Guidelines for the treatment of acute myeloid leukemia (AML) have recently been updated by the World Health Organization (WHO) and the European LeukemiaNet (ELN). These new guidelines will help clinicians differentiate the most appropriate treatments for their AML patients.
In a recent presentation at the 2022 National Comprehensive Cancer Network Annual Meeting: Malignant Hematology, Daniel A. Pollyea, MD, MS, professor of medicine-hematology and clinical director of leukemia services at the University of Colorado at Aurora, Colorado introduced these concepts.
He was joined on the panel by Meredith G. Beaton, MSN, RN, AG-ACNP, assistant professor of medicine-hematology at the University of Colorado and clinical director of the Center for Blood Disorders and Therapies Advanced Practice Provider cell phones from the University of Colorado. in Aurora, Colorado; and Jennifer K. Tobin, PharmD, RPh, clinical pharmacy specialist at the University of Colorado and clinical instructor at Skaggs School of Pharmacy at the University of Colorado in Aurora, Colorado.
During the presentation, panelists discussed new AML classifications, treatment options using both induction and venetoclax (Venclexta) regimens, and post-treatment action plan.
The WHO has classified AML in 2 ways; either by genetic abnormalities that do not need 20% blasts, or by differentiation.1 When considering genetic abnormalities, some mutations notably ruled out RBC::ABL1, CEPBAand those that were related to myelodysplasia (MDS).
The ELN classified AML and related neoplasms as those with recurrent genetic abnormalities requiring at least 10% blasts such as AML with recurrent translocations, mutations MNP1and BCR::ABL1.2 The AML classification was also determined according to the existence or not of a TP53 genetic mutation, MDS-related gene mutations and/or MDS-related cytogenetic abnormalities. Additionally, FLT3-ITD was determined to be an intermediate risk factor through prognostic categorization. It has also been observed to have an increased risk of adverse events and cytogenetic abnormalities.
The panel then turned to patients who have a TP53 mutation vs wild type in people with low-risk and intermediate-risk cytogenetics.3 In those who were at low risk, there was a complete response (CR) rate of 20.4% in those receiving venetoclax plus azacitidine (Vidaza; n=54) versus 11.1% in those receiving azacitidine alone (n=18). For those who were low-risk and wild-type, the OR was 38.0% in the combination arm (n=50) versus 13.6% in the azacitidine arm (n=22). The intermediate risk was then examined and showed that wild-type patients had an OR of 45.8% in the combination arm (n=166) versus 19.7% in the azacitidine arm (n=66).
Combinations of Venetoclax vs Induction Therapy
The treatment options in AML were then analyzed, with the main question being: should induction therapy or a venetoclax (Venclexta)-based regimen be used? The University of Colorado conducted a retrospective analysis of 359 patients who did not identify a central linking factor.4 When patients received venetoclax plus azacitidine (n=143), the CR was 62.2%, the overall response rate (ORR) was 76.9%, and 4.9% of patients died prematurely . Intensive chemotherapy was analyzed in 149 patients, and the CR was 64.4%, ORR was 70.5%, and 5.4% of patients died prematurely.
A comparison of survival found that the median overall survival was 884 days in people receiving intensive chemotherapy versus 483 days in those receiving the combination treatment (P = .0020). In the combination arm, 65.0% had an adverse risk of ELN versus 40.3% in the intensive chemotherapy arm (P P
In addition, this study examined variables that would predict response to treatment. For patients receiving combination therapy, age 65 or older (OR, 2.793; 95% CI, 1.18-6.59; P = 0.019), RUNX1 mutations (OR, 5.4; 95% CI, 1.1-26.9; P = 0.0397) and secondary AML (OR, 2.36; 95% CI, 1.0-5.3; P = 0.0382) were identified as variables that predicted the response. For patients receiving intensive chemotherapy, FAB (French, American, British)-M5 AML (OR, 0.088; 95% CI, 0.01-0.5; P = 0.0078) was identified.
Patient response after transplant
The panel focused on a study from the American Society of Hematology Annual Meeting of patients who received transplants after treatment.5 A total of 304 patients were recruited and 31 received stem cell transplantation (SCT). Treatment regimens included venetoclax plus azacitidine (42% vs 61%), venetoclax plus decitabine (Dacogen; 28% vs 35%), and venetoclax plus low dose cytarabine (30% vs 3%) in all patients and SCT patients, respectively.
At 12 months post-transplant, 68% of patients were alive and 55% had post-transplant remission at 12 months or more. Of these patients, 71% remained in remission for 2 years or more. Sixty-nine percent of patients with complete CR/response with incomplete count recovery and 59% of patients with complete CR/remission with partial hematologic recovery were in remission for 12 months or longer post-transplant.
Additionally, panelists compared whether intensive chemotherapy versus venetoclax treatment regimens was better as a bridge to transplantation. Intensive chemotherapy is a traditional approach with no waiting for treatment. Venetoclax-based regimens are used primarily in outpatients, improve quality of life, exhibit less toxicity, and allow older patients or those with comorbidities to be considered for transplant.
Supportive care management
Finally, the panel discussed therapy management for elderly patients. This discussion focused on tumor lysis syndrome, which is a big concern for those receiving venetoclax-based regimens.6 The panel emphasized the need to increase the dose during cycle 1 to 100 mg venetoclax on day 1, 200 mg on day 2, 400 mg on day 3 and day 4 and beyond 600 mg with low dose cytarabine or 400 mg with a hypomethylating agent.
Myelosuppression is also a consideration when administering venetoclax therapies. To help mitigate this, clinicians should verify a response after the first cycle, discontinue therapy between cycles if morphological remission occurs, and consider dose reductions. Growth factor support between cycles and antibiotic prophylaxis may also work as mitigation strategies.
IDH inhibitors have also been discussed as supportive care. The presentation compared the use of enasidenib (IDHIFA) and ivosidenib (Tibsovo). When enasidenib was used, there was off-target inhibition of the enzyme UGT1A1, Gilbert’s syndrome-like indirect bilirubin elevation in 80% of patients, and no dose modification is necessary except if the disease is severe or prolonged.seven For ivosidenib use, there may be significant QT prolongation, patients should be monitored, concomitant QT prolonging medications should be minimized, and dose reduction may be warranted. necessary.8
Gilteritinib has also been studied as a supportive care strategy, and grade 3 or higher AEs have been observed.9 In those receiving gilteritinib (n=246), there was an increase in alanine aminotransferase in 13.8% compared to 4.6% of those receiving salvage chemotherapy (n=109). Additionally, aspartate aminotransferase was increased in 14.6% of patients receiving gilteritinib versus 1.8% receiving chemotherapy.
1. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of hematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1
2. Dohner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international panel of experts on behalf of the ELN. Blood. 2022;140(supplement 12):1345-1377. doi:10.1182/blood.2022016867
3. Pollyea DA, DiNardo CD, Arellano ML, et al. Impact of venetoclax and azacitidine in treatment-naïve patients with acute myeloid leukemia and IDH1/2 mutations. Clin Cancer Res. 2022;28(13):2753-2761. doi:10.1158/1078-0432.CCR-21-3467
4. Cherry EM, Abbott D, Amaya M, et al. Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia. Blood Adv. 2021;5(24):5565-5573. doi:10.1182/bloodadvances.2021005538
5. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax in combination with decitabine or azacitidine in treatment-naïve elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. doi:10.1182/sang-2018-08-868752
6. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971
7. Enasidenib tablets. Prescribing Information. Agios Pharmaceuticals; 2017. Accessed October 14, 2022. https://bit.ly/2WkaQXR
8. Ivosidenib tablets. Prescribing Information. Servier; 2018. Accessed October 14, 2022. https://bit.ly/3EIhoV6
9. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory AML with FLT3 mutation. N Engl J Med. 2019;381(18):1728-1740. doi:10.1056/NEJMoa1902688