Tag: Acute Myeloid Leukemia

FDA Approves KOMZIFTI® for Relapsed or Refractory Acute Myeloid Leukemia with a NPM1 mutation

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SUMMARY: The FDA on November 13, 2025, approved Ziftomenib (KOMZIFTI®), a menin inhibitor, for adults with relapsed or refractory Acute Myeloid Leukemia (AML) with a susceptible Nucleophosmin 1 (NPM1) mutation who have no satisfactory alternative treatment options.

The American Cancer Society estimates that in 2025, 22,010 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,090 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. With the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

NPM1 mutations present in up to 30% of newly diagnosed adult AML define a unique disease subset recognized by both the WHO and the International Consensus Classification. Although NPM1-mutated AML often responds well to initial intensive therapy, outcomes deteriorate sharply after relapse or refractory disease. Patients in this setting frequently face limited therapeutic options and dismal response rates with conventional salvage strategies.

Mounting evidence shows that NPM1-mutated and KMT2A-rearranged (KMT2A-r) leukemias rely on an aberrant transcriptional program maintained through the interaction between menin and KMT2A. This dependency includes pathologic overexpression of HOX and MEIS1, which reinforce leukemic self-renewal and block differentiation. Inhibiting the menin–KMT2A complex has therefore emerged as a compelling therapeutic strategy capable of reversing leukemic transcriptional programs.

Ziftomenib, a potent and selective oral menin inhibitor, disrupts this interaction and restores myeloid differentiation in preclinical models. The registrational Phase II portion of the KOMET-001 study provides the most definitive evidence to date of its clinical potential in relapsed/refractory NPM1-mutated AML, and was used for the primary efficacy analysis and formed the basis for the FDA approval.

Mechanistic Rationale for Menin Inhibition

Menin serves as a scaffold protein essential for recruitment of the KMT2A/MLL methyltransferase complex to chromatin. This interaction drives leukemogenic transcriptional circuits in both KMT2A-r and NPM1-mutated AML, promoting expression of HOXA9, MEIS1, PBX3, and downstream effectors such as FLT3 and BCL2.

Key mechanistic insights include:

  • Menin–KMT2A blockade releases mutant NPM1 from chromatin, reducing HOX/MEIS1 signaling and triggering differentiation.
  • Ziftomenib promotes terminal maturation of AML blasts, rather than direct cytotoxicity, consistent with its differentiation-based mechanism.
  • NPM1 cytoplasmic mislocalization, a hallmark of the mutation, creates vulnerabilities that can be exploited through menin inhibition and related targeted approaches.

This biology underpins the therapeutic activity observed in KOMET-001 and supports the broader pursuit of menin inhibition across multiple AML subtypes.

KOMET-001 Trial Overview

KOMET-001 is a global, multicenter Phase I/II study evaluating single-agent Ziftomenib in adults with relapsed/refractory NPM1-mutated or KMT2A-rearranged AML. The Phase II portion which serves as the registrational dataset, focused on patients with relapsed/refractory NPM1-mutated disease treated at the recommended monotherapy dose of Ziftomenib 600 mg once daily.

Among the 92 patients with relapsed/refractory NPM1-mutated AML included in Phase II:

  • Median age: 69 years (range 33–84); 64% were ≥65 years
  • Median prior therapies: 2 lines (range 1–7)
  • Prior venetoclax exposure: 59%
  • Prior allogeneic transplantation: 24%
  • Common co-mutations: FLT3 (56%), IDH1/2 (33%)
  • ECOG 0–1: 83%

Efficacy was established based on the rate of Complete Remission (CR) plus CR with partial hematological recovery (CRh), the duration of CR plus CRh, and the rate of conversion from transfusion dependence to transfusion independence. The median follow-up was 4.2 months.

This heavily pretreated population reflects real-world patients with few remaining therapeutic options and particularly poor expected outcomes.

Efficacy Findings

Ziftomenib met its Primary endpoint with a CR/CRh rate of 22% (95% CI 14–32; P=0.0058), exceeding the historical 12% benchmark for this setting.

Key efficacy results:

  • CR/CRh rate: 22% (14% CR; 8% CRh)
  • Composite CR rate: 26%
  • Overall Response Rate (ORR): 33%
  • Median time to first response: 1.9 months
  • Median duration of response: 4.6 months
  • MRD negativity: 61% of evaluable CR/CRh responders
  • Median Overall Survival (OS): 6.6 months
  • Median OS among responders: 18.4 months

Two responders were successfully bridged to allogeneic stem cell transplantation and resumed Ziftomenib maintenance afterwards.

Efficacy was maintained across clinically relevant subgroups:

  • Age <65 vs ≥65: 21% vs 22% CR/CRh
  • Prior venetoclax exposure: 22% CR/CRh
  • Prior HSCT: 23% CR/CRh
  • FLT3 co-mutations: 13% (ITD), 33% (TKD)
  • IDH1/2 co-mutations: 50% and 31%, respectively

The activity in Venetoclax-exposed patients is particularly noteworthy given real-world salvage CR rates as low as 4% in this population.

Transfusion Independence

  • RBC independence conversion: 23%
  • Platelet independence conversion: 15%
  • Overall transfusion independence conversion: 20%

These improvements reflect meaningful clinical benefit and enhanced quality of life.

Safety and Tolerability

Ziftomenib demonstrated a favorable safety profile with low rates of treatment-related discontinuation (3%). Most adverse events were consistent with underlying AML or expected from differentiation-based therapies. Common Grade ≥3 TEAEs included febrile neutropenia (26%), anemia (20%) and thrombocytopenia (20%). Differentiation Syndrome occurred in 25% (15% grade 3; none grade 4–5) managed effectively using protocol-defined measures including cytoreduction and steroid prophylaxis, reinforcing the necessity of early recognition and continued therapy through differentiation-associated changes. Overall, ziftomenib showed no clear intrinsic myelosuppression, minimal cardiac toxicity, and a manageable safety profile appropriate for a predominantly older patient population.

Clinical Implications

The KOMET-001 data establish Ziftomenib as a meaningful therapeutic advance for patients with relapsed/refractory NPM1-mutated AML, an area historically characterized by low response rates and short survival. The durability of responses, high rate of MRD clearance, and consistent efficacy across age groups, co-mutational backgrounds, and prior therapies position Ziftomenib as a valuable monotherapy option and a potential bridge to curative transplantation. These results also strengthen the biological rationale for integrating menin inhibitors earlier in the treatment course. Ongoing frontline trials including the global Phase III KOMET-017 study will clarify the role of Ziftomenib-based combinations in newly diagnosed fit and unfit patients with NPM1-mutated or KMT2A-rearranged AML.

Conclusion

Ziftomenib, a first-in-class oral menin inhibitor, demonstrated clinically meaningful activity and durable responses in heavily pretreated relapsed/refractory NPM1-mutated AML, meeting its registrational Phase II endpoint. With a manageable safety profile including low myelosuppression, minimal QTc effects, and predictable differentiation syndrome, Ziftomenib represents an important new targeted therapy for a genetically defined AML subset.

The KOMET-001 results mark a significant step forward in addressing an area of profound unmet need, and they lay the foundation for expanding menin inhibition into earlier lines of therapy with the goal of transforming long-term outcomes for patients with NPM1-mutated AML.

Ziftomenib in Relapsed or Refractory NPM1-Mutated AML. Wang ES, Montesinos P, Foran J, et al. J Clin Oncol. 2025;43:3381-3390

FDA Approves REVUFORJ® for Acute Leukemia with KMT2A Translocation

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SUMMARY: The FDA on November 15, 2024, approved Revumenib (REVUFORJ®), a menin inhibitor, for Relapsed or Refractory acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients 1 year and older. The American Cancer Society estimates that in 2024, 20,800 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,220 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5-year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients based on risk, and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high-risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia, and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium. Over 50% of AML cases lack targetable mutations, relying instead on toxic chemotherapy.

Rearrangements of KMT2A gene previously known as MLL are found in 80% of infant Acute Lymphoblastic Leukemia (ALL) and in 5-15% of acute leukemia cases in children and adults, including myeloid, lymphoid, or mixed phenotypes. NPM1 mutations are the most common genetic alteration in adult Acute Myeloid Leukemia (AML), occurring in up to 30% of cases. Acute leukemias with KMT2A rearrangements have a poor prognosis, with a 5-year overall survival rate of less than 25%. There are no targeted therapies currently approved specifically for acute leukemia with KMT2A gene rearrangements or NPM1 mutations. Both KMT2A gene rearrangements and NPM1 mutations cause blood cells to regress to a stem-cell-like state, leading to the formation of leukemia cells. For leukemias driven by KMT2A gene rearrangements and NPM1 mutations, menin is a critical oncogenic cofactor. Menin interacts with the protein MLL1 (produced by KMT2A), forming a menin–MLL1 complex. This complex binds to chromatin and activates aberrant gene pathways, specifically HOX genes and their cofactor MEIS1, critical for leukemia development.

Revumenib is a potent, oral, small molecule menin inhibitor. It blocks the menin–MLL1 interaction, preventing the formation of the menin–MLL1 complex. By disrupting this complex, Revumenib stops the aberrant activation of HOX and MEIS1 gene expression and allows leukemia cells to either die or differentiate back into normal blood cells. Unlike other targeted therapies that block dysfunctional proteins, Revumenib prevents aberrant gene expression at its source. Its ability to target a common mechanism in AML makes it broadly applicable. Preclinical Studies demonstrated that menin inhibition reverses leukemia progression by downregulating HOX and MEIS1 transcription disrupting oncogenic complexes formed by either option for patients with KMT2A gene arrangements or NPM1-mutated AML. Revumenib showed dramatic antileukemic activity, making this agent promising.

AUGMENT-101 is a single-arm cohort of an open-label, multicenter trial which included 104 adult and pediatric patients (at least 30 days old) with Relapsed or Refractory (R/R) acute leukemia with a KMT2A translocation. Eligible patients had a corrected QT interval of less than 450 milliseconds and those with an11q23 partial tandem duplication were excluded. Revumenib was administered at a dose that was approximately equivalent to 160 mg in adults orally twice daily. Treatment was continued until progressive disease, unacceptable toxicity, failure to achieve a morphological leukemia-free state by 4 cycles of treatment, or Hematopoietic Stem Cell Transplantation (HSCT). The median patient age was 37 years, 83% of patients had AML, 15% had Acute Lymphoblastic Leukemia, and 2% had mixed phenotype acute leukemia. Approximately 59% had relapsed/refractory disease, 21% had primary refractory disease, 20% of patients had untreated relapsed disease and 44% of patients underwent prior HSCT. The main efficacy outcome measures were Complete Remission (CR) plus CR with partial hematologic recovery (CRh), the duration of CR plus CRh, and conversion from transfusion dependence to independence.

The CR plus CRh rate was 21.2%, and the median CR plus CRh duration was 6.4 months. Of the 22 patients achieving CR or CRh, the median time to CR or CRh was 1.9 months. Among the 83 patients dependent on RBC and/or platelet transfusions at baseline, 14% became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 21 patients independent of both RBC and platelet transfusions at baseline, 48% remained transfusion independent during any 56-day post-baseline period. The most common adverse reactions noted in this study were hemorrhage, nausea, increased phosphate, musculoskeletal pain, neutropenia, infection, elevated liver enzymes, differentiation syndrome, QT prolongation and fatigue.

It was concluded that Revumenib is the first menin inhibitor and its efficacy represents a substantial improvement over previously available therapies, and represents a major breakthrough for patients with Relapsed or Refractory acute leukemia with a KMT2A translocation.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation

Late Breaking Abstract- ASH 2023: ERG is a New Predisposition Gene for Bone Marrow Failure and Hematological Malignancy

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SUMMARY: ERG (ETS-Related Gene) is a known oncogene located on chromosome 21, and is a member of the ETS (erythroblast transformation-specific) family of transcription factors. The ERG gene encodes for a protein also called ERG that functions as a transcriptional regulator, and regulates differentiation of early hematopoietic cells.

ERG has been linked to Down syndrome- associated Acute Megakaryocytic Leukemia. ERG typically via gene-fusions can lead to dysregulated ERG overexpression in hematologic malignancies and solid tumors. ERG can fuse with TMPRSS2 protein to form an oncogenic fusion gene that is commonly found in Hormone-Refractory Prostate Cancer, suggesting that ERG overexpression may contribute to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling. EWS1-ERG fusion has been noted in 10% of Ewing’s Sarcoma cases. ERG is also involved in oncogenesis by generating fusion genes with FUS/TLS in Acute Myeloid Leukemia.

The researchers in this study identified a germline ERG variant associated with bone marrow failure and hematological malignancies. The study originated from a family case involving thrombocytopenia and neutropenia, where the mother developed Acute Myeloid Leukemia (AML) and MyeloDysplastic Syndrome (MDS). ERG, a known oncogene, was discovered as a predisposition gene for bone marrow failure and hematological malignancy. A germline ERG ETS domain variant (p.Y373C) was identified, segregating with thrombocytopenia in a family, leading to AML and therapy-related MDS. Copy neutral Loss of Heterozygosity of chromosome 21q, including the ERG locus, was observed in affected individuals. Validation of their findings involved functional assays, demonstrating Loss of Function variants in ERG, affecting DNA binding and nuclear localization. Experiments using a fetal liver assay confirmed the role of ERG in cytokine-independent growth and leukemia development.

Through global collaborations, 15 heterozygous variants in the ERG gene were identified, including 13 missense and 2 truncating variants in 17 individuals with cytopenia, hematological malignancy or lymphedema. Of these 15 variants, 12 have been confirmed germline. Onset of hematological symptoms ranged from birth to 38 years for truncating and constrained ETS domain variants. Functional studies revealed that most ETS domain missense variants displayed Loss-of-Function (LOF) characteristics affecting transcriptional transactivation, DNA binding, and/or nuclear localization.

This ERG syndrome parallels GATA2 deficiency syndrome (hematological malignancy with lymphedema) and RUNX1 Familial Platelet disorder-myeloid malignancy (thrombocytopenia and hematological malignancy). ERG, like the well-known disease genes GATA2, and RUNX1 is a member of the transcription factor heptad involved in hematopoietic stem cell maintenance and differentiation.

The researchers concluded that germline ERG variants predispose to diverse cytopenia, bone marrow failure and hematological malignancies in both children and adults and ERG adds to a growing list of genes whose unregulated expression contributes to hematological malignancy and other cancers. Identification of germline ERG variants has direct clinical implications for patient and family management including diagnosis, counseling, surveillance, and treatment strategies, such as bone marrow transplant and targeted therapies. Potential clinical implications include ERG screening in germline panels for bone marrow failures and hematological malignancies. Additionally there is a need for further longitudinal studies to understand the natural history of ERG-related syndromes.

ERG is a New Predisposition Gene for Bone Marrow Failure and Hematological Malignancy. Scott HS, Zerella J, Homan C, et al. ASH Annual Meeting & Exposition 2023. LBA-6.

VANFLYTA® (Quizartinib)

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The FDA on July 20, 2023, approved VANFLYTA® (Quizartinib) with standard Cytarabine and Anthracycline induction and Cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed Acute Myeloid Leukemia (AML) that is FLT3 Internal Tandem Duplication (ITD)-positive, as detected by an FDA-approved test. VANFLYTA® is a product of Daiichi Sankyo, Inc.

Long Term Overall Survival Benefit with VIDAZA® plus VENCLEXTA® in Elderly AML Patients

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SUMMARY: The American Cancer Society estimates that in 2023, 20,380 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,310 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5-year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients based on risk, and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high-risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia, and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by AML cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® (Venetoclax) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. VIDAZA® (Azacitidine) is a hypomethylating agent that promotes DNA hypomethylation by inhibiting DNA methyltransferases. VIDAZA® has been shown to significantly improve Overall Survival (OS), when compared to conventional care regimens, in elderly unfit patients with newly diagnosed AML, who are not candidates for intensive chemotherapy. The combination of VIDAZA® and VENCLEXTA® in a previously published Phase Ib study was highly efficacious, with significant responses, duration of response and Overall Survival benefit.

VIALE-A is a Phase III, multicenter, randomized, double-blind, placebo-controlled confirmatory trial, conducted to evaluate the efficacy and safety of a combination of VIDAZA® and VENCLEXTA®, as compared with VIDAZA® plus placebo (the control regimen), in previously untreated patients with AML, who were ineligible for intensive induction therapy. In this study, 431 patients (N=431) with previously untreated AML were randomly assigned in a 2:1 ratio to receive either VIDAZA® plus VENCLEXTA® (N=286), or VIDAZA® plus placebo (N=145). Enrolled patients were ineligible for standard induction chemotherapy because of coexisting conditions, 75 years of age or older, or both. All patients received VIDAZA® 75 mg/m2 subcutaneously or IV on days 1 through 7 of every 28-day cycle. Patients in the study group also received VENCLEXTA® 100 mg orally on day 1 and 200 mg on day 2 and target dose of 400 mg on day 3, and continued daily until day 28 during cycle 1, to mitigate Tumor Lysis Syndrome. The dose of VENCLEXTA® was initiated at 400 mg daily in all subsequent 28-day cycles. In the control group, a matching placebo was administered orally, once daily, in 28-day cycles. The median age was 76 years in both groups, approximately 60% were male and 76% were Caucasian. Molecular abnormalities of interest included FLT-3, observed in 14% of patients receiving VIDAZA® plus VENCLEXTA®, IDH1/2, observed in 25% of patients, TP53, observed in 23.3% of patients and NPM1, observed in 16.6% of patients. Secondary AML was reported in 25% of the patients in the VIDAZA® plus VENCLEXTA® group and in 24% of the patients in the control group. All the patients were hospitalized on or before day 1 of cycle 1 and for at least 24 hours after receiving the final dose of VENCLEXTA®, in order to receive prophylaxis against the Tumor Lysis Syndrome and for monitoring. The Primary endpoint was Overall Survival (OS). The Secondary end points included Complete Remission (CR) rates, composite Complete Remission (Complete Remission or Complete Remission with incomplete hematologic recovery), RBC and platelet transfusion independence, and Quality of Life according to Patient-Reported Outcomes.

At a median follow up of 20.5 months, the median OS was 14.7 months in the VIDAZA® plus VENCLEXTA® group versus 9.6 months in the VIDAZA® plus placebo group (HR=0.66; P<0.001). VIDAZA® plus VENCLEXTA® combination resulted in a CR rate of 36.7% versus 17.9%; P<0.001 and composite CR of 66.4% versus 28.3%; P<0.001, when compared to the control regimen. Most responses were seen after the first 28-day cycle. The median time to first response was 1.3 versus and 2.8 months respectively, duration of CR was 17.5 months versus 13.3 months and median duration of composite CR was 17.5 months in the VIDAZA® plus VENCLEXTA® group and 13.4 months in the control group. RBC transfusion independence occurred in 59.8% of the patients in the VIDAZA® plus VENCLEXTA® group and in 35.2% of those in the control group (P<0.001), and platelet transfusion independence occurred in 68.5% and 49.7% (P<0.001), respectively. The benefits with VIDAZA® plus VENCLEXTA® were noted in almost all molecular subgroups compared to the control regimen. The response rates were highest among patients with FLT3 mutations (72.4% versus 36.4%, P=0.02) and those with IDH1 or IDH2 mutations (75.4 % versus 10.7%, P<0.001), respectively.

The researchers conducted 2 years of additional follow-up to determine the long-term survival benefit of VIDAZA® plus VENCLEXTA® combination and at this meeting reported the analysis of VIALE-A trial, after the occurrence of 100% of the pre-planned survival events. With a median follow-up of 43.2 months, the median Overall Survival (OS) benefit since the interim analysis in the overall population was maintained and was 14.7 months in the VIDAZA® plus VENCLEXTA® group versus 9.6 months in the VIDAZA® plus placebo group (HR=0.58; P<0.001). Among patients with Measurable Residual Disease (MRD) <10-3 who had achieved either Complete Remission (CR) or CR with incomplete hematologic recovery (CRi), the median OS was reached at 34.2 months in the VIDAZA® plus VENCLEXTA® group and 25.0 months in the control group. For patients in the IDH1/2 mutant subgroup, the median OS at final analysis with VIDAZA® plus VENCLEXTA® was 19.9 months and was 6.2 months in the control group (HR=0.31; P<0.001). Overall safety profiles were comparable between the treatment groups.

The 2-year follow up analysis of the VIALE-A trial confirmed the sustained Overall Survival benefit of VIDAZA® plus VENCLEXTA® combination in patients with AML, ineligible for intensive chemotherapy, with no new safety findings noted.

Long-Term Follow-up of the Phase 3 Viale-a Clinical Trial of Venetoclax Plus Azacitidine for Patients with Untreated Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy. Pratz KW, Jonas BA, Pullarkat VA, et al. Presented at the 64th ASH Annual Meeting and Exposition, December 10-13, 2022, New Orleans, Louisiana. Abstract # 219

FDA Approves Quizartinib for Newly Diagnosed Acute Myeloid Leukemia

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SUMMARY: The FDA on July 20, 2023 approved Quizartinib (VANFLYTA®) with standard Cytarabine and Anthracycline induction and Cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed Acute Myeloid Leukemia (AML) that is FLT3 Internal Tandem Duplication (ITD)-positive, as detected by an FDA-approved test. FDA also approved LeukoStrat CDx FLT3 Mutation Assay as a companion diagnostic for Quizartinib.

The American Cancer Society estimates that in 2023, 20,380 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,310 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy, or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5-year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients based on risk, and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high-risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia, and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

The Fms-Like Tyrosine kinase 3 (FLT3) protein is a receptor tyrosine kinase in the PDGF family of growth factor receptors located on the hematopoietic stem cell surface (transmembrane). FLT3 normally promote cell survival, growth, and differentiation. FLT3 plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML. Approximately 25% of patients with newly diagnosed AML have FLT3-ITD mutations and approximately 7% have point mutations in the Tyrosine Kinase Domain (TKD). FLT3-ITD (Internal Tandem Duplication) mutation is caused by tandem duplication within the coding region of the gene. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations have poor outcomes with shorter remission duration and significantly decreased Leukemia Free and Overall Survival.

Quizartinib is an oral, highly potent, selective, Type 2 FLT3 inhibitor. This agent in combination with chemotherapy showed antitumor activity with an acceptable safety profile in patients with FLT3-ITD-positive newly diagnosed AML.

QuANTUM-First is a randomized, double-blind, placebo controlled, global, Phase III trial in which the efficacy of Quizartinib with chemotherapy was evaluated in patients with newly diagnosed FLT3-ITD positive AML aged 18–75 years. In this study, 539 patients (N=539) with newly diagnosed FLT3-ITD positive AML were randomly assigned 1:1 to receive chemotherapy plus Quizartinib (N=268) or placebo (N=271). Treatment consisted of induction with standard 7 plus 3 induction regimen of Cytarabine 100 mg/m2 daily (or 200 mg/m2 daily per institutional standard) by continuous IV from Days 1-7 and anthracycline (Daunorubicin 60 mg/m2 daily or Idarubicin 12 mg/m2 daily, by IV infusion on Days 1, 2, and 3, then Quizartinib 40 mg orally or placebo once daily, starting on day 8, for 14 days. Patients in complete remission or complete remission with incomplete neutrophil or platelet recovery received standard consolidation with high-dose Cytarabine plus Quizartinib (40 mg orally daily) or placebo, allo- Hematopoietic Stem Cell Transplantation (HSCT), or both as consolidation therapy, followed by continuation of single-agent Quizartinib or placebo for up to 3 years. There was no re-randomization at the initiation of post-consolidation therapy. Patients who proceeded to HSCT initiated maintenance therapy after HSCT recovery. FLT3-ITD status was determined prospectively with a clinical trial assay and verified retrospectively with the companion diagnostic LeukoStrat CDx FLT3 Mutation Assay. This study included patients aged 18 to 75 years, 55% male and 45% female, with newly diagnosed primary or secondary AML harboring a FLT3-ITD activating mutation, with an allelic ratio of 3% or more. The median age was 56 years. The aim of this study was to assess the effect of Quizartinib versus placebo on Overall Survival in patients with FLT3-ITD-positive newly diagnosed AML. The Primary end point of the trial was Overall Survival (OS). Secondary end points included Event-Free Survival (EFS), post induction rates of Complete Remission (CR) rate, composite CR (CRc) rate, Safety, and pharmacokinetics.

At a median follow up of 39.2 months, the median Overall Survival was 31.9 months for Quizartinib versus 15.1 months for placebo (HR=0.78; P=0.032), a 22% reduction in the risk of death. The CR rate in the Quizartinib group was 55%, with median response duration of 38.6 months, whereas the CR rate in those receiving placebo was 55% with median response duration of 12.4 months. Approximately 42% of patients treated with Quizartinib versus 38% treated with placebo were MRD negative at the time of Complete Remission or Complete Remission with incomplete neutrophil or platelet recovery. However, patients in both groups who were MRD negative had improved Overall Survival (HR 0.57), compared with those who remained MRD positive. The most common Grade 3 or 4 adverse events were febrile neutropenia, hypokalaemia, and pneumonia in both groups, and neutropenia in the Quizartinib group.

It was concluded that the addition of Quizartinib to standard chemotherapy with or without allo-HSCT, followed by continuation monotherapy for up to 3 years, resulted in improved Overall Survival in adults patients with FLT3-ITD-positive newly diagnosed AML, and provides a new, effective, and generally well tolerated treatment option for this patient group. The authors added that this is the first time a FLT3 inhibitor was studied in patients aged 18-75 years and is specifically approved for patients who have the worst FLT3 mutation, the ITD mutation.

Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Erba HP, Montesinos P, Kim H-J, et al. on behalf of the QuANTUM-First Study Group. The Lancet 2023;401:1571-1583.