For many years, treatment options for acute myeloid leukemia (AML) were limited mainly to the 7 + 3 regimen. However, more recently, a mini-explosion of AML therapies aimed at newly identified genetic targets makes discussions about treatment of this disease much more complicated. In fact, these new treatments raise important questions that need to be answered, explained Daniel A. Pollyea, MD, MS, of the University of Colorado Cancer Center. Dr. Pollyea moderated and participated in a session on evolving concepts and management strategies for AML at the 2022 National Comprehensive Cancer Network (NCCN) Annual Congress: Hematologic Malignancies.1
Daniel A. Pollyea, MD, MS
Defining Disease
One area of evolving concepts relates to diagnostic and prognostic categories. There are two main ways to define disease, Dr. Pollyea explained: one is by the presence of cytogenetic abnormalities or gene mutations regardless of the percentage of blasts. “In the past, you needed 20% blasts to make the diagnosis of AML, but this has changed,” he noted. The second way to make the diagnosis of AML is based on the degree of differentiation for patients who do not have cytogenetic or molecular abnormalities.
Both the World Health Organization (WHO) and the International Consensus Classification (ICC) recently updated their guidelines for the diagnosis of AML, and there are differences between the two systems.2,3
“The ICC classification states that patients with more than 10% blasts are considered to have AML if they have particular cytogenetic abnormalities or gene mutations,” he explained.
“The difference between AML and MDS with increased blasts is minimal. This is really the same disease, and we are trying to recognize this with our diagnostic systems,” he added. “The two sets of diagnostic criteria create the potential for confusion, as patients can fall into gray areas between these two systems.”
Dr. Pollyea said the new understanding of the disease will impact enrollment in clinical trials to evaluate drugs approved for MDS or AML, “specifically for patients with MDS, who have been difficult to enroll. In the future, these two systems might align once the nuances and differences between them are understood,” Dr. Pollyea continued.
Prognostic Changes
The identification of genetic mutations and abnormalities associated with AML as well as therapies directed to those abnormalities have led to shifts in prognostic categorization by the European Leukemia Network (ELN). The genetic categories of favorable risk remain similar, but the presence of FLT3-ITD mutation now puts the patient in the intermediate-risk category. Some patients with the FLT3-ITD mutation were formerly considered to be at adverse risk, with more proliferative disease and worse outcomes.
“But now that we can target FLT3, having this mutation moves patients into the intermediate-risk category. We use midostaurin for upfront therapy or gilteritinib for relapsed or refractory FLT3-positive patients. Other FLT3 inhibitors in development show promise,” Dr. Pollyea said. On the other hand, he added, “an expanded list of adverse-risk genetic abnormalities can move a patient into the unfavorable group.”
That said, the ELN system has an inherent bias, he commented, based on treatment with intensive chemotherapy in mostly younger patients. With new treatments that can be used in older patients, the relevant prognostic factors can change. For example, the combination of venetoclax plus azacitidine is now widely used to treat newly diagnosed AML, but it was unknown whether this regimen could overcome the adverse risk associated with TP53 mutation. An article by Dr. Pollyea and colleagues showed that patients with the TP53 mutation and other poor-risk cytogenetics achieved more than two times higher rates of complete remission or complete remission with incomplete hematologic recovery on venetoclax plus azacitidine compared with azacitidine alone: 40.8% vs 16.7%, respectively, for those with the TP53 mutation, and 70% vs 22.7%, respectively, for those with poor-risk cytogenetics.4
“With new therapies, we need new prognostic factors. We don’t have to consider poor-risk cytogenetics as poor risk if we give venetoclax. This points out the need to study every new therapy. There are no adverse risk factors that are universal,” Dr. Pollyea stated. “Risk factors are context-dependent.”
Therapeutic Choices
In an audience poll at the NCCN Congress, responses were evenly split between venetoclax/azacitidine and intensive chemotherapy with daunorubicin/3 + 7 as treatment for a patient with newly diagnosed AML. “This is a question we deal with almost on a daily basis,” Dr. Pollyea told listeners.
“In the past, when intensive chemotherapy was our only option, it was easier to decide between intensive chemotherapy or no therapy. Now, we have several good options, and selection criteria for intensive chemotherapy vs newer therapies are evolving. In the current era, there are patients who are good candidates for either therapy—venetoclax plus azacitidine or intensive chemotherapy,” he explained. “We have to use [patient-specific] information to make decisions, and this is reflected in NCCN Guidelines. It hasn’t been pinned down yet,” he noted.
A retrospective study at the University of Colorado Cancer Center included 359 patients without mutations in core binding factor–encoding genes treated with either venetoclax/azacitidine or intensive chemotherapy; the investigators found no difference between the two regimens in response rates or early death rates.5 When the investigators looked at survival, baseline factors were divergent between the two treatment groups for age, risk group, and those who went on to transplantation. The investigators developed a propensity score matching technique for these factors and found that venetoclax plus azacitidine improved survival and produced an improved trend for progression-free survival.
Further study identified the following factors as associated with better outcomes with venetoclax-based treatment: age > 65, presence of RUNX1 mutation, and secondary AML (ie, adverse risk on intensive chemotherapy). On the other hand, FAB M5 and a FLT3 mutation favored intensive chemotherapy with 7 + 3, the historical standard of care, for intermediate-risk AML.
“This is still a work in progress. You need to have molecular results before you select a regimen. We know that RUNX1 is associated with poor risk on intensive chemotherapy, but this may not be the case for venetoclax,” Dr. Pollyea commented.
Patients in Remission?
During the question-and-answer session following the formal presentation, a major concern among attendees was what to do with patients in long-term remission on venetoclax.
“Many of them don’t want to continue the azacitidine infusions. One retrospective study showed that after 1 year of remission, there was no difference between remission and survival rates if patients continued treatment or stopped. We don’t know the answer to that. I customize treatment. If patients want to continue, they do. If we are able to reduce azacitidine to 3 or 5 days of infusion, we do. I don’t know what the right answer is, because there is a population that doesn’t relapse. But if you stop treatment, you can rechallenge, and people do well,” Dr. Pollyea told the audience.
An audience question related to how to convince patients in remission to go on to transplantation, the only curative option for AML. “Patients in remission feel great and don’t want to proceed to transplant. We default to measurable residual disease [MRD]—if there is any evidence of MRD, relapse will follow, so we encourage the patient to go on to transplant,” he said.
Intensive Chemotherapy and Transplantation
Another evolving concept is that some patients who are not candidates for intensive chemotherapy and are treated with venetoclax plus azacitidine can benefit from allogeneic stem cell transplantation (SCT). A recent study showed that 10% of newly diagnosed patients older than 60 went on to transplantation with positive outcomes.6 At Dr. Pollyea’s center, about 50 of 120 patients had a transplant consultation, and about 25 went on to transplantation.7
“Transplant after venetoclax [or venetoclax-based therapy] can be a viable route to long-term remission or potentially a cure. This is an evolving area. The question is whether the expanded number of patients in remission should trade that in for hematopoietic SCT for potentially long-term survival,” Dr. Pollyea said.
Supportive Care for AML Therapies in Older Patients
Meredith Beaton, RN, MSN, AG-ACNP
Turning to toxicities of newer treatments, Meredith Beaton, RN, MSN, AG-ACNP, of the University of Colorado Cancer Center, discussed venetoclax-based regimens, isocitrate dehydrogenase (IDH) inhibitors, and the FLT3 inhibitor gilteritinib.
Venetoclax-based regimens allow for outpatient treatment, improved quality of life, and fewer transfusions. They may enable older patients and those with comorbidities to be considered for transplant.
Venetoclax requires a dose ramp-up period, during which there is a risk of tumor-lysis syndrome. “Although not common, tumor-lysis syndrome can be significant when it occurs. This requires monitoring of patients with frequent laboratory tests,” Ms. Beaton said.
“Patients should be supported while they are receiving venetoclax,” she stated. They should be hydrated and given [agents to prevent metabolic complications of tumor-lysis syndrome, eg, allopurinol]. Myelosuppression can occur but can be mitigated. Frequent monitoring is advised. Patients in morphologic remission can have breaks in therapy. Dose reductions, growth factor administration, and antibiotic prophylaxis are measures that can help prevent adverse events.
IDH inhibitors—enasidenib and ivosidenib—are generally associated with good tolerability. About 10% of patients on ivosidenib may develop significant QT prolongation. The main concern with IDH inhibitors is differentiation syndrome, which occurs in about 10% of patients treated with either drug, Ms. Beaton said. “Watch out for this. Signs might include fever, dyspnea, pulmonary infiltrates, and hypoxic infiltrates,” she noted.
Gilteritinib is generally well tolerated. Elevation in liver enzymes are possible with this agent, and the package insert should be used to guide treatment if this occurs.
DISCLOSURE: Dr. Pollyea has served as a scientific advisor for AbbVie, Aprea Therapeutics, Acellx, Astellas Pharma, AstraZeneca, BeiGene, BerGenBio, Bristol Myers Squibb, Celgene, Foghorn Therapeutics, Genentech, Gilead Sciences, GlycoMimetics, HiberCell, ImmunoGen, Jazz Pharmaceuticals, Kiadis Pharma, Kura Oncology, Magenta Therapeutics, Medivir AB, Novartis, Qihan Biotech, Ryvu Therapeutics, Syndax Pharmaceuticals, Syros Pharmaceuticals, Takeda Pharmaceuticals, and Zentalis Pharmaceuticals; and has received research support from AbbVie, Bristol Myers Squibb, Karyopharm Therapeutics, and Teva. Ms. Beaton reported no conflicts of interest.
REFERENCES
1. Pollyea D: Evolving concepts and management strategies for acute myeloid leukemia. 2022 NCCN Congress: Hematologic Malignancies. Presented October 14, 2022.
2. Hwang SM: Classification of acute myeloid leukemia. Blood Res 55(suppl):S1-S4, 2020.
3. 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 140:1345-1377, 2022.
4. Pollyea DA, Pratz KW, Wei AH, et al: Outcomes in patients with poor-risk cytogenetics with or without TP53 mutations treated with venetoclax and azacitidine. Clin Cancer Res. September 14, 2022 (early release online).
5. 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 5:3492-3496, 2021.
6. Pratz KM, DiNardo C, Arellano M, et al: Outcomes after stem cell transplant in older patients with acute myeloid leukemia treated with venetoclax-based therapies. Blood 54(suppl 1):264, 2019.
7. Pollyea DA, Winter A, McMahon C, et al: Venetoclax and azacitidine followed by allogeneic transplant results in excellent outcomes and may improve outcomes versus maintenance therapy among newly diagnosed AML patients older than 60. Bone Marrow Transplant 57:160-166, 2022.
