Triplet Therapies Show Promise in Treating Leukemias: ASH 2024 Highlights
核心洞察
Novel triplet therapies are demonstrating significant positive results in treating relapsed/refractory and newly diagnosed leukemias, according to multiple clinical trials.
A revumenib-based triplet achieved an 82% overall response rate in relapsed/refractory AML patients with KMT2A (搜索) or NUP98 (搜索) rearrangements, offering an improved treatment option.
Ivosidenib, venetoclax, and azacitidine triplet showed a 94% overall response rate in IDH1 (搜索)-mutant hematologic malignancies, positioning it as a potential standard-of-care.
Three clinical trials have highlighted the potential of novel triplet therapies in treating various forms of leukemia (搜索). Researchers from The University of Texas MD Anderson Cancer Center presented these findings at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, showcasing improved outcomes for patients with relapsed or refractory and newly diagnosed leukemias.
Revumenib-Based Triplet Therapy in Relapsed/Refractory AML
A Phase I/II SAVE trial, led by Dr. Ghayas Issa, explored a triplet regimen combining the menin inhibitor revumenib, the hypomethylating agent ASTX727, and venetoclax. The study focused on adult and pediatric patients with relapsed or refractory advanced acute myeloid leukemia (搜索) (AML) harboring KMT2A (搜索) or NUP98 (搜索) rearrangements. The results demonstrated an impressive 82% overall response rate in 33 patients.
Notably, 48% of patients achieved complete remission or complete remission with partial hematologic recovery using this all-oral combination. Two patients who underwent stem cell transplantation completed maintenance therapy and remain in remission. The measurable residual disease (MRD) negativity rate was particularly high in patients with NUP98 (搜索) rearrangements. With a median follow-up of 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," said Dr. Issa. "This is a major step forward for treating acute leukemias with these genetic rearrangements."
Revumenib, a potent and selective oral inhibitor of the menin-KMT2A (搜索) interaction, received FDA approval in November as a single-agent therapy for relapsed or refractory AML with KMT2A rearrangement, based on the AUGMENT-101 trial results. The SAVE trial enrolled patients with a median age of 35 years, including five pediatric patients, who had received an average of three prior lines of therapy. The most common side effects were manageable and included QT interval prolongation and elevated liver enzymes. The trial is ongoing and supported by Astex (搜索) and Syndax.
Ivosidenib, Venetoclax, and Azacitidine in IDH1-Mutant Hematologic Malignancies
In a Phase Ib/II trial, the combination of ivosidenib, venetoclax, and azacitidine was evaluated in 56 patients with newly diagnosed or relapsed/refractory IDH1 (搜索)-mutant hematologic malignancies, including AML, myelodysplastic syndromes (搜索), and myeloproliferative neoplasms (搜索). Led by Dr. Courtney DiNardo and presented by Dr. Jennifer Marvin-Peek, the triplet regimen achieved a 94% overall response rate and a 93% composite complete remission rate.
The three-year overall survival rate was 70.5%, and patients who proceeded to stem cell transplant had a remarkable 94.7% three-year overall survival rate. Among those who did not undergo transplant, 47% remained on 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 had 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," said Dr. Marvin-Peek. "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."
This research builds on previous findings that ivosidenib plus azacitidine, and venetoclax plus azacitidine, are effective in treating IDH1 (搜索)-mutant AML. The multi-center trial included patients with a median age of 69 years, who received a median of four treatment cycles. Common adverse events were low blood counts and gastrointestinal side effects, with four patients experiencing differentiation syndrome. The trial was supported by Servier and Abbvie/Genentech (搜索).
Pirtobrutinib, Obinutuzumab, and Venetoclax in Previously Untreated CLL
A Phase II trial investigated a triplet regimen consisting of the noncovalent BTK-inhibitor pirtobrutinib, the CD20 monoclonal antibody obinutuzumab, and the BCL2 (搜索) inhibitor venetoclax in patients with previously untreated chronic lymphocytic leukemia (搜索) (CLL). Dr. Nitin Jain presented the results, which demonstrated high rates of undetectable measurable residual disease (MRD).
After 13 cycles, the undetectable MRD rate was 98% in bone marrow and 100% in blood at 10-4 sensitivity (less than one CLL cell per 10,000 lymphocytes) among 41 evaluable patients. At a more sensitive threshold of 10-6, MRD rates 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," said Dr. Jain. "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 of 63 years. Of these, 79% had immunoglobulin heavy chain unmutated CLL, and 13% had del(17p)/TP53 mutation. Responses were monitored by imaging and bone marrow assessment, with MRD assessed by next-generation sequencing. After completing therapy, patients were 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. The trial was funded by Eli Lilly.