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Integrating New AML Drugs
Integrating New AML Drugs Into a Rapidly Changing Treatment Paradigm

Released: March 22, 2019

Expiration: March 20, 2020

Farhad Ravandi
Farhad Ravandi, MD
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During the past 20 years, several leukemogenic processes, including somatic mutations, have been elucidated in patients with acute myeloid leukemia (AML) and are now being translated into therapeutic strategies. FLT3 inhibitors are the most advanced of the new drug classes, with the FLT3 inhibitor midostaurin approved in 2017 as the first new drug in decades for AML. In just the 2 years since, another 7 new drugs have been approved for AML, dramatically changing the treatment landscape. In this commentary, I take a brief look at the data and clinical relevance of these new agents.

FLT3 Inhibitors
FLT3 mutations, including internal tandem duplication mutations and tyrosine kinase domain mutations, occur in approximately 30% of patients with AML. Several new FLT3 inhibitors are now either approved or close to approval. Midostaurin is a multikinase inhibitor approved for frontline therapy of FLT3‑mutated AML based on the randomized phase III RATIFY trial, which demonstrated a significant survival benefit for the addition of midostaurin to standard 7 + 3 chemotherapy. In this study, median OS was 74.7 months with midostaurin vs 25.6 months with placebo (P = .009). More recently, gilteritinib was approved by the FDA for relapsed/refractory FLT3-mutated AML based on early results from the ongoing phase III ADMIRAL trial of gilteritinib vs salvage chemotherapy, although the full data have not yet been reported. Results reported at ASH 2018 from the phase III QuANTUM‑R trial of the FLT3 inhibitor quizartinib vs standard salvage chemotherapy demonstrated that in patients with relapsed/refractory FLT3-ITD–mutated AML, single-agent quizartinib significantly prolonged OS compared with salvage CT (HR: 0.76; P = .0177). These results will likely lead to FDA approval of this agent. It is important to note that quizartinib has efficacy only with FLT3-ITD–mutated AML, whereas gilteritinib is effective in both FLT3-ITD– and FLT3-TKD–mutated AML.

FLT3 inhibitors will continue to become an important component of treatment for patients with FLT3-mutated AML; they will be incorporated in the frontline and salvage regimens, including chemotherapy-based and hypomethylator-based regimens in younger and older patients. At my institution, sorafenib has been added to various clinical trials in the frontline and salvage settings and is being replaced by the newly approved agents in more recent, ongoing trials.

IDH1 and IDH2 Inhibitors: Enasidenib and Ivosidenib
A great deal of interest has been generated regarding IDH1 and IDH2 inhibitors. IDH1 and IDH2 mutations occur in approximately 15% to 20% of patients with AML. The 2 FDA-approved IDH inhibitors, enasidenib (IDH2) and ivosidenib (IDH1), produce response rates of approximately 30% to 40% in relapsed/refractory AML patients with an IDH mutation. Although currently only approved in the relapsed/refractory setting, in studies of previously untreated AML with IDH mutations, the ORRs when combined with standard induction and consolidation chemotherapy are as high as 80%, showing promising potential in the frontline setting. Additional combinations of IDH1 and IDH2 inhibitors with chemotherapy or hypomethylating agents are hoped to provide even better outcomes. These combinations are being evaluated in various clinical trials at our institution.

BCL2 Inhibitor: Venetoclax
Much excitement surrounded the recent FDA approval of venetoclax, a BCL2 inhibitor that, when combined with hypomethylating agents or with low‑dose cytarabine (LDAC) in elderly, unfit patients with AML, produces remarkable and durable responses (CR/CR with incomplete blood counts rates > 70% with up to two thirds of patients maintaining the response at 12 months) that are essentially transforming treatment in this subgroup of patients. The ongoing confirmatory phase III studies VIALE-A (NCT02993523) and VIALE-C (NCT03069352) are evaluating venetoclax in combination with azacitidine or LDAC (primary endpoint: OS). Venetoclax is also being evaluated in combination with cytarabine- and anthracycline-based chemotherapy in younger patients in both relapsed and frontline settings at the MD Anderson Cancer Center and other institutions.

Hedgehog Pathway Inhibitor: Glasdegib
Glasdegib is a hedgehog pathway inhibitor that was approved by the FDA (in combination with LDAC) in 2018 for the frontline treatment of newly diagnosed AML in patients aged 75 years or older or who were unfit for intensive induction chemotherapy. Approval was based on results from the randomized phase II BRIGHT AML 1003 trial of glasdegib plus LDAC vs LDAC alone in older, unfit, newly diagnosed patients with AML or with high-risk myelodysplastic syndromes. At a follow-up of 20 months, median OS was 8.8 months with glasdegib plus LDAC vs 4.9 months with LDAC alone (HR: 0.51; P = .0004).

Of note, in 2 cross-trial analyses presented at ASH 2018, the addition of glasdegib to LDAC or hypomethylating agents did not significantly improve response rates, and the combination of glasdegib and LDAC did not produce longer survival than venetoclax plus LDAC. Further clarification is expected with randomized clinical trials.

CD33 ADC: Gemtuzumab Ozogamicin
Gemtuzumab ozogamicin is a CD33-targeted antibody–drug conjugate that was originally approved for AML in 2000, removed from the market in 2010 due to safety concerns (early mortality, sinusoidal obstruction syndrome), and then reapproved by the FDA in 2017 at a lower dose for newly diagnosed CD33+ AML in adults and relapsed/refractory disease in adults and children.

Of note, the label now contains a “black box” warning for hepatotoxicity. However, in a retrospective analysis of patients (N = 80) who received an allogeneic stem cell transplant in the ALFA-0701 trial (presented at ASH 2018), the new dosing of gemtuzumab ozogamicin was not associated with significantly higher sinusoidal obstruction syndrome in newly diagnosed AML, helping to allay fears of increased risk in this setting.

Gemtuzumab ozogamicin may be used with daunorubicin and cytarabine in adults with newly diagnosed AML and as a monotherapy for selected adult or pediatric patients. Approval was based on the phase III ALFA-0701 study, the phase III AML-19 study, and the phase II Mylo France-1 trial. Of importance, I find gemtuzumab ozogamicin particularly beneficial in patients with core binding–factor AML, defined by the cytogenetic aberrations inv(16) and t(8;21). In addition, gemtuzumab ozogamicin has also been effectively used for the treatment of patients with high-risk acute promyelocytic leukemia based on studies conducted at my institution as well as others.

Conclusions
After decades without improvements in drug options, AML has recently undergone a transformation of treatment approaches. Numerous very effective and useful agents, including venetoclax and the FLT3 and IDH inhibitors, alone or in combination with chemotherapy, have recently been approved by the FDA and are transforming the care of patients with AML, particularly those who are unfit or elderly. In addition, the efficacy of gemtuzumab ozogamicin in AML has rekindled interest in antibody‑based therapy in this setting, with new agents in clinical trials for AML including both antibody–drug conjugates and bispecific antibodies. The future will likely show that combining these drugs with chemotherapy or hypomethylating agents will produce even stronger responses. Overall, the future of AML treatment has never been brighter.

Have you begun using these new agents in your practice? Share your experience in the comment box below.

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