In the past 2 years, a host of new targeted treatments for acute leukemia have become available—most notably the FLT and IDH inhibitors—and yet the best way to treat these patients remains a challenge. Here are five things to know about the therapeutic landscape of this disease and emerging evidence surrounding its risk factors.
1. There is no consensus on how to treat older adults with acute myeloid leukemia (AML).
Experts do not agree on the best approach for treating older patients with AML. Patients aged 65 years and older tend to have more aggressive disease and a worse prognosis compared with their younger peers. The 5-year survival estimates for this older cohort is 5%, whereas the rate for patients younger than 20 years is 67%.
Chemotherapy, which is the first-line therapy for the majority of patients with AML, often fails in older patients because the agents are too toxic or simply not effective. In fact, more than half of older patients with AML receive no care.
A central question for clinicians treating older patients with AML is whether to provide more-intensive or less-intensive therapy. Oncologists can make a case for both. For example, data from the Swedish Acute Leukemia Registry show that intensive treatment is well tolerated and extends survival in most patients aged 60-75 years. However, support for a low-intensity strategy also exists. A 2019 phase 1b/2 clinical trial found that a combination of the chemotherapy agents venetoclax and low-dose cytarabine led 54% of patients aged 82 years and older to achieve complete remission or complete remission with incomplete blood count recovery.
Oncologists can turn to a patient's degree of frailty and tumor biology to provide clues about which therapeutic strategy to pursue. Frail patients, for instance, are less likely to tolerate aggressive chemotherapy. Understanding the tumor biology of AML, which is often more complex in older patients, can also indicate how responsive a patient will be to different approaches. Overall, experts are working toward a more standardized way of assessing these metrics and how each should inform treatment decisions.
2. Novel therapies for AML show promise of improving patient outcomes.
In the past 2 years, a host of new targeted treatments for AML have become available. Most of these drugs inhibit key genetic mutations associated with AML. Midostaurin, which targets FLT3 mutations, was the first such inhibitor to receive approval from the US Food and Drug Administration in April 2017, but more potent agents soon followed—gilteritinib for FLT3 mutations, ivosidenib for IDH1 mutations, and enasidenib for IDH2 mutations.
The new crop of targeted drugs show promise for improving outcomes.
A phase 3 randomized controlled trial evaluating oral gilteritinib versus salvage chemotherapy reported a median overall survival of 9.3 months in patients who received gilteritinib compared with 5.6 months for those receiving chemotherapy. About one third of patients receiving gilteritinib achieved complete remission with partial hematologic recovery compared with 15% of those receiving chemotherapy alone.
An alternative targeted approach is to disrupt key players along metabolic or cell maintenance pathways instead of genetic mutations. A phase 2 randomized controlled trial found that glasdegib, which targets the Hedgehog pathway, almost doubled overall survival when combined with low-dose cytarabine compared with cytarabine alone (8.8 months vs 4.9 months).
Immunotherapy represents another potential treatment option for patients with AML. The antibody-drug conjugate gemtuzumab ozogamicin is designed to deliver the antitumor antibiotic calicheamicin directly to leukemia cells expressing the CD33 transmembrane receptor. The CD33 receptor is only expressed by cells of myeloid origin, not normal stem cells, which allows the drug to pursue cancerous cells with greater specificity.
Gemtuzumab ozogamicin has an interesting history. It was withdrawn from the market in 2010 after concerns over its safety and efficacy surfaced, but it was then reapproved in 2017 after further research showed its value. Recent analyses have found that, when added to conventional induction therapy, gemtuzumab ozogamicin improves relapse rates and overall survival in patients with CD33-positive AML.
Medscape Oncology © 2019 WebMD, LLC
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Cite this: Acute Leukemia: 5 Things to Know - Medscape - Dec 13, 2019.