.
New Developments in Lymphoma 