Category: Research Publications

Acalabrutinib for Patients with Previously Untreated Chronic Lymphocytic Leukemia

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By Richard Furman, M.D.

Acalabrutinib is a second generation Bruton’s tyrosine kinase (BTK) inhibitor that targets the B-cell receptor signaling and is considered a prime target for the treatment of CLL. Acalabrutinib inhibits BTK activity preventing the activation of the B-cell antigen receptor pathway, and leads to CLL cell death. Recently at the 2016 ASCO annual meeting researchers presented preliminary results from an ongoing phase 1-2 study using acalabrutinib to treat patients with previously untreated CLL. Of the 74 patients enrolled in the trial 72 were evaluable for response. Acalabrutinib was well tolerated, with 72 of 74 patients remaining on treatment at time of analysis and evaluable for response. Neither of the two patients discontinued treatment for drug related adverse events.

The most common side effects were headaches, diarrhea, arthralgia, contusion, nausea, and weight increase, all characterized as mild. Treatment related lymphocytosis occurred in 53% of patients and was resolved in 97% of the affected patients at a median of 7 weeks. Patients who took acalabrutinib experienced a 96% overall response rate (PR=86%, PR-L=10%) with the median time to response being 2-8 months. For patients with untreated CLL the initial safety profile and high response rates are promising. Based on these results a phase 3 trial of acalabrutinib versus ibrutinib has commenced to further study the use of acalabrutinib in the treatment of patients with CLL.

Mathematical Analysis of Drug Resistance in CLL

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Dan Avi Landau, M.D., Ph.D.

According to a recent study published in Nature Communications by Weill Cornell Medicine investigator Dr. Dan Avi Landau the rate at which genetically mutated cancer cells grow could be a key to explaining why some CLL patients develop resistance to treatment. Dr. Landau’s findings demonstrate how an individual’s cell mutations can influence that individual’s response to treatment, leading to the development of resistance to treatments like ibrutinib. CLL patients who are treatment resistant require treatment strategies that take account of their treatment resistance. Using mathematical modeling researchers investigated how:

 “…some patients with chronic lymphocytic leukemia (CLL)…become resistant to the drug ibrutinib, which is used to treat the disease once other chemotherapy drugs have failed. They performed mathematical modeling of the growth rates of the sensitive and resistant cells, and discovered that a small cluster of cancer cells survived ibrutinib therapy due to a genetic mutation that was present prior to treatment, allowing these ibrutinib-resistant cells to multiply and the disease to progress unabated. The findings could offer scientists a framework to guide the development of combination therapies that overcome drug resistance in CLL and in other cancers.”

These findings could potentially allow for physicians to develop more precise treatment plans for patients. In theory physicians could be more easily able to treat their patients not just for their present conditions, but also take into account their future conditions.

Lymphoma Researchers Receive LRF Grants to Investigate Potential New Treatments

Last week the Lymphoma Research Foundation (LRF) announced the awarding of $1.62 million in funding for lymphoma research and lymphoma related training grants. Among the awardees were two Lymphoma Program research collaborators, Dr. Leandro Cerchietti and Dr. Pilar Dominguez Rodriguez.

Leandro Cerchietti
Leandro Cerchietti, M.D.

Dr. Cerchietti is an Assistant Professor of Medicine and Raymond and Beverly Sackler Research Scholar at Weill Cornell Medicine. He received a grant from the LRF for his work in predicting follicular lymphoma transformation without biopsy. For follicular lymphoma (FL) patients their slow growing tumor can turn into a much more aggressive follicular lymphoma that limits their treatment options. The mechanisms behind these transformations are poorly understood, but researchers are trying to better understand the mechanism of transformation. Currently invasive and expensive biopsies are the only way to determine whether a patient is at risk for follicular transformation. Based on his previous research Dr. Cerchietti has determined that FL cells release certain products into a patient’s body, and that these products in the bloodstream can be used to anticipate FL transformation. Dr. Cerchietti plans to build on his previous research and potentially develop new non-chemotherapy treatments for follicular lymphoma.

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Pilar Dominguez Rodriguez, Ph.D.

Dr. Dominguez Rodriguez is a Post-Doctoral Associate, who specialized in cancer biology in Dr. Ari Melnick’s lab at Weill Cornell Medicine. Her current research focuses on the ten eleven translocation 2 (TET2) gene. TET2 is associated with DNA methylation, a process involved in the regulation of certain genes. Previously in patients with diffuse large B-cell lymphomas (DLBCL) the deregulation of DNA methylation has been identified as a source of DLBCL cell growth. However, researchers are still searching for answers as to why the methylation mechanisms malfunction. TET2 could potentially be a link due to its role in DNA methylation and the fact that is frequently mutated in lymphomas. Dr. Dominguez Rodriguez project seeks to discover whether there is a relationship between TET2 and DNA methylation in B-cells, and then identify how TET2 affects the development of DLBCL. If this relationship can be established the findings have the potential to identify new treatment targets for patients with B-cell lymphomas.