A hallmark of acute myeloid leukemia (AML) is a maturation arrest of myeloid-committed hematopoietic cells, and the specific sensitivity of acute promyelocytic leukemia (APL) to retinoic acid was identified in the early 1980s.

 This discovery paved the way for initial clinical trials using all-trans retinoic acid (ATRA) in APL, which demonstrated efficacy through promoting differentiation to mature myeloid phenotypes.

 Findings from subsequent studies identified a novel fusion of the 

 gene as the molecular basis of this response.

 This molecular vulnerability of APL has been exploited with dual differentiating therapy using ATRA and arsenic trioxide, leading to more than 95% of patients being cured from this once highly fatal disease without the use of traditional cytotoxic chemotherapy.

Although targeted therapies have revolutionized how we care for patients with AML, with significant improvements in both survival and quality of life, persistent challenges remain in developing treatments with durable responses in non-APL subtypes. Recent research from our team at Roswell Park Comprehensive Cancer Center in Buffalo, New York, supports a rationale for expanding the use of differentiation therapy to patients with other aggressive leukemia subtypes.

Newer Targets for Differentiation Therapy

The advent of next-generation sequencing technologies has largely identified the molecular underpinnings of the non-APL subtypes of AML. Unfortunately, we have yet to see similar results with differentiation therapy in other forms of AML. Mutations in 

 have been successfully targeted with specific inhibitors including ivosidenib (Tibsovo) and olutasidenib (Rezlidhia), with complete remission rates of 30% to 35% observed in findings from clinical trials in the relapsed/refractory AML setting.

 Differentiation syndrome (DS), a frequent and potentially fatal adverse effect seen with ATRA therapy in APL, was also seen with the IDH1/2 inhibitors enasidenib (Idhifa) and ivosidenib in 19% of patients treated with each inhibitor.

 Symptoms of DS include fevers and capillary leak (eg, edema, effusions, hypotension) associated with leukocytosis. DS onset occurs in a bimodal fashion with APL, with most cases of DS developing within 1 week of treatment initiation. In contrast, more than 80% of DS cases with IDH1/2 inhibitors occurred more than 1 week and up to 3 months after treatment initiation, making them more difficult to monitor for.

Recently, several companies have developed inhibitors that disrupt the menin-KMT2A interaction that is critical to 

-mutated AML; revumenib (SNDX-5613) and ziftomenib (KO-539) are 2 inhibitors that are farther along in their clinical development.

 Data from the phase 2 AUGMENT-101 study (NCT04065399) on revumenib were recently reported in the population with relapsed/refractory AML, and patients achieved a complete response (CR) rate of 44%, with DS occurring in 26.6% of patients.

 A new drug application was submitted to the FDA for revumenib with a Prescription Drug User Fee Act date in September 2024. Studies assessing menin inhibitors in other AML subtypes and in combination with standard chemotherapies are ongoing. The phase 1/2 KOMET-001 (NCT04067336) substudies of ziftomenib in patients with 

-nonmutated AMLs and the phase 1 KOMET-007 study (NCT05735184) of ziftomenib with 7+3, azacitidine plus venetoclax (Venclexta), or venetoclax in patients with 

-mutated AML—the latest in a series of KOMET clinical trials my colleague Eunice S. Wang, MD, chief of the Leukemia Service at Roswell Park Comprehensive Cancer Center, has helped shape and lead—are currently enrolling patients at Roswell Park.

 is one of the most commonly mutated genes in AML and is targetable with tyrosine kinase inhibitors such as midostaurin (Rydapt), quizartinib (Vanflyta), and gilteritinib (Xospata). Both quizartinib and gilteritinib have been shown to induce myeloid differentiation in approximately half of patients, though the incidence of clinical DS is low.

 Differentiation primarily manifests with granulocyte development; however, FLT3 inhibitor–induced erythroid and monocytic differentiation has also been reported.

Importantly, of the patients responding with differentiation to gilteritinib in one study, most had partial responses and none had a true CR. The ongoing phase 1 KOMET-008 (NCT06001788) study, which we are opening at Roswell Park, includes a cohort for patients with 

–comutated disease to assess the combination of gilteritinib and ziftomenib as dual differentiation therapy

 are frequent cooperating mutations, but what do we do for other patients with 

My laboratory at Roswell Park recently demonstrated a dependency of 

-mutated AML on the histone methyltransferase, EZH2.

 It catalyzes trimethylation of histone 3 lysine 27, largely resulting in gene repression as part of PRC2. EZH2 is overexpressed in several tumor types, including AML, lymphomas, and prostate cancers, which promotes a stem cell–like state through repression of differentiation. The EZH2 inhibitor tazemetostat (Tazverik) is FDA approved for patients with follicular lymphoma and epithelioid sarcoma.

 EZH1, a homologue of EZH2, can compensate for reduced EZH2 activity, which led to the development of dual EZH1/2 inhibitors such as valemetostat. Valemetostat is currently approved in Japan for the treatment of adult patients with T-cell leukemia/lymphoma and recently demonstrated clinical activity in relapsed/refractory peripheral T-cell lymphomas.

We showed that FLT3 inhibitors reduced EZH2 expression in 

 internal tandem duplication (ITD)–mutated AML, leading to reduced PRC2 activity and upregulation of 

 target genes. EZH1 expression was increased as a potential compensatory mechanism that prevents full differentiation of the leukemic clone. When we combined the FLT3 inhibitor gilteritinib with valemetostat, we found improved responses and increased myeloid maturation in mouse models of 

 ITD–mutated AML. Similar findings were seen in a patient-derived xenograft model, and additional models are in progress. We hope to translate these findings into clinical trials in the near future.

The new era of differentiation therapy in AML is here. From clinical trial findings, we have learned that DS manifests with varied timing and symptoms with each drug. As we gain more experience with these agents, we will be better equipped to recognize and manage the effects of DS. More preclinical research is needed to convert these differentiation responses into cures. For now, a chemotherapy-free curative regimen for AML remains elusive for non-APL subtypes.

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Articles

Acute promyelocytic leukemia (APL) has seen significant advancements with the use of all-trans retinoic acid (ATRA) and arsenic trioxide, achieving high cure rates. However, non-APL acute myeloid leukemia (AML) subtypes still face challenges in achieving durable responses. Recent research highlights the potential of differentiation therapy for other AML subtypes, focusing on molecular targets like IDH1/2, menin-KMT2A, and FLT3 mutations. Preclinical studies suggest combining FLT3 inhibitors with EZH2 inhibitors could enhance differentiation and treatment efficacy, paving the way for future clinical trials.

Pamela J Sung, MD, PhD, details differentiation therapy in acute myeloid leukemia, focusing on newer targets and preclinical evidence for a 
novel FLT3 combination.

Pamela J. Sung, MD, PhD

Articles

Differentiation Therapy in Acute Myeloid Leukemia: Not Just for APL Anymore