Tag: ASH2014

The Story of Ibrutinib in Mantle Cell Lymphoma

Picture1By Peter Martin, MD

Just over one year ago, in November 2013, the United States Food and Drug Administration (FDA) approved the oral drug ibrutinib for patients with previously treated mantle cell lymphoma (MCL). The FDA based its decision upon promising results from the PCYC-1104 trial that took place at several centers around the world, including Weill Cornell Medical College (WCMC). During the 56th Annual Meeting of the American Society of Hematology, long-term follow up from the PCYC-1104 trial was presented. At the two year time point, roughly one third of patients remain free from progression. Moreover, serious side effects appear to become less frequent with time.

Because bias and chance can sometimes lead to promising results, investigators from around the world, including WCMC performed a second trial (MCL2001) to evaluate the effects, good and bad, of ibrutinib in 120 patients with previously treated MCL. Preliminary data from MCL2001 was also presented during ASH, and they appear to be consistent with the PCYC-1104. With roughly 15 months of follow up, two-thirds of patients responded and responses lasted for a little more than one year on average. No new side effects were identified.

Finally, preliminary results from the MCL4001 Early Access Program (EAP), were presented. The EAP was designed to provide ibrutinib to patients with relapsed or refractory MCL prior to its approval by the FDA and was open at several sites around the world, including WCMC. One hundred forty-nine patients with MCL received daily oral ibrutinib and were followed for safety. Like the PCYC-1104 and MCL2001 trials, MCL4001 confirmed the safety of ibrutinib. Less than 10% of patients stopped ibrutinib due to an adverse event and most patients continued to receive ibrutinib through the EAP until the FDA approved it. Taken together, these three trials confirm the important role of ibrutinib in the management of mantle cell lymphoma.

Unfortunately, despite the recognized efficacy of ibrutinib in patients with MCL, roughly one-third of patients are resistant and among those that respond, secondary resistance to ibrutinib is common. In a retrospective cohort study we identified 32 patients at WCMC and Ohio State University, who experienced progression of lymphoma while receiving ibrutinib. There was no clear association between prior number of therapies, ibrutinib response, morphology, Ki67 prior to ibrutinib, response to ibrutinib, duration of ibrutinib, or choice of subsequent therapy and overall survival. Ultimately primary and secondary ibrutinib resistance was associated with poor clinical outcomes, and there were no identifiable predictors of response to subsequent therapy following development of ibrutinib resistance.

These data underscore the importance of ongoing research in MCL. As we learn more about potential mechanisms of resistance to ibrutinib we are able to design rational combinations that build on the remarkable safety and activity of the drug. Moreover, there is clearly a need for new treatments that have the potential to help patients that experience progression of lymphoma while on ibrutinib. Fortunately, investigators at WCMC and around the world have identified the emergence of this new unmet need and are working on new treatment options. Stay tuned to the WCMC Lymphoma Program Blog for new developments.

Dr. Wendy Beguelin Receives Basic Research Fellows Award from the American Society of Hematology

wendybeguelin
Dr. Wendy Beguelin

Last week the American Society of Hematology announced recipients for its 2015 awards. Dr. Wendy Beguelin a postdoctoral scientist at WCMC, under the supervision and mentorship of Dr. Ari Melnick received a Basic Research Fellows award for her work in lymphoma epigenetics. Recipients receive $100,000 over a two to three year period to support basic translational and clinical research that advances the hematology field.

In her work Dr. Beguelin identified novel epigenetic and transcriptional mechanisms that contribute to B-cell differentiation and lymphomagenesis. She revealed the role of the Polycomb protein EZH2 in humoral immunity and the mechanism through which somatic gain of function EZH2 mutations occurring in human lymphoma patients reprograms the epigenome to mediate malignant transformation. Her group introduced the novel concept of “bivalent gene targeted therapy”, by showing that mutant EZH2 freezes bivalent domains (genes featuring overlapping repressive and activation histone marks) in a locked silenced configuration that can be reversed to great therapeutic effect using specific EZH2 inhibitors. This led to the identification of biomarkers indicating the subset of human lymphoma patients amenable to EZH2 inhibitor therapy. This new information was used to design the first in vivo clinical trial of the first GSK EZH2 specific inhibitor that is currently underway at our institution.

Transcription Regulation Targeting Presents Potential New Paradigm in Treating Patients with Peripheral T-cell Lymphoma

lecBy Leandro Cerchietti, MD

Peripheral T-cell lymphomas (PTCL) are a clinically aggressive disease with poor responses to current modes of therapy and a dismal survival rate. In an abstract presented before the 56th annual American Society of Hematology conference we sought to identify an active new drug for PTCL patients.

We began by performing a cell-based progressive screen from a library of 105 anti-neoplastic drugs in clinical use. Initially within the clinical-range limit we identified 3 active drugs groups HDAC inhibitors (HDI, romidepsin), proteasome inhibitors (bortezomib, carfilozimib), and transcription inhibitors (dactinomycin). Secondary screenings were conducted for the active drug groups with six drug concentrations, in an extended panel of 9 TCL cell lines. To expand the scope of our drug groups we added vorinostat, panobinostat and valproic acid for HDI and SNS032 (CDK9>2>>7 inhibitor) and THZ1 (CDK7>12 inhibitor) for transcription inhibitors.

We found that the most active drugs were bortezomib, carfilzomib, romidepsin, dactinomycin, and THZ1, focusing on the transcriptional inhibitors, using THZ1 to investigate the functional relevance of CDK7/12 targeting in PTCL. THZ1 was found to decrease mRNA and protein levels of MCL1, JAK1, and MYC as early as 3 hours into treatment. The levels of anti-apoptotic proteins BCL2, BCL-XL, JUND, and NFkB also decreased, while proteins like the pro-apoptotic BAX increased.

In conclusion we found a mechanism by which CDK7/12 inhibition with the compound THZ1 simultaneously inhibits prominent PTCL survival pathways, causing apoptosis and re-sensitization to BCL2-family inhibitors. These findings led us to identify a mechanism by which CDK7/12 inhibition and presents a potential new paradigm in treating patients with PTCL.