Breakthroughs in treatment options for lymphomas and chronic lymphocytic leukemia (CLL)were among the highlights of the 2014 annual meetings of the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO)—and Memorial Sloan Kettering researchers were involved in the development of almost all of the exciting new drugs profiled.
New Insights into Pathway Disruptions
Research in non-Hodgkin lymphoma (NHL) and CLL has focused on several common signal transduction pathways and survival mechanisms crucial to the propagation of malignant lymphocytic disorders.
One of the pathways exploited by malignant NHLs is B-cell receptor (BCR) pathway, which is normally activated in response to antigen stimulation. Mutations in the B-cell receptor and its downstream signaling molecules can cause antigen-independent activation of Bruton’s tyrosine kinase, protein kinase C , and spleen tyrosine kinase.
Activation of these proteins potentiates some of the most prolific oncogenic pathways known in both solid and hematologic malignancies, including the PI-3k/mTOR, Jak/STAT and NF-kB signal transduction pathways. An early attempt at disrupting the constitutive activation of the BCR involved use of the drug ibrutinib. In fact, Memorial Sloan Kettering was one of the lead recruiters for a trial that established a 40 percent response rate of this drug in DLBCL.
As predicted by its mechanism of action, ibrutinib is almost exclusively active in the activated B-Cell (ABC) subtype of this disease, and samples gathered from an extension study involving mostly Memorial Sloan Kettering patients are being analyzed to help us more specifically identify individuals likely to benefit from its use.
Memorial Sloan Kettering is currently accruing to trials that combine ibrutinib with the following agents:
- R-CHOP in the front-line therapy of patients with ABC-DLBCL
- bendamustine in mantle cell lymphoma (This trial is closed to accrual.)
- rituximab in follicular lymphoma (This trial is closed to accrual.)
- rituximab as a single agent in marginal zone lymphoma (This trial is closed to accrual.)
We are also actively involved in identifying targets further down this signal transduction pathway. Three different inhibitors of PI-3 kinases have been studied in Memorial Sloan Kettering trials.
The delta isoform of PI3K is thought to be active in most forms of lymphoma, and the highly active agent inhibiting this isoform, idelalisib, is likely to be approved by the FDA in 2014 or 2015. Activation of the other isoforms (a, b and g) may act as escape mechanisms if the delta isoform is blocked. We led two recently completed phase II trials in this area: one involving BKM120 (Younes PI), a pan-inhibitor of PI3k isoforms and the other involving IPI-145 (Horwitz PI), an inhibitor of the delta and gamma isoforms.
We are currently looking at a bifunctional PI3k/HDAC inbibitor (CUDC907, Younes, PI), and we will soon be leading an international phase 3 trial comparing copanlisisb, a new potent inhibitor of the alpha and delta PI3k isoforms presented at ASH in 2013. Copanlisib will be given in combination with rituximab versus rituximab plus placebo in patients with relapsed indolent NHL (Gerecitano, PI).Back to top
At the other end of the tumorigenic cascade lies apoptosis, which we now know is largely governed by the BCL-2 family of proteins. Irreparable damage to normal cells leads to the activation of a pathway that then triggers increased expression of pro-apoptotic proteins, culminating in programmed cell death. Lymphoid malignancies often overexpress BCL-2 and other anti-apoptotic members of this family of proteins. ABT-199 is a specific inhibitor of BCL-2 that has shown dramatic results in both CLL/SLL and other NHLs.Back to top
Best Percent Change from Baseline of Nodal Masses with ABT-199
Responses were observed with the use of the ABT-199 in a range of patients, many of which have been durable with ongoing maintenance treatment of this well-tolerated drug.
Due to the development of Tumor Lysis Syndrome in a subset of individuals, participation requires overnight observation of patients at high risk for the syndrome. We are currently the lead recruiters of patients with NHL for an ongoing single phase 1 trial of ABT-199, have developed an infrastructure to accommodate those travelling from a distance to enroll in this trial.
We are also in the process of opening a trial combining ABT-199 with R-CHOP chemotherapy in patients with B-cell NHL.Back to top
Pursuing Multiple Options for NHL Patients
These trials represent just a fraction of those currently available and in our pipeline.
Our trial portfolio aims to provide multiple options for NHL patients referred at different stages of disease, so that more than one option can be provided in most cases.
We look forward to continuing our invaluable collaborations with oncologists outside of Memorial Sloan Kettering to provide the best new drugs to our patients and to advance the science that will enable us to continue our progress against these diseases.Back to top