Modern Approaches for Diagnosing and Treating Acute Myeloid Leukemia

Mitul Gandhi, MD

With the consistent introduction of new research, the recommendations for diagnosing and treating acute myeloid leukemia (AML) are ever-changing. Recently, both the National Comprehensive Cancer Network (NCCN)¹ and the European LeukemiaNet (ELN) published updated guidelines.²

The most important update, according to Mitul Gandhi, MD, is that guidelines are recommending and indicating the importance of conducting a myeloid mutational analysis. There are several mutations that can arise in a patient with AML, but those with therapeutic potential include NMP1 mutations, FLT3 or FLT3-internal tandem duplication (ITD) mutations, and IDH1/2 mutations. This information is relevant to subsequent lines of therapy following chemotherapy, or chemotherapy with BCL-2 inhibition. The guidelines also provide insight around how to sequence therapies.

“The sequencing really depends on the ability to achieve initial complete response or not and how you would consolidate them. The role of targeted therapy or subsequent therapy would be predicated upon those responses. That probably is kind of an important framework, especially in treating these patients in the community,” said Gandhi, a medical oncologist at Virginia Cancer Specialists, in an interview with Targeted Oncology™.

In the interview, Gandhi reviewed the latest guideline recommendations for the workup and treatment of AML.

TARGETED ONCOLOGY: Can you explain the latest recommendation for testing in patients with AML?

Gandhi: For new patients that are suspected to have acute myeloid leukemia, there are numerous initial tests that we would advocate for. The standard laboratory tests are blood counts and chemistry panel. For most patients, they should get a coagulation profile as well, particularly if there's a suspicion for acute promyelocytic leukemia, or APL. Then, in general, we screen for relevant viruses during the initial laboratory workup, things like HIV and hepatitis panel. Patients will get a bone marrow biopsy. For that, we look at histopathology flow cytometry and then conventional cytogenetics, along with AML FISH studies. [This is] critically important, especially in the last year or so.

What’s recommended by the ELN guidelines that were updated in 2022 is sending for some version of a next-generation sequencing [NGS] panel or myeloid NGS panel to help identify relevant mutations that help prognosticate and subtype acute leukemia. That's increasingly important for determining options for therapy, both during induction or for adding on to a cytotoxic backbone along with prognostication purposes, and to help elucidate a role of consolidated therapy. Those would be the sort of initial tests that we would want to do. The main sort of update is to be proactive about getting a myeloid mutational analysis in all patients.

What other information would be helpful for physicians when deciding on treatment for a patient with AML?

Treatment decision making is kind of a heterogeneous process that involves patient-specific factors and then disease-specific factors. This is a disease of elderly patients with a median time of diagnosis in the seventh decade. A lot of it depends on when we talked about the host factors or the patient factors, their age, their fitness, their comorbidities, and then disease-specific factors, namely, being the subtype of AML that they have or don't have and some of the relevant molecular factors. As an example, if we have a young patient that is diagnosed with FLT3-positive acute myeloid leukemia, it would be a candidate for induction chemotherapy with targeted therapies, specifically midostaurin [Rydapt]. That's reflective of using the sort of host factors in young patients, along with disease factors, and presence of an action or mutation on a chemotherapy backbone.

This is also relevant in our older patients who perhaps may not be eligible for induction cytotoxic therapy and identifying potential targets such as IDH1/IDH2 mutations, and even FLT3, because those can be acted upon, if not initially, then later. In that sort of stepwise fashion, considering the fitness and health, along with age of a patient, along with disease-specific factors can help shape how a treatment would be pursued.

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What are the guideline recommendations in terms of getting patients with AML induction or subsequent therapy with disease control?

The goal of all initial therapy would be to lower and hopefully eliminate, at least morphologically, evidence of leukemia, to try to reconstitute normal bone marrow function in an effort to resolve symptomatic cytopenias or disease-related issues in terms of cellular immunodeficiency, coagulopathies, and then the symptomatic cytopenias. That is primarily the goal of what we're trying to do. This, of course, translates to improved survival in terms of how we identify what our initial goal for remission induction is. It's taking into account a lot of the things that we talked about in terms of the fitness, health, and age of the patient, along with an honest conversation with them regarding their personal goals of care for patients that are younger than 65. Perhaps there are several options for curative intent therapy, and that may rely on induction chemotherapy, whether it was targeted agents on top of the cytotoxic backbone, and then consolidation predicated upon the molecular findings, which may involve consolidation with chemotherapy or in many instances, consolidation with an allogeneic transplant in first complete remission. That would be the goal in younger patients that are eligible for curative intent therapy.

In the community, what we see oftentimes is many older patients above the age of 70 who are often candidates for shorter than 10 therapy because of the intensity, their comorbidities, or various socioeconomic factors. In those circumstances, the goal for treatment is to improve quality of life and restore as much of normal bone marrow function as possible. In doing this, we mitigate the need for transfusion support and improve upon cellular immunity-related issues that can otherwise predispose these patients to infections. When we talk about remission or goals towards remission, it is in context of the patient and their underlying biology in front of us.

What are the recommended strategies for supportive care in patients with AML who experience adverse events?

Adverse events and toxicities are embedded into the management of acute myeloid leukemia, whether it’s our younger patients who are eligible for curative intent or older patients who are being treated for their disease with goal of life prolongation. I'll split them into a few separate tiers. One is symptomatic cytopenias. For those, even all newly diagnosed patients, we check for obvious nutrient deficiencies, whether it's B12 folate, iron, or anything else should be adequately corrected. Primarily, it involves transfusion support for symptomatic anemia, or platelet transfusion support for symptomatic, or critical thrombocytopenia typically below 10,000 to 15,000, trying to prevent the development of spontaneous hemorrhages. Those 2 interventions would need to be continued until therapy elicits a response, and hopefully, [there is an] improvement in bone marrow function.

When patients are going to induction therapy, the cytopenias are protracted, often lasting several weeks, so they need the hospitalization and transfusion support with respect to the leukopenia, and often common in neutropenia, that should cycle down with therapy and then hopefully back up with normal bone marrow rest reconstitution. But in that vein, we have patients on prophylactic antimicrobial therapy often placed on typically Acyclovir PCP or prophylaxis with either Bactrim, dapsone or inhaled pentamidine. Then, depending on the neutrophil count, they often need antifungal prophylaxis. In parallel, we have to make sure their other symptoms are attended to, they’re getting physical activity and management with physical therapy to make sure they're as fit as they can be during treatment. And then attending to various gastrointestinal toxicities associated with therapy like, nausea, vomiting, and diarrhea. These toxicities often require prophylaxis and rescue antiemetic therapy and anti-diarrheal therapy. Those are kind of a cursory issues, depending on the subtype of AML.

There are also things related to coagulopathies that require monitoring and preemptive support. For patients who have suspected APL, pay close attention to partial thromboplastin time and their fibrinogen levels requiring prophylactic cryoprecipitate, so we can supplement that and correct any coagulopathy with supplemental fresh or frozen plasma, or vitamin K.

What key advice do you have on individualizing AML treatment?

For those of us in the community who still take care of these patients, I think it kind of harkens back to the central theme of looking at the patient in front of you in terms of their underlying host and patient-specific factors, and having an honest sort of assessment of what they are candidates for or not. Then, think [about] the disease-specific factors that are heavily predicated upon their cytogenetics, FISH, and myeloid NGS studies, because that dovetails into how we would individualize therapy. One, we always look to see if a patient is eligible for a clinical trial, and if we have a clinical trial for a patient, that still often represents the best option. This is for both younger patients and older patients. We have young patients that come in. If we do not have an induction clinical trial available, we look at our nearby academic centers, and we'll ask our colleagues over there if there are any studies that patients would be candidates for.

If there are not any clinical trials, or if they elect not to go or enroll, then it would be dependent on if any of their mutation profile would require targeted therapy. FISH translocation for 15;17 is one, and those patients would be treated like a [patient with] APL. If they're young patients with a FLT3-ITD mutation, then they would be candidate for midostaurin on top of a 7 + 3 backbone. Then, consolidation therapy would be predicated upon, A lot of these molecular factors could range from consolidation with chemotherapy or stem cell transplantation.

The other area where targeted therapy may be a role is in core binding factor leukemia, or CBF, depending on their FISH study. In version 16, for example, in which case there's a role for an antibody-drug conjugate targeting CD33, which can be added onto the chemotherapy backbone and then also added on consolidation, a lot of that same sort of paradigm can apply to our elderly patients, but increasingly, many of them are being treated with azacitidine and venetoclax [Venclexta]. This is for someone initially agnostic of their molecular features, although there's a lot of work with IDH1/IDH2 mutations, or FLT3 mutations.

What is your advice of sequencing the available therapies?

You kind of have to start with a dichotomy of where the patient is and their candidacy for aggressive therapy. I think the sequencing is increasingly playing a role in our larger cohort of patients that are older, many of them are being induced with venetoclax in conjunction with a hypomethylating agents, such as these azacitidine or decitabine. If patients have actionable mutations, those may play a role for relapse. We know that patients who have an IDH1/IDH2 mutation or an NPM1 mutation tend to preferentially benefit from a more prolonged outcome from that regimen of induction, but that those targeted options may remain available at a potentially an inevitable relapse, even though it may be quite a bit down the line.

In terms of younger patients, I think the sequencing is about remission induction. Historically, we used 7 + 3, but there is increasing interest in using venetoclax on top of that backbone, or alternative backbone, such as the fludarabine, cytarabine and granulocyte colony stimulating factor with idarubicin backbone. Then, the sequencing depends on the ability to achieve initial complete response or not and how you would consolidate them.

The role of targeted therapy or subsequent therapy would be predicated upon those responses.

That probably is kind of an important framework, especially in treating these patients in the community.

_REFERENCES:

_{1. Dohner H, Wie 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(12):1345-1347. doi:10.1182/blood.2022016867}

_{2. Pollyea DA, Altman JK, Assi R, et al. Acute myeloid leukemia, Version 3.2023, NCCN clinical practice guidelines in oncology. JNCCN. 2023;21(5). doi:10.6004/jnccn.2023.0025}