FAT1 Mutations Influence Time to First Treatment in Untreated CLL

john-allan-mdBy John Allan, M.D.

Despite recent strides in mapping the mutational landscape of chronic lymphocytic leukemia (CLL) there is still limited information regarding the clinical impact of some less common gene mutations in the treatment of CLL. As next generation sequencing (NGS) has become more readily available physicians have more information about their patient’s genome, but this information is often lacking in context.

Using a commercially available NGS platform researchers from Weill Cornell Medicine identified a high prevalence of mutations in the FAT1 gene in people with CLL. FAT1 plays a role in regulating WNT signaling and tumor suppression and mutations have previously been associated with leukemia. Given the prevalence of FAT1 mutations in our CLL database and evidence suggesting FAT1 contributes to tumor growth, researchers investigated the clinical impact of FAT1 mutations.

Altogether 172 patients were included in the study. Nineteen (11%) patients were found to have a FAT1 mutation and 153 (89%) were lacking the mutation. In total 21 mutations were identified with 17 being unique. No significant differences were found between groups based on age or co-occurrence of high risk mutations, although 17p deletions occurred significantly more in mutated FAT1 patients (24%) compared to people lacking the mutation (7%). Mutated FAT1 patients had a significantly shorter TTFT at 50 months compared to 143 months for people lacking the mutation.

Researchers identified a higher prevalence of FAT1 mutations in untreated CLL patients than previously reported. FAT1 was found to associate with the 17p deletion, but no other high-risk mutations. We also found a vast difference in TTFT between mutated FAT1 and those lacking the mutation, although there was no difference in response rates when treated with novel agents.

These findings suggest that FAT1 mutations may be more common in patients, who have yet to receive treatment than commonly supposed. Results warrant additional research to investigate the influence of FAT1 mutations and association with the 17p deletion.

Dr. Peter Martin Discusses Ibrutinib Plus Palbociclib for Patients with Previously Treated Mantle Cell Lymphoma

healio

In an interview during the 2016 American Society of Hematology Annual Meeting, Dr. Peter Martin discusses results from a phase I clinical trial designed to evaluate the safety and activity of ibrutinib plus palbociclib in people with previously treated MCL. A  full link to the video of Dr. Martin discussing the trial can be found by clicking above or be seen on Healio.com.

Ibrutinib in Combination with Lenalidomide and Rituximab Displays Improvement for Patients with Relapsed or Refractory DLBCL

Dr. Jia Ruan

By Jia Ruan, M.D., Ph.D.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma. While 50-60% of patients are cured with the standard R-CHOP chemotherapy, only 10-20% of patients who fail R-CHOP experience improvements and long-term remission with other therapies. Current treatments options for DLBCL after R-CHOP include high-dose chemotherapy or autologous stem cell transplant (ASCT). However, patients are often ineligible to receive these treatments due to their advanced age or other health problems. Younger patients with relapsed DLBCL may not be able to move onto transplant due to refractory disease. This highlights the unmet medical need to explore additional treatment options for high risk patients whose DLBCL is refractory or relapsed (R/R) within 12 months of diagnosis.

Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase, which has shown clinical activity as a single agent in R/R DLBCL, particularly in the non-germinal center B-cell–like (non-GCB) subtype. Lenalidomide is an immunomodulatory agent that is active in combination with rituximab (RTX) in R/R DLBCL.  The combination ibrutinib and lenalidomide, plus rituximab, has been evaluated in a multicenter, open-label, phase 1b/2 study in pts with R/R DLBCL . The preliminary results of the phase 1b portion of the study has been reported in a podium presentation at the 2016 American Society of Hematology annual meeting in San Diego.

The primary objective of this Phase 1b trial was to determine the maximum tolerated dose of and/or recommended phase 2 dose of ibrutinib in combination with lenalidomide and rituximab.  A total of 37 patients were enrolled in the trial. Their median age was 63 and they had a median of 3 prior treatment regimens, and were refractory to their last treatment. The most serious side effects were grade 3/4 neutropenia (32%), thrombocytopenia (14%), and maculopapular rash (11%). On the 15mg dose level of lenalidomide, the overall response rate for patients was 44%, including 3 complete responses and 5 partial responses. Response evaluation is ongoing for 20 mg lenalidomide dose level.

Based on the safety data from this phase 1B study, the phase 2 portion of the study is currently being initiated with lenalidomide at 20 mg dose level and ibrutinib at 560 mg.  Despite the small number of patients involved in this trial the results are encouraging for the treatment of high-risk refractory DLBCL. The combination of ibrutinib + lenalidomide/rituximab offers a potentially promising novel option.