Newly identified genetic abnormalities in AML have led to novel therapies that can target some of them, as the landscape for treatment continues to evolve. During the 2021 National Comprehensive Cancer Network (NCCN) Annual Congress: Hematologic Malignancies, Alice S. Mims MD, presented updates in the treatment of newly diagnosed AML, reviewing current treatment strategies as well as the impact of cytogenetic and molecular markers on treatment selection. 1 Dr. Mims is AML Research Director and Associate Professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center, James Cancer Hospital, and Solove Research Institute.
Alice S. Mims, MD
Current Strategies for AML
The availability of agents targeted to specific mutations in AML plus the approval of venetoclax “has opened up the possibility for different therapeutic options for newly diagnosed AML,” Dr. Mims told listeners.
Patients who are candidates for intensive induction regimens are treated with anthracycline and cytarabine–based regimens. For all comers, the 7 + 3 regimen (cytarabine + anthracycline) is an option. Treatment for patients with core-binding factor AML adds the CD33 monoclonal antibody gemtuzumab ozogamicin to 7 + 3 chemotherapy. For FLT3/ITD- or TKD-mutated AML, the FLT3 inhibitor midostaurin is added to 7 + 3 chemotherapy, she said, but the clinical trial that led to the approval was in patients 18 to 59 years old, so less is known about this regimen for patients older than 60. Secondary AML or therapy-related has the option of treatment with liposomal cytarabine plus daunorubicin (known as CPX-351).
Gemtuzumab ozogamicin was withdrawn from the market by the U.S. Food and Drug Administration (FDA) in 2010 because of toxicity concerns, but it was subsequently reintroduced in 2017 as a single agent or in combination with the 7 + 3 regimen. This decision was based on a meta-analysis of randomized controlled trials in patients aged 15 or older with overall survival as an endpoint. This meta-analysis showed the drug improved 5-year overall survival in patients with favorable- and intermediate-risk cytogenetics, with the most robust response reported in favorable-risk patients.2
“There was no benefit seen in overall survival with the addition of gemtuzumab ozogamicin in poor-risk patients,” Dr, Mims said.
The phase III RATIFY trial showed that although the complete response rate was no different with midostaurin vs placebo added to 7 + 3 induction, there was an overall survival benefit with the addition of the FLT3 inhibitor: median overall survival was 74.7 months vs 25.6 months with placebo (P = .0009). Also, event-free survival was significantly longer with midostaurin (P = .002).3
The availability of agents targeted to specific mutations in AML plus the approval of venetoclax has opened up the possibility for different therapeutic options for newly diagnosed AML.— Alice S. Mims, MD
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Induction therapy with CPX-351 vs standard therapy with 7 + 3 chemotherapy led to an overall survival improvement of about 4 months with CPX-351: median overall survival of 9.6 months vs 6.0 months (P = .003), with a similar rate of grades 3 to 5 adverse events in both treatment arms. This trial included adults with newly diagnosed therapy-related or secondary AML.4
Less Intensive Induction Regimens
Less intensive regimens that are not genomically specified include venetoclax plus a hypomethylating agent; venetoclax plus low-dose cytarabine; glasdegib plus low-dose cytarabine; hypomethylating agents as monotherapy, low-dose cytarabine, or supportive care/hospice.
According to Dr. Mims, a “hot topic” in AML is BCL2 inhibitors, specifically venetoclax. A recent randomized, double-blind, placebo-controlled, phase III study compared venetoclax plus azacitidine vs azacitidine plus placebo in 431 patients with AML (aged 75 or older or with comorbidities that precluded intensive induction therapy).5 In the study, venetoclax was given daily, and azacitidine was given subcutaneously or intravenously on days 1 to 7 in 28-day cycles.
Venetoclax plus azacitidine outperformed azacytidine plus placebo in terms of response rates and event-free survival (P < .001, for all endpoints for response and event-free survival), Dr. Mims commented. Complete response or complete response with incomplete hematologic recovery rates were 66.4% vs 28.3%, respectively. Significantly higher response rates with venetoclax plus azacitidine were observed in patients with IDH1/2, FLT3, NPM1, and TP53 mutations. Adverse events were more frequent with combination therapy but were mostly grade 1 or 2.
Overall survival was a median of 14.7 months for the combination vs 9.6 months for the control arm—a 34% improvement favoring the addition of venetoclax (P < .001). Subgroup analysis of overall survival favored venetoclax plus azacitidine for all prespecified subgroups, including age, gender, type of AML, cytogenetic risk category, and molecular markers.
“Further analysis of venetoclax in combination with hypomethylating agents has not been shown to improve outcomes compared to hypomethylating agents alone in patients with TP53 mutations. This highlights the need for effective therapy for TP53-mutated AML,” Dr. Mims stated.
A second multicenter, randomized, double-blind, placebo-controlled phase III trial compared low-dose cytarabine with or without venetoclax in 210 adults with previously untreated AML who were ineligible for standard therapy because of age or comorbidities.6 Complete response and event-free survival rates were superior with venetoclax plus cytarabine: 25% vs 7% for low-dose cytarabine plus placebo. At a median follow-up of 12 months, no difference in overall survival was observed between the two treatment arms. However, with an additional 6 months of follow-up, median overall survival was 8.4 months with venetoclax plus low-dose cytarabine vs 4.1 months with low-dose cytarabine plus placebo—a 30% improvement in favor of venetoclax. This study confirmed venetoclax plus low-dose cytarabine as an effective front-line option for patients with AML who are unfit for standard therapy.
The open-label, multicenter, randomized phase II BRIGHT AML 1003 study compared the Hedgehog inhibitor glasdegib plus low-dose cytarabine vs low-dose cytarabine alone in 132 patients with newly diagnosed AML or high-risk myelodysplastic syndrome who were not candidate for intensive induction.7 Overall survival was significantly improved with glasdegib plus low-dose cytarabine: median of 8.8 months vs 4.9 months with low-dose cytarabine alone (P = .0004). Grade 5 treatment-related adverse events were reported in 28.6% of the glasdegib arm vs 41.5% of the control arm. This study led to FDA approval of glasdegib in combination with low-dose cytarabine.
The IDH1 inhibitor ivosidenib and the IDH2 inhibitor enasidenib are being used to treat patients with these mutations. “It is also unclear at this time the optimal treatment for upfront therapy for IDH-mutated AML patients in the upfront setting as there are high reported complete response rates with venetoclax plus a hypomethylating agent but also with IDH inhibitors, and these therapies have not been compared in a prospective fashion,” she told listeners.
IDH inhibitors may result in a complication called differentiation syndrome in about 19% of patients treated with these drugs. “Differentiation syndrome [in patients treated with IDH inhibitors] should be recognized quickly and treated with dexamethasone as indicated. Sometimes concurrent management with hydroxyurea and holding the IDH inbibitor may be needed,” Dr. Mims cautioned.
Venetoclax has not been shown to improve outcomes in patients with TP53 mutations. This highlights the need for effective therapy for TP53-mutated AML.— Alice S. Mims, MD
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Cytogenetic Markers
Stratification according to favorable, intermediate, or poor/adverse risk for AML depends on the presence of various cytogenetic and molecular abnormalities. Some of them are targetable with current treatment options, she explained.
Targetable mutations that influence clinical practice include NPM1 (affecting 25%–30% of all patients with AML and a favorable-risk factor if present without FLT3-ITD or FLT-ITD–low); FLT3-ITD/TKD (accounting for 25%–30% of newly diagnosed patients and treated with the 7 + 3 regimen plus midostaurin); double CEBPA (a favorable-risk factor accounting for about 10% of AML); c-KIT (accounting for 6% of patients with AML; the presence of c-KIT changes a favorable-risk factor t(8;21) to an intermediate-risk factor); IDH2 (accounting for 10%–15% of AML; treated with enasidenib at relapse); IDH1 (accounting for 7%–10% of AML; treated with ivosidenib for newly diagnosed or relapsed AML). The presence of TP53 (accounting for 10%–15% of AML) portends an unfavorable prognosis for which there are no effective treatment options.
“These risk categories will evolve as further long-term data about outcomes for specific genomic subgroups and new therapeutics are available, and with these new data, there will be changes that incorporate advances,” Dr. Mims predicted.
Future Directions
Future directions for AML include combination therapies with intensive induction regimens. “The current wave is combination therapies,” Dr. Mims emphasized.
Such therapies include the following agents:
- IDH inhibitors
- second-generation FLT3 inhibitors
- venetoclax
- menin inhibitors
- CD47 antibodies.
Other avenues being explored include triple combinations with a hypomethylating agent and venetoclax backbone and all-oral treatment regimens, as there are now options with oral hypomethylating agents.
Questions From Listeners
During the question-and-answer session following Dr. Mims’ presentation, there was a question about which is preferable for a newly diagnosed older patients with AML who has an IDH mutation: venetoclax plus a hypomethylating agent or an IDH inhibitor?
“I have a conversation with the patient about the risks and benefits of each of these choices,” commented Dr. Mims. “For some patients, an IDH inhibitor may be preferable because of quality-of-life considerations. I have used both options in this type of patient.”
Another audience member asked whether patients with TP53-mutated AML should receive venetoclax. Dr. Mims responded: “I am less inclined to give venetoclax to these patients based on current data. We have gone back to a hypomethylating agent for patients with TP53 mutations. However, none of the standard-of-care options work that well.”
Several questions related to the optimal duration of venetoclax and the ideal number of cycles to give before assessing benefit. “How this drug is tolerated is patient-dependent. After two or three cycles, we can judge whether it is not working,” she said.
Dr. Mims continued: “If patients continue to respond, the optimal number of cycles is still debated. We don’t have good data on stopping treatment for these patients. It may turn out that a small subset can stop venetoclax,” she said. “There is still a lot we need to learn.”
DISCLOSURE: Dr. Mims has served as a consultant or advisor to Agios, PTC Therapeutics, Astellas Pharmaceuticals, Jazz Pharmaceuticals, Syndax Pharmaceuticals, Kura Oncology, and AbbVie.
REFERENCES
1. Mims AS: Updates in the management of newly diagnosed acute myeloid leukemia. 2021 NCCN Congress: Hematologic Malignancies. Presented October 14, 2021.
2. Hills RK, Castaigne S, Appelbaum FR, et al: Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukemia: A meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol 15:986-996, 2014.
3. 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.
4. 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.
5. DiNardo CD, Jonas BA, Pullarkat V, et al: Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 383:617-629, 2020.
6. Wei AH, Montesinos P, Ivanov V, et al: Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: A phase 3 randomized placebo-controlled trial. Blood 135:2137-2145, 2020.
7. Cortes JE, Heidel FH, Hellmann A, et al: Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute leukemia or high-risk myelodysplastic syndrome. Leukemia 33:379-389, 2019.
