ASH: Triplet combination regimens demonstrate high response rates in multiple leukemias
Three clinical trials yield strong results with undetectable measurable residual disease and overall response rates
MD Anderson News Release December 09, 2024
SAN DIEGO ― Three clinical trials led by researchers from The University of Texas MD Anderson Cancer Center demonstrated significant positive results from novel triplet therapies in the treatment of relapsed or refractory and newly diagnosed leukemias. The results were presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition. More information on all ASH Annual Meeting content from MD Anderson can be found at MDAnderson.org/ASH.
Study demonstrates strong overall responses with triplet regimen that includes novel menin inhibitor (Abstract 216)
Combining the menin inhibitor, revumenib, plus the hypothemylating agent, ASTX727, and venetoclax achieved an overall response rate of 82% in 33 adult and pediatric patients with relapsed or refractory advanced acute myeloid leukemia (AML) with KMT2A or NUP98 rearrangements, according to results from the Phase I/II SAVE trial led by Ghayas Issa, M.D., associate professor of Leukemia.
Forty-eight percent of patients achieved a complete remission or a complete remission with a partial hematologic recovery with these all-oral agents. Two patients completed the maintenance therapy after receiving a stem cell transplant and remain in remission. The measurable residual disease (MRD) negativity rate was the lowest in patients with NUP98r rearrangements. With a median follow-up was 9.3 months, the six-month overall survival was 68% and the median duration of response was not reached.
"We demonstrated significant clinical benefits and efficacy from this therapy combination, which provides patients with an improved option for treatment,” Issa said. “This is a major step forward for treating acute leukemias with these genetic rearrangements.”
Revumenib is a potent, oral selective inhibitor of the menin-KMT2A interaction. In November, the Food and Drug Administration approved revumenib as a single-agent therapy for the treatment of adults and pediatric patients with relapsed or refractory advanced acute leukemia with KMT2A rearrangement based on results from the AUGMENT-101 clinical trial lead by Issa.
To date, 33 patients have been enrolled in the SAVE trial, with a median age of 35 years. The trial also included five pediatric patients. Trial participants had three previous lines of therapy on average. Of the total patients, 16 had KMT2A rearrangements, 12 had NPM1 mutations, five had NUP98 rearrangements, and five had extramedullary disease.
Side effects were manageable and consistent with previous studies. The most common side effects patients experienced were prolongation of the QT interval on electrocardiogram monitoring and an elevation in liver enzymes.
Issa presented updated findings Dec. 7. The investigator-initiated trial is on-going and continues to enroll patients. This study was supported by Astex and Syndax. A complete list of collaborating authors and their disclosures can be found with the abstract.
Triplet regimen targeting IDH-1 mutant AML demonstrates strong response with long term follow-up (Abstract 219)
In a Phase Ib/II trial, the triplet regimen of ivosidenib, venetoclax and azacitidine demonstrated an overall response rate of 94% and a composite complete remission rate of 93% in 56 patients with newly diagnosed or relapsed/refractory IDH1-mutant hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndromes and myeloproliferative neoplasms.
The trial was led by Courtney DiNardo, M.D., professor of Leukemia, and presented by Jennifer Marvin-Peek, M.D., clinical hematology/oncology fellow.
The three-year overall survival rate was 70.5%, and patients who went on to receive a stem cell transplant had a three-year overall survival rate of 94.7%. Of the trial participants who did not undergo a stem cell transplant, 47% still are receiving trial therapy. Measurable residual disease (MRD) negativity by flow cytometry was achieved in 77% of patients. With a median follow-up of 36 months, the median overall survival has not been reached at the time of data cutoff.
“This triplet regimen is safe, well tolerated and provided impressive response rates for those enrolled in the trial,” Marvin-Peek said. “Thus far, the results we are seeing really position this triplet regimen as a potential standard-of-care option for treating this subtype of AML.”
Previous research identified ivosidenib combined with azacitidine as an effective and well-tolerated treatment of IDH1-mutant AML. An additional clinical trial found venetoclax and azacitidine effective in treating this disease. Thus, researchers sought to explore the triplet combination treatment to further improve long-term patient outcomes.
The multi-center trial included 56 adult patients with newly diagnosed AML (31), relapsed/refractory AML (13), or myelodysplastic syndromes and myeloproliferative neoplasms (12). The median age of participants was 69 years. Patients received a median of four treatment cycles, though several patients received more than 40 cycles of the triplet regimen.
Side effects were consistent with what was observed in previous studies with these medications and were manageable with supportive care. The most common adverse events were low blood counts and gastrointestinal side effects. Four patients also experienced differentiation syndrome.
Marvin-Peek presented updated findings Dec. 7. The trial was supported by both Servier and Abbvie/Genentech. A complete list of collaborating authors and their disclosures can be found with the abstract.
First-line triplet regimen for CLL yields high rates of undetectable measurable residual disease (Abstract 1011)
A triplet regimen combining the noncovalent BTK-inhibitor, pirtobrutinib, with the CD20 monoclonal antibody, obinutuzumab, and BCL2 inhibitor, venetoclax, demonstrated high rates of undetectable measurable residual disease (MRD) in patients with previously untreated chronic lymphocytic leukemia (CLL), according to Phase II trial results presented by Nitin Jain, M.D., professor of Leukemia.
After 13 cycles, the undetectable MRD rate was 98% in bone marrow and 100% in blood at 10-4 sensitivity – indicating less than one CLL cell per 10,000 lymphocytes – among 41 evaluable patients. The corresponding MRD rates at a more sensitive threshold of 10-6 were 80% and 85% in bone marrow and blood, respectively.
“We were extremely impressed by the results of this frontline triplet regimen for our patients, as we observed some of the highest depths of remission, we have ever seen in patients with CLL,” Jain said. “Today, we have several patients who are no longer on the therapy and are monitored by regular blood MRD testing.”
The trial enrolled 80 adult patients with a median age was 63 years. Of trial participants, 79% had immunoglobulin heavy chain unmutated CLL, and 13% had del(17p)/TP53 mutation. As part of the trial, responses were monitored by imaging and bone marrow assessment. MRD was assessed by next generation sequencing in both blood and bone marrow following cycles 7 and 13. After completing therapy, all patients are monitored by blood MRD every three months for one year, followed by every six months.
The most common grade 3-4 side effects were neutropenia and thrombocytopenia, which were consistent with previous trials.
Jain presented updated findings Dec. 9. The trial was funded by Eli Lilly. A complete list of collaborating authors and their disclosures can be found with the abstract.