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Improving Prospects in AML and ALL
Major Discoveries and the Prospect of Improved Patient Survival in AML and ALL

Released: July 26, 2016

Expiration: July 25, 2017

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Several developments in the past 2 years have significantly improved survival prospects for patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). The increased understanding of leukemic transformation has led to the identification of a number of molecular targets for drug development, and several agents aimed at these targets are showing promise in clinical trials. These advances have raised the expectations for approval of a number of new agents that may substantially change standards for treating patients with acute leukemias.

In AML, Stone and colleagues conducted the phase III RATIFY trial of the tyrosine kinase inhibitor midostaurin combined with standard chemotherapy in the initial treatment of patients with FLT3-mutated AML. Results from this large trial showed a significant improvement in the response rate and long-term survival of patients who received midostaurin with standard chemotherapy vs standard chemotherapy alone, demonstrating the potential benefit of FLT3 inhibitors in this subset of patients. The FDA granted midostaurin breakthrough therapy status based on these results. New, potentially more-potent FLT3 inhibitors such as quizartinib and gilteritinib are being investigated in clinical trials and may provide even better outcomes. Other recently defined targets include mutated IDH1 and IDH2, and numerous ongoing early trials are investigating IDH inhibitors such as AG-221, AG-120, and AG-881, both as single agents and in combination with other agents such as hypomethylating agents and conventional chemotherapy. Early studies have demonstrated the excellent efficacy and tolerability of these drugs, which makes them strong candidates for combination with other agents and allows long-term continuous use without significant toxicity.

In ALL, tyrosine kinase inhibitors (imatinib and dasatinib for induction and dasatinib, nilotinib, bosutinib, and ponatinib for relapsed/refractory ALL) have been incorporated into the treatment of patients with Philadelphia chromosome–positive ALL. Recent trials have clearly demonstrated that early and continuous therapy with these agents, in addition to chemotherapy and allogeneic stem cell transplantation, has significantly improved long-term survival compared with historical reports.

Furthermore, the treatment of ALL is being revolutionized with the introduction of a number of antibody-based strategies. For example, the addition of rituximab to standard cytotoxic chemotherapy has been shown, in randomized trials, to improve the outcome of patients whose leukemia cells harbor the target CD20 antigen. Novel antibody–drug conjugates such as inotuzumab ozogamicin and bispecific antibodies such as blinatumomab have significantly improved survival of patients with relapsed ALL in clinical trials and are being incorporated in frontline strategies. Better characterization of subtypes of Philadelphia chromosome–negative ALL may also provide new molecular pathways for drug development. Furthermore, advances in cellular therapy and harnessing the immune system have shown significant promise in early trials of chimeric antigen receptor T-cell (CAR T) therapies. Further experience with and insights into the management of toxicities of these agents, particularly cytokine release syndrome, as well as increasing their feasibility and availability, may lead to improvements in outcomes of patients with ALL and other hematologic neoplasms.

Although antibody-based therapies in AML have lagged behind those in ALL (eg, the withdrawal of gemtuzumab ozogamicin based on phase III results of a SWOG trial), other studies have clearly demonstrated their potential. Several large randomized trials have shown that gemtuzumab is an effective agent in some subsets of patients with AML. Furthermore, the role of gemtuzumab in acute promyelocytic leukemia (APL) is well established, and it can be of significant benefit in patients with high-risk APL. New antibody–drug conjugates such as the anti-CD33 agent vadastuximab talirine are showing promise in early clinical trials; results of these and future studies involving bispecific anti-CD33 and anti-CD123 antibodies are highly anticipated. Similarly, CAR T strategies directed against AML antigens are under early development.

Finally, numerous novel cytotoxic agents have been evaluated in AML and have shown promise in specific settings. CPX-351 is a 5:1 molar liposomal-encapsulated combination of cytarabine and daunorubicin that has proven superiority to the traditional cytarabine plus daunorubicin regimen in older patients with secondary AML. Vosaroxin, an anticancer quinolone derivative that has topo-isomerase II inhibitory activity in combination with cytarabine, has been demonstrated to be superior to cytarabine alone in older patients with relapsed AML. Some of the above agents are likely to become available in the near future and will provide increased treatment options and, potentially, significant improvements in the outcomes of patients with acute leukemias.

Which of these agents shows the most promise for your clinical practice? Share your thoughts below!

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This ClinicalThought focused on new approaches to treating AML and ALL. Which of these do you most look forward to being available for use in your clinic in the future?
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