Classification, Treatment, and Supportive Care Options in AML

Guidelines for the treatment of acute myeloid leukemia (AML) have recently been updated by both the World Health Organization (WHO) and the European LeukemiaNet (ELN). These new guidelines will help clinicians differentiate which treatments would be most appropriate for their patients with AML.

At a recent presentation during the National Comprehensive Cancer Network 2022 Annual Congress: Hematologic Malignancies, Daniel A. Pollyea, MD, MS, professor of medicine-hematology and clinical director of Leukemia Services at the University of Colorado in Aurora, Colorado presented 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 Advanced Practice Provider Clinical Director of the University of Colorado Health Blood Disorders and Cell Therapies Center in Aurora, Colorado; and Jennifer K. Tobin, PharmD, RPh, Clinical Pharmacy Specialist at the University of Colorado and clinical instructor at the University of Colorado Skaggs School of Pharmacy in Aurora, Colorado.

During the presentation, the panelists discussed the new AML classifications, treatment options utilizing both induction and venetoclax (Venclexta) regimens, as well as post-treatment course of action.

AML Classification

The WHO has classified AML in 2 ways; either through genetic abnormalities that do not need 20% blasts or by differentiation.¹ When looking at genetic abnormalities, certain mutations were excluding including BCR::ABL1, CEPBA, and those that were myelodysplastic (MDS) related.

The ELN has classified AML and related neoplasms as those with recurrent genetic abnormalities requiring at least 10% blasts such as AML with recurring translocations, mutated NPM1, and BCR::ABL1.² AML classification was also determined by whether there was a TP53 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 was also observed to have a more risk of adverse events and cytogenetic abnormalities.

The panel then turned to look at patients who have a TP53 mutation vs wild-type in those with poor-risk and intermediate-risk cytogenetics.³ In those who were poor risk, there was a 20.4% complete response (CR) rate in those receiving venetoclax plus azacitidine (Vidaza; n = 54) vs 11.1% in those receiving azacitidine alone (n = 18). For those who were poor risk and wild-type, the CR was 38.0% in the combination arm (n = 50) vs 13.6% in the azacitidine arm (n = 22). Intermediate risk was looked at next and showed those with wild-type had a 45.8% CR in the combination arm (n = 166) vs 19.7% in the azacitidine arm (n = 66).

Venetoclax Combinations vs Induction Treatment

Treatment options in AML were analyzed next, 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 have a core binding factor identified.⁴ When patients were given venetoclax plus azacitidine (n = 143), the CR was 62.2%, the overall response rate (ORR) was 76.9%, and 4.9% of patients had an early death. Intensive chemotherapy was analyzed in 149 patients, and the CR was 64.4%, the ORR was 70.5%, and 5.4% of patients had an early death.

A survival comparison found the median overall survival was 884 days in those receiving intensive chemotherapy vs 483 days in those receiving the combination treatment (P = .0020). In the combination arm, 65.0% had ELN adverse risk vs 40.3% in the intensive chemotherapy arm (P < .0001). Transplant occurred in 23.1% of patients in the combination arm vs 74.8% in the chemotherapy arm (P < .0001).

In addition, this study looked at variables that would predict response to treatment. For patients receiving the combination therapy, age of 65 years or older (OR, 2.793; 95% CI, 1.18-6.59; P = .019), RUNX1 mutations (OR, 5.4; 95% CI, 1.1-26.9; P = .0397), and secondary AML (OR, 2.36; 95% CI, 1.0-5.3; P = .0382) were identified as variables that predict response. For patients receiving intensive chemotherapy, FAB (French, American, British)-M5 AML (OR, 0.088; 95% CI, 0.01-0.5; P = .0078) was identified.

Patient Response After Transplant

The panel focused on a study from the American Society of Hematology Annual Meeting on patients who received a transplant after treatment.⁵ A total of 304 patients were enrolled, and 31 received stem cell transplant (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 those patients, 71% remained in remission for 2 years or more. Sixty-nine percent of patients with a CR/complete response with incomplete count recovery and 59% with CR/complete remission with partial hematologic recovery were in remission for 12 months or more post-transplant.

Additionally, the panelists compared whether intensive chemotherapy vs venetoclax regimens are better to be a bridge to transplant. Intensive chemotherapy is a traditional approach with no need to wait for treatment. Venetoclax-based regimens are used primary in those who were outpatients, improved quality of life, had less toxicity, and allowed for older patients or those with comorbidities to be considered for a transplant.

Supportive Care Management

Lastly, the panel discussed therapy management for older patients. This discussion covered tumor lysis syndrome, which is a big concern for those receiving venetoclax-based regimens.⁶ The panel emphasized the need for dose ramp-ups during cycle 1 at 100 mg of venetoclax on day 1, 200 mg on day 2, 400 mg on day 3, and on days 4 and beyond 600 mg with low-dose cytarabine or 400 mg with a hypomethylating agent.

Myelosuppression is also something to be aware of when administering venetoclax therapies. To help mitigate this, clinicians should check for a response after the first cycle, break from therapy between cycles if morphologic remission occurs, and consider dose reductions. Growth factor support between cycles and antibiotic prophylaxis can also work as mitigation strategies.

IDH inhibitors were also 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 UGT1A1 enzyme, Gilbert syndrome-like elevation of indirect bilirubin in 80% of patients, and no need for dose modifications unless the disease is severe or prolonged.⁷ For the use of ivosidenib, there can be significant QT prolongation, patients need to be monitored, the concomitant QT prolongation medications should be minimizec, and potentially dose reduction could be required.⁸

Gilteritinib has also studied as a supportive care strategy, and grade 3 or higher AEs were observed.⁹ In those receiving gilteritinib (n = 246), there was alanine aminotransferase increase in 13.8% vs 4.6% of those receiving salvage chemotherapy (n = 109). Additionally, aspartate aminotransferase was increased in 14.6% of patients receiving gilteritinib vs 1.8% receiving chemotherapy.

_References:

_{1. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid 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 expert panel on behalf of the ELN. Blood. 2022;140(suppl 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 combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. doi:10.1182/blood-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 FLT3-mutated AML. N Engl J Med. 2019;381(18):1728-1740. doi:10.1056/NEJMoa1902688}