Leukemia Awareness Month: Biomarker Testing Proves Vital at Every Stage of AML Care

In partnership with City of Hope and Allegheny Health Network

Although acute myeloid leukemia (AML) is a malignancy primarily treated with a standard chemotherapy regimen, the use of molecular testing has better informed oncology care providers at every point in the treatment process. Molecular subtyping and particular mutations help confirm the diagnosis of AML and inform early treatment decisions. Then, the results of genetic testing can shape how patients are stratified for risk. Finally, discovering mutations can open new avenues for targeted therapies.

“[There are] 3 purposes that the biomarkers serve in terms of performing those tests at the time of diagnosis,” Salman Fazal, MD, director of the cell transplantation program in the division of hematology & cellular therapy at Allegheny Health Network, said in an interview with Targeted Oncology. During the interview, he highlighted diagnosis, prognosis, and therapeutics as the key areas where molecular testing plays a role.

The need to start therapy as soon as possible has long been at odds with the time needed for genetic testing to be completed. There are valuable findings that can justify waiting for results to come back, and various studies have investigated whether physicians can wait as much as a week from diagnosis before starting induction. Reflex testing will often be limited to relevant biomarkers to accelerate results.

Another important consideration in patients with AML is using repeat testing following key points such as disease progression. The National Comprehensive Cancer Network (NCCN) guidelines for AML recommend that molecular testing be repeated at each relapse or progression.¹ The potential to find changes in disease biology such as expression of a targetable mutation makes repeat testing a valuable opportunity to find a new treatment strategy.

Rapid and Comprehensive Testing at Diagnosis

Cytogenetic analysis using fluorescence in situ hybridization is necessary for risk stratification and guiding treatment for AML. Additionally, polymerase chain reaction panels and next-generation sequencing (NGS) are strongly recommended to identify any potential driver mutations. The NCCN recommends expedited results for actionable abnormalities in CBF, FLT3, NPM1, IDH1, or IDH2 genes.¹

“The main question is the speed of testing,” said Tibor Kovacsovics, MD, medical director of the leukemia program at City of Hope Phoenix, in a Targeted Oncology interview. “In too many cases, I have seen that some labs order the chromosomes—they take time—and then they do only the FLT3 testing, and then it’s followed by additional testing that takes a lot of time. How can we circumvent that?”

Salman Fazal, MD

The time to start therapy and its relationship with molecular testing at diagnosis has been heavily investigated in the past few years. The Beat AML trial (NCT03013998) of adults aged 60 and older with AML screened patients based on biomarkers to assign to a sub-study within 7 days; those who received experimental treatment rather than standard-of-care treatment were found to have better 30-day mortality and overall survival (OS).²

“They were able to show that in 95% of the cases, they could obtain genetic results within a week and start treatment. Delaying for up to a week did not worsen the prognosis. Based on other observational trials, even in younger patients, we know that we can wait for up to a week,” explained Kovacsovics. “But we don't want to wait too long, because patients have an impaired immune system or they're at risk of neutropenia and bleeding, and the longer you wait, the higher they are at risk of developing opportunistic infections.”

“The idea that once a diagnosis of AML is made, you have to institute treatment as soon as possible has been dispelled by some of these studies,” said Fazal. “For most of the patients, we’re assured that it is OK to delay treatment until you have all of the information available.³ On the other hand, we try to get all the relevant information as soon as possible. There are always exceptions where the delay can be harmful such as organ dysfunction or proliferative disease.”

Fazal also noted that in 2022 World Health Organization reclassified NPM1-mutated AML as a distinct disease entity making up 30% of cases with its own pathophysiology and prognosis as well as treatment strategies.⁴ He said that in the past 2 years he has had patients who would have previously been diagnosed with myelodysplastic syndrome based on increased blasts be diagnosed with AML because of an NPM1 mutation found at diagnosis.

Tibor Kovacsovics, MD

Prognosis and Risk

The NCCN and European Leukemia Network (ELN) have similar classifications of risk for AML that incorporate new biomarkers as they are studied. The mutations that play a role include NPM1, which is associated with favorable outcomes, and FLT3 ITD, which has poor prognosis. However, advances in FLT3-targeted therapy have placed these patients in a separate intermediate-risk category based on the efficacy of the kinase inhibitor midostaurin (Rydapt).¹ Recently FDA has granted approval to the combination of quizartinib (Vanflyta) and standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, and as continuation monotherapy following consolidation, for the treatment of adult patients with newly-diagnosed, FLT3-ITD-positive AML . Patients with TP53 mutations have very poor prognosis, though Fazal said there are ongoing clinical trials to support this unmet need.

Patients with favorable risk can receive standard 7+3 (cytarabine plus daunorubicin) plus gemtuzumab ozogamicin (Mylotarg) and don’t require stem cell transplant (SCT) or targeted therapy. Poor-risk patients need intensive chemotherapy plus SCT, provided they can tolerate it. The intermediate-risk group can receive either approach, though data suggests that SCT would be a better approach for younger patients, according to Kovacsovics.

“As we learn more about the impact of different mutations and genetic abnormalities, those molecular abnormalities are…incorporated in those classifications,” said Fazal.

Progress of Targeted Therapies

Many mutations have been identified as present in AML cells, but Kovacsovics said the challenge is identifying which are most important and which drive the leukemogenic process. The next step is determining whether driver mutations are targetable, and finally small molecule inhibitors must be tested in clinical trials.

According to Fazal, several targeted therapies have been introduced including midostaurin for FLT3-ITD and ivosidenib (Tibsovo) for IDH1-mutated AML as a single-agent or added to azacitidine (Vidaza) for induction-ineligible patients.^5,6 Enasidenib (Idhifa) is approved in the relapsed/refractory setting for patients with IDH2 mutations, and olutasidenib (Rezlidhia) is approved in this setting for those with IDH1 mutations.^7,8 Gilteritinib (Xospata) showed superiority to chemotherapy in relapsed/refractory FTL3-mutated AML.⁹

The BCL2 inhibitor venetoclax (Venclexta) in combination with a hypomethylating agent has also proven to be extremely effective, though it does not target a particular mutation; it has an impact on several abnormalities in AML. Combining venetoclax with gilteritinib in patients with relapsed/refractory FLT3-mutated AML has resulted in high rates of composite complete response in a phase 1b trial (NCT03625505).¹⁰

Agents that show promise in the recurrent setting are often then investigated as frontline therapy in addition to chemotherapy, as has been done with gilteritinib and ivosenib, Fazal said. He cited menin inhibitors, which demonstrated efficacy in patients with NPM1 mutations/KMT2A rearrangements, as a class that could play a role as upfront therapy eventually.^11,12

Molecular Testing Post-Diagnosis

To Fazal, the recommendations for repeat testing are crucial for guiding the overall treatment strategy. “I think it’s very important for physicians who treat AML that we talk with our patients and our colleagues about the importance of doing testing at the time of diagnosis and at relapse as well,” he said. Disease heterogeneity can mean leukemic clones that were not detected at a significant level at diagnosis may become major clones at relapse.

Fazal said that the disease may express an abnormality such as a FLT3 mutation that can be targeted, changing the treatment approach, or they could no longer have a targetable alteration at the time they are eligible for the targeted agent. According to Kovacsovics, although repeat testing is recommended strongly in all patients who relapse, it is most important in older patients who cannot receive intensive treatment, since they have a pressing unmet need that could be met by targeted therapies.

Additionally, biomarker testing is relevant to patients in remission, according to Fazal. “Biomarkers have been incorporated in assessment of minimal residual disease [MRD] as well. Even at the time patients are in remission, we're doing molecular abnormality testing…to help us detect low-level disease that would have been otherwise gone undetected by conventional assessment.” Fazal said in addition to using biomarkers to stratify risk for these patients, he is hopeful that based on the efficacy of blinatumomab (Blincyto) in MRD-negative patients with acute lymphoblastic leukemia,¹³ a similar treatment could improve OS for patients with MRD-negative AML.

Trends in Targeted Therapies

Optimizing current targeted therapies is an ongoing process. FLT3- and IDH-targeted agents are being incorporated into standard chemotherapy regimens as well as being combined with azacitidine and venetoclax particularly in older patients. In younger patients, trials combining IDH inhibitor with 7+3 chemotherapy are ongoing, as is comparing gilteritinib with midostaurin when combined with 7+3. Kovacsovics highlighted menin inhibitors in NPM1/KMT2A rearranged disease as a treatment that stands to meet a major unmet need.

The CD47-directed monoclonal antibody magrolimab, which blocks the “do not eat me” signal over-expressed on cancer cells, is under investigation in the ENHANCE-2 (NCT04778397) and ENHANCE-3 (NCT05079230) trials. Fazal said that the most promising aspect of this agent is that it was able to achieve responses in the highest-risk population with AML including patients with TP53 mutations.¹⁴

Clinical trials focusing on underexplored biomarkers are valuable since current options are insufficient for many patients. “Even though we have significant improvement in our in the results based on our understanding of the biology and the target to treatment, the prognosis remains poor, and participation in clinical trials can provide very useful information,” said Kovacsovics.

Keeping all targeted therapy options open through comprehensive molecular testing strongly benefit patients whose performance status keeps them from receiving intensive therapy. “Before…in very old patients, AML was a fatal disease and not worth treating,” Kovacsovics said. “Even in an 80- or 90-year-old patient, if we find a mutation, we can treat them gently with a single agent in many cases, and we can improve their quality of life. We can…reduce transfusion requirements. We’re not going to cure them, but we can treat them or improve their outcomes.”

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Acute myeloid leukemia, version 4.2023. Accessed September 5, 2023. http://tinyurl.com/2z7vn9kk}

_{2. Burd A, Levine RL, Ruppert AS, et al. Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial. Nat Med. 2020;26(12):1852-1858. doi:10.1038/s41591-020-1089-8}

_{3. Röllig C, Kramer M, Schliemann C, et al. Does time from diagnosis to treatment affect the prognosis of patients with newly diagnosed acute myeloid leukemia? Blood. 2020;136(7):823-830. doi:10.1182/blood.2019004583}

_{4. 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}

_{5. FDA approves new combination treatment for acute myeloid leukemia. News release. FDA. April 28, 2017. Accessed September 6, 2023. https://tinyurl.com/yc3cjj9r}

_{6. FDA approves ivosidenib as first-line treatment for AML with IDH1 mutation. News release. FDA. May 2, 2019. Accessed September 6, 2023. https://tinyurl.com/ysbjxhy6}

_{7. FDA granted regular approval to enasidenib for the treatment of relapsed or refractory AML. News release. FDA. August 1, 2017. Accessed September 6, 2023. https://tinyurl.com/2s3pzxxk}

_{8. FDA approves olutasidenib for relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation. News release. FDA. December 1, 2022. Accessed September 6, 2023. https://tinyurl.com/42km88tz}

_{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}

_{10. Daver N, Perl AE, Maly J, et al. Venetoclax Plus gilteritinib for FLT3-mutated relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2022;40(35):4048-4059. doi:10.1200/JCO.22.00602}

_{11. Issa GC, Aldoss I, DiPersio J, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023;615(7954):920-924. doi:10.1038/s41586-023-05812-3}

_{12. Erba HP, Fathi AT, Issa GC, et al. Update on a phase 1/2 first-in-human study of the menin-KMT2A (MLL) inhibitor ziftomenib (KO-539) in patients with relapsed or refractory acute myeloid leukemia. Blood. 2020;140(suppl_1):153-156. doi:10.1182/blood-2022-167412}

_{13. Litzow MR, Sun Z, Paietta E, et al. Consolidation therapy with blinatumomab improves overall survival in newly diagnosed adult patients with B-lineage acute lymphoblastic leukemia in measurable residual disease negative remission: Results from the ECOG-ACRIN E1910 randomized phase III National Cooperative Clinical Trials Network trial. Blood. 2022;140(suppl_2):LBA-1. doi:10.1182/blood-2022-171751}

_{14. Daver NG, Vyas P, Kambhampati S, et al. Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in frontline TP53m AML patients: Phase 1b results. J Clin Oncol. 2022;40(suppl_16):7020. doi:10.1200/JCO.2022.40.16_suppl.7020}