Greater understanding of biological disease factors in acute myeloid leukemia (AML) has led to more effective and personalized treatment options. At the 2023 National Comprehensive Cancer Network (NCCN) Annual Congress: Hematologic Malignancies,1 Rebecca Olin, MD, MSCE, of UCSF Helen Diller Family Comprehensive Cancer Center, discussed how to optimize treatment selection for patients with newly diagnosed and secondary AML based on the following factors: morphology, flow cytometry, cytogenetics, fluorescence in situ hybridization (FISH) panels, and genetic testing (polymerase chain reaction [PCR]-based for actionable mutations, next-generation sequencing panels, or both).
According to Dr. Olin, these factors are of profound importance, as they can identify therapeutic targets (ie, FMS-like tyrosine kinase 3 [FLT3] or isocitrate dehydrogenase [IDH] 1 or 2), actionable targets, and prognostic information such as ASXL1 or RUNX1. These mutations can then be tracked over time, providing essential determinants in treatment selection.
“When selecting initial treatment for AML, stratification is based on whether patients are fit or unfit for intensive induction—a consideration that goes beyond chronologic age,” Dr. Olin explained. “This categorization is becoming more complex with developing lower-intensity therapies, and some patients who are technically fit for intensive induction might benefit from these less-intense therapies.”
Rebecca Olin, MD, MSCE
Fit for Induction
Current treatment protocols for patients requiring induction treatment have intensified in recent years. For decades, the standard of care, known as the “7+3” regimen (cytarabine and daunorubicin), has proved its efficacy and reliability, said Dr. Olin, making it the “vanilla” of treatment options. However, she noted, there is a subset of patients who may benefit from an enhanced treatment protocol.
Specifically, patients who are deemed fit for induction and have a FLT3 mutation, either an internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutation, are potential candidates for intensified treatment. Dr. Olin recommended the addition of midostaurin to the 7+3 regimen based on evidence derived from the RATIFY/C10603 trial; this study showed a survival advantage with 7+3 plus midostaurin vs 7+3 alone.2 Toxicities associated with midostaurin included anemia, rash, and nausea.
Dr. Olin also highlighted an upcoming treatment option for patients with FLT3-ITD–positive AML: 7+3 plus the tyrosine kinase inhibitor quizartinib.3 In clinical evaluation, this therapy was seen to confer survival advantages (hazard ratio = 0.78; P = .032). However, quizartinib comes with a black box warning for QT prolongation, which necessitates precautions such as baseline and follow-up ECG monitoring and electrolyte repletion.
Dr. Olin discussed a newer treatment for patients with FLT3-positive disease from ongoing comparison studies of midostaurin plus 7+3 vs the tyrosine kinase inhibitor gilteritinib plus 7+3. The outcomes of these studies could play a crucial role in dictating front-line therapy choices for patients with FLT3-positive disease, she added.
For patients fit for induction who have favorable-risk cytogenetics, Dr. Olin recommended 7+3 plus the antibody-drug conjugate gemtuzumab ozogamicin, supported by results from a recent meta-analysis.4 However, the benefits appear to be smaller for those with intermediate-risk cytogenetics and nonexistent for patients with adverse-risk cytogenetics.
The 7+3 plus gemtuzumab ozogamicin regimen may be considered for patients with NPM1-positive disease, said Dr. Olin. However, data from the AMLSG 09-09 trial suggest results for NPM1-positive disease may not be convincing for everyone because of increased toxicity levels with gemtuzumab ozogamicin.5 Toxicities associated with gemtuzumab ozogamicin include hepatic adverse events along with veno-occlusive disease, infusion-related reactions, and an elevated risk of hemorrhage.
Secondary AML
For patients with secondary AML, Dr. Olin suggested CPX-351 (dual-drug liposomal cytarabine and daunorubicin) as the standard of care, based on data comparing patients between the ages of 60 and 75 receiving either standard induction (7+3) or CPX-351.6 Results showed that the group receiving CPX-351 had improved overall survival and event-free survival as well as tended to show better survival after transplantation. These results were consistent regardless of the patient’s age, type of secondary AML, and karyotype.
“It’s noteworthy that although the study included patients between the ages of 60 and 75, the FDA approval covered adults of all ages,” Dr. Olin reported.
In terms of toxicity, CPX-351 was shown to potentially cause less hair loss and gastrointestinal toxicity but slower blood cell count recovery and increased instances of rash than standard induction therapy. Another key point to keep in mind is the cost difference, said Dr. Olin, with CPX-351 being more expensive.
Dr. Olin also raised critical points about the lack of clear data on what to do with induction-fit patients, specifically those with IDH1 or IDH2 mutations, and those with TP53 mutations. Although some safety data exist to support the inclusion of IDH1/2 inhibitors with upfront induction chemotherapy, she said, there are limited comparative efficacy data against 7+3 alone.
“Standard therapy for patients with a FLT3 mutation applies the 7+3 approach plus midostaurin, whereas patients with favorable-risk disease, especially those with core binding factor, receive 7+3 plus gemtuzumab ozogamicin,” commented Dr. Olin. “Patients with secondary AML could consider CPX-351.”
She also noted that the term “unfit” remains a difficult concept to define. As lower-intensity therapies improve, there could be a shift where so-called fit patients might opt to receive these less-intensive therapies. The current standard regimen for patients deemed unfit for induction is a hypomethylating agent (HMA) combined with venetoclax, grounded in data from the VIALE-A trial.7 The combination showed a survival benefit in diverse patient subsets.
Genetic Subtypes
Genetic subtypes play an important role in determining initial therapy choices for patients who are unfit for induction therapy. According to Dr. Olin, an HMA plus venetoclax has demonstrated effectiveness across different genetic subtypes, but for patients with FLT3-mutated disease, there are alternative regimens. These options, categorized as off-label, include azacitidine plus gilteritinib or sorafenib.
The azacitidine/gilteritinib combination was investigated in a phase III trial vs azacitidine alone in newly diagnosed patients with FLT3-mutated AML who were ineligible for intensive chemotherapy.8 Despite the trial not meeting its overall survival endpoint, a significant difference was observed in response rates between the experimental and control arms.
Dr. Olin also highlighted the potential of combination therapy in managing FLT3-positive AML. The doublet regimen of gilteritinib and venetoclax showed a “remarkable” modified composite complete response rate of 75%.9
Preliminary data stemming from a triplet study of gilteritinib, venetoclax, and azacitidine showed similar activity among newly diagnosed patients, with a 100% response rate and a 95% complete response rate.10 However, Dr. Olin also noted the triplet regimen’s more challenging tolerance levels.
Finally, she turned to patients with IDH1-mutated AML who are unable to undergo induction. For this patient group, azacitidine/ivosidenib has emerged as a compelling treatment option, supported by data from the AGILE trial.11 Results of the study showed improvements in both overall survival and event-free survival, with a median overall survival in the investigational arm of approximately 24 months. Given azacitidine/ivosidenib’s preferential tolerability, according to Dr. Olin, it is a reasonable option for this patient population.
Alternative options for patients with IDH1- and IDH2-mutated AML include single-agent ivosidenib, single-agent enasidenib, or an azacitidine/enasidenib combination.
Results with single-agent olutasidenib (an IDH1 inhibitor) and the triplet regimen of ivosidenib, venetoclax, and azacitidine have been presented recently. According to Dr. Olin, however, despite showing potential, these last two options remain off-label for upfront use and are not included in the current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Furthermore, the possible occurrence of differentiation syndrome was flagged as a side effect concern for the clinical use of IDH1 and IDH2 inhibitors.
“A hypomethylating agent plus venetoclax remains the preferred regimen for patients without actionable mutations,” Dr. Olin concluded. “However, for those harboring a FLT3 or IDH1/2 mutation, alternative regimens are recommended for consideration, though a hypomethylating agent plus venetoclax is still very reasonable.”
DISCLOSURE: Dr. Olin has received research funding from Cellectis, and consulting fees from Servier and Rigel.
REFERENCES
1. Olin R: Acute myeloid leukemia: Selecting induction therapy based on biological disease factors. 2023 NCCN Annual Congress: Hematologic Malignancies. Presented September 22, 2023.
2. Stone RM, Mandrekar SJ, Sanford BL, et al: Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377:454-464, 2017.
3. Erba HP, Montesinos P, Kim HJ, et al: 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. Lancet 401:1571-1583, 2023.
4. Hills RK, Castaigne S, Appelbaum FR, et al: Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: A meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol 15:986-996, 2014.
5. Schlenk RF, Paschka P, Krzykalla J, et al: Gemtuzumab ozogamicin in NPM1-mutated acute myeloid leukemia: Early results from the prospective randomized AMLSG 09-09 phase III study. J Clin Oncol 38:623-632, 2020.
6. Lancet JE, Uy GL, Cortes JE, et al: CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol 36:2684-2692, 2018.
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9. Daver N, Perl AE, Maly J, et al: Venetoclax plus gilteritinib for FLT3-mutated relapsed/refractory acute myeloid leukemia. J Clin Oncol 40:4048-4059, 2022.
10. Short N, Macaron W, Dinardo C, et al: P485: Azacitidine, venetoclax and gilteritinib for patients with newly diagnosed FLT3-mutated acute myeloid leukemia: A subgroup analysis from a phase II study. HemaSphere 7(suppl 3):e535260f, 2023.
11. Montesinos P, Recher C, Vives S, et al: Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med 386:1519-1531, 2022.
