Dr Stein on the Efficacy of Revumenib in KMT2A+ R/R Acute Leukemia

"What [the data] say to me is: [approximately] 23% of patients are clearing their blasts and having nice blood count recovery [with revumenib], but there's a large group of patients who are still able to clear their blasts. If those patients are eligible to receive [ASCT], the clearance of those blasts does allow those patients to proceed to transplant, [which will] hopefully be successful."

Eytan M. Stein, MD, director, Program for Drug Development in Leukemia, chief, Leukemia Service, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses key efficacy findings from the phase 1/2 AUGMENT-101 study (SNDX-5613-0700; NCT04065399), which supported the November 2024 

-rearranged relapsed/refractory acute leukemia.

In the efficacy portion of the study involving 104 patients with relapsed or refractory acute leukemia and a 

 rearrangement, 21.2% (95% CI, 13.8%-30.3%) of patients achieved a complete remission (CR) or a complete remission with partial hematologic recovery (CRh), meeting the FDA's regulatory bar for approval, Stein begins. The median duration of CR or CRh was 6.4 months (95% CI, 2.7-not estimable), with a time to response of 1.9 months (range, 0.9-5.6 months), he adds. Importantly, 14% of patients who were previously transfusion dependent achieved transfusion independence [TI]; 48% of patients at baseline remained independent. These findings highlight revumenib’s potential to improve not only remission rates but quality of life for patients by reducing transfusion dependency, Stein states.

 from a subset of 57 patients showed a similar trend, with an overall response rate of 63.2% and a CR/CRh rate of 22.8%, Stein notes. This dataset further reinforces the ability of revumenib to clear blasts, providing patients an opportunity to proceed to an allogeneic stem cell transplant (ASCT), which could offer long-term disease control, he explains. Although the CR/CRh rate produced by revumenib represents a significant achievement, the ability of additional patients to clear their blasts underscores the broader potential of revumenib in combination with subsequent treatments, offering hope for better outcomes in a patient group with historically poor prognosis, Stein concludes.

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Eytan M. Stein, MD, discusses efficacy findings from the phase 1/2 AUGMENT-101 study of revumenib in KMT2A-rearranged relapsed/refractory acute leukemia.
 
 

Dr Stein on the Impact of Revumenib on Survival Outcomes in KMT2A-Rearranged R/R Acute Leukemia

"This is a difficult-to-treat type of leukemia and the approval of revumenib gives these patients some hope that they'll be able to take a generally well tolerated oral therapy that can put them back into remission."

Eytan M. Stein, MD, director, Program for Drug Development in Leukemia, chief, Leukemia Service, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses how the FDA approval of revumenib (Revuforj) could improve survival outcomes for patients with 

-rearranged relapsed/ refractory acute leukemia.

The menin inhibitor received FDA approval

 in November 2024 for the treatment of adult and pediatric patients aged 1 year and older with relapsed/refractory acute leukemia with a 

 translocation. Data from the phase 1/2 AUGMENT-101 study (SNDX-5613-0700; NCT04065399), which demonstrated a 21.2% complete remission (CR) or complete remission with partial hematologic recovery (CRh) rate among those treated with revumenib (n = 104), supported this regulatory decision.

The approval of revumenib is particularly significant given the poor prognosis of patients with KMT2A rearrangements in relapsed/refractory acute leukemia, whether it be acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL), Stein begins. These patients, particularly those who have received multiple lines of prior therapy, face an extremely limited life expectancy. Retrospective data in AML, for instance, shows that the overall survival (OS) for patients with more than 2 lines of therapy after relapse is measured in mere months, Stein emphasizes. For patients who have undergone 3 or more lines of therapy, the median OS is approximately 2.4 months, he adds.

Revumenib's approval provides these patients with a new, generally well-tolerated oral therapy option that may offer a chance to achieve remission. Stein states. This is a hopeful development for a group of patients who have historically had few treatment options and poor outcomes, representing a significant advancement in the management of relapsed/refractory 

-positive acute leukemia, Stein concludes.

Eytan M. Stein, MD, discusses how the FDA approval of revumenib could improve survival outcomes in KMT2A-rearranged relapsed/refractory acute leukemia.
 

Dr Stein on the Development of Targeted Therapies in Splicing Mutant Hematologic Malignancies

Eytan M. Stein, MD, director, Program for Drug Development in Leukemia, chief, Leukemia Service, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses the ongoing development and investigation of therapies targeting splicing mutations in hematologic malignancies.

The investigational oral IRAK4 inhibitor emavusertib (formerly CA-4948) is currently being investigated as a targeted therapy for patients with hematologic malignancies, such as acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), whose disease harbors a spliceosome or 

 mutation, Stein begins. IRAK4, a critical component in the pathogenesis of splicing-mutant AML, is selectively and reversibly inhibited by emavusertib, he explains. This small molecule demonstrates favorable pharmacological characteristics, including oral bioavailability, moderate plasma binding, stability, and rapid absorption and clearance.

This novel agent is currently being evaluated in the phase 1/2 TakeAim Leukemia trial (NCT04278768) both as a monotherapy and in combination with azacitidine and venetoclax (Venclexta) in patients with relapsed/refractory acute AML or high-risk MDS. Initial results showed a significant reduction in blast count irrespective of dose level, mutation status, or number of prior lines of treatment. Notably, 2 of the 3 evaluable patients with 

mutations treated with the recommended phase 2 dose of 300 mg twice-daily achieved a complete response (CR), and 2 of 3 patients with a spliceosome mutation achieved a CR with partial hematologic recovery.

Despite advancements in the investigation of emavusertibas a potential therapeutic agent in this population, questions remain about its specificity for splicing mutations and broader applicability beyond this specific genetic subset, Stein notes.

In addition to emavusertib, there is growing interest in a novel class of drugs known as CLK inhibitors, Stein continues. These agents inhibit CLK protein kinases involved in pre-mRNA splicing to reduce cell growth and promote cell death. Preliminary data from a phase 1/2 study in Japan (JapicCTI-184188) have shown a promising response rate with the first-in-class CLK inhibitor CTX-712 in a small cohort of patients with MDS. These CLK inhibitors may exhibit activity specific to patients with splicing factor mutations, hinting at a potential avenue for future therapeutic developments, Stein concludes.

Editor's Note: Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

Eytan M. Stein, MD, discusses the ongoing development and investigation of therapies targeting splicing mutations in hematologic malignancies.
 

Eytan M. Stein, MD, director, Program for Drug Development in Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, discusses the phase 2 SELECT-AML-1 trial (NCT04905407) in patients with newly diagnosed acute myeloid leukemia (AML).

The phase 2 SELECT-AML-1 trial is examining the utilization of tamibarotene (Amnolake) plus venetoclax (Venclexta) and azacitidine (Vidaza) in patients with retinoic acid receptor alpha (RARA)–positive AML who are unlikely to tolerate standard intensive chemotherapy as a frontline treatment.

The first part of the trial will examine the safety of combining tamibarotene with venetoclax and azacitidine, followed by the second part of the study where patients will be randomized 1:1 to receive venetoclax and azacitidine with or without tamibarotene, Stein explains.

Notably, a subset of patients receiving venetoclax and azacitidine alone will be permitted to cross over to receive tamibarotene with venetoclax and azacitidine if they fail on treatment, Stein continues. The primary end points of SELECT-AML-1 will be complete remission rates and overall response rates, and exploratory end points included pharmacokinetics and additional safety, Stein concludes.

Eytan M. Stein, MD, discusses the phase 2 SELECT-AML-1 trial in patients with newly diagnosed acute myeloid leukemia.


Dr. Stein on the SELECT-AML-1 Trial in Newly Diagnosed AML

Eytan Stein, MD, attending physician in the leukemia service at Memorial Sloan Kettering Cancer Center, discusses new data from a phase I study exploring the oral IDH2 inhibitor AG-221 in patients with advanced hematologic malignancies, primarily acute myelogenous leukemia (AML) and myelodysplastic syndrome.

At the time of the data cut-off, 45 patients with 

 mutations were analyzed for response. Overall, by investigator-accessed criteria, 56% of patients responded to therapy, Stein explained.

Responses were comprised of complete remissions (CR; n = 6), CR with incomplete platelet recovery (n = 4), marrow CR (n = 4), CR with incomplete hematologic recovery (n = 1), and partial remissions (n = 10). Responses were durable and lasted for 3 months or longer in the majority of patients.

These findings were from an interim analysis of a phase I trial, Stein emphasized. However, if these results are confirmed in larger trials, it could represent a quantum leap over previous treatments for patients with AML that could potentially lead to durable remissions.

View more from the 2014 ASH Annual Meeting

Eytan Stein, MD, from the Memorial Sloan Kettering Cancer Center, discusses new data from a phase I study exploring the oral IDH2 inhibitor AG-221 in patients with advanced hematologic malignancies, primarily acute myelogenous leukemia and myelodysplastic syndrome.


Eytan Stein, MD

Articles

Dr Stein on the Efficacy of Revumenib in KMT2A+ R/R Acute Leukemia

Dr Stein on the Impact of Revumenib on Survival Outcomes in KMT2A-Rearranged R/R Acute Leukemia

Dr Stein on the Development of Targeted Therapies in Splicing Mutant Hematologic Malignancies

Dr. Stein on the SELECT-AML-1 Trial in Newly Diagnosed AML

Dr. Eytan Stein Discusses the IDH2 Inhibitor AG-221 in AML