On January 19, 2017, the United States Food and Drug Administration (FDA) approved ibrutinib to treat patients that have received at least one line of prior therapy for marginal zone lymphoma (MZL), a type of non-Hodgkin lymphoma (NHL).
MZL is an indolent B-cell lymphoma that accounts for 5-10% of all lymphomas and lacks a standard of care. Current MZL treatments include anti-CD-20 antibody therapy (e.g. rituximab) or chemotherapy. However, ibrutinib is the first-ever treatment to specifically be approved for MZL.
Ibrutinib works by inhibiting Bruton’s tyrosine kinase (BTK), an enzyme responsible for transmitting pro-growth and survival signals from the surface of a cell to its nucleus. In this way, ibrutinib may interfere with chronic stimulation arising from inflammation in the tumor microenvironment; thus slowing the growth of B-cells.
The Weill Cornell Lymphoma Program is proud to have played a role in the phase 2 trial — the largest trial to date for people with previously treated MZL of all subtypes —leading to FDA approval for ibrutinib. Roughly half of all patients had a significant response to ibrutinib, with some degree of tumor shrinkage observed in almost 80% of all patients in the trial. Roughly one-third remained on treatment 18 months after beginning treatment.
The most common side effects included fatigue, diarrhea, and anemia. These side effects were manageable, and consistent with previous research, although some cases required the discontinuation of treatment with ibrutinib.
Results from this study support the use of ibrutinib as an effective well tolerated chemotherapy-free option for the treatment of previously treated MZL. However, some questions remain. MZL is a heterogeneous group of lymphomas, and it is unclear which subtypes might respond best to ibrutinib. With only half of all previously treated MZL patients responding to ibrutinib, improvements might be realized by combining ibrutinib with other drugs and/or using it earlier in the treatment of MZL.
At Weill Cornell, we are currently studying ibrutinib in combination with the immunotherapy drug durvalumab in people with previously treated indolent non-Hodgkin lymphoma, including MZL.
Dr. John Leonard Discusses Results from the GALLIUM Trial for Patients with Previously Untreated Follicular LymphomaPosted: December 20, 2016
Click on the graphic above to watch this interview from the 2016 annual meeting of the American Society of Hematology, Lymphoma Program Director, Dr. John Leonard discusses results from the recently completed GALLIUM trial. In this trial researchers compared the safety and efficacy of either rituximab or obinutuzumab with chemotherapy followed by maintenance with the same agent as first-line therapy for patients with previously untreated follicular lymphoma.
The survival of tumor cells is dependent on the tumor cells maintaining a normal interaction with the healthy microenvironment. An increasingly important strategy in the treatment of CLL is to develop new therapies that do not necessarily attack the cancerous cells themselves, but instead attack the molecular processes that allow the cancerous cells to function and thrive in the microenvironment. One potential target for treating CLL is the protein complex NF-kB, which controls important cell functions including the regulation of cell death, cell survival, and cell proliferation. If NF- kB function can be inhibited then CLL can be more easily treated.
The purpose of this recent study presented at the 2016 ASH meeting was to test the efficacy of the newly developed NF-bK inhibitor IT901 in the treatment of CLL and its aggressive transformation Richter’s Syndrome (RS). RS is a transformation that occurs within 5-10% of CLL’s and turns the disease into a fast growing diffuse large B-cell lymphoma, an aggressive non-Hodgkin lymphoma. The treatment of RS currently represents an unmet therapeutic need.
Results from this study were confirmed in a mouse xenograft model for people with CLL and in cell samples obtained from people with RS. In both models the use of IT901 was characterized by decrease in tumor growth and Researchers found that IT901 induced death in cancerous cells within 24 hours of treatment with a minimal impact on normal B-cells.
Researchers concluded that IT901 is effective in rapidly blocking NF-kB activity by decreasing the functions that allow the cell to flourish in the microenvironment. The results from this study are encouraging and point to a potential new treatment option for patients with CLL and RS.
Patients with CLL who relapse after or become refractory to treatments like ibrutinib or idelalisib have poor outcomes. Venetoclax (also known as ABT-199) is an oral inhibitor of the BCL-2 (B-cell lymphoma 2) protein. The BCL-2 protein plays a critical role in preventing cells from undergoing apoptosis (cell death), in healthy cells and in CLL cells. In a recent study presented at the 2016 annual ASH meeting, we evaluated the effectiveness of venetoclax in treating people who relapsed after or were refractory to ibrutinib or idelalisib.
During this phase 2 trial 64 people with CLL were divided into two arms. The first arm consisted of those who were relapsed or refractory to ibrutinib, while the second arm included those who were relapsed or refractory to idelalisib. 43 patients were enrolled in the first arm and were on ibrutinib for a median of 17 months, receiving venetoclax for a median of 13 months, while 21 patients in the second arm were on idelalisib for a median of 8 months and received venetoclax for a median of 9 months. Thirty-nine patients in the ibrutinib arm and 21 patients in idelalisib arm completed the full course of treatment. The objective response rate as determined by investigators was 69% (27/39) for people who were ibrutinib resistant, and 57% (12/21) for the idelalisib resistant. At the time of analysis no median progression free survival or overall survival has been reached. Overall the progression free survival was 72% and overall survival was 90% for all participants.
The results from this trial demonstrate that venetoclax has displayed robust activity and is tolerable for people whose CLL has progressed after treatment with ibrutinib and idelalisib. Although there have been few complete responses, patients will continue to be monitored to chart any further improvements. Additional follow up will be required to assess how long lasting venetoclax responses will be.
Dr. John Leonard Discusses CHOP Versus DA-EPOCH-R for the Use of Untreated Diffuse Large B-Cell LymphomaPosted: December 7, 2016
In an interview during the 2016 American Society of Hematology Annual Meeting, Dr. John Leonard discusses results from a phase III trial where researchers compared the treatments R-CHOP to DA-EPOCH-R in DLBCL patients specifically from either the GCB or ABC subtypes.
A full link to the video of Dr. Leonard discussing the trial can be found by clicking above or be seen on Healio.com.
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 LymphomaPosted: December 6, 2016
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.