IMPROVING SURVIVAL RATES IN PATIENTS WITH RELAPSED AND REFRACTORY ACUTE MYELOID LEUKEMIA
The Evolving Role and Development of New Targeted Therapies Anna Love, M.B.S., Ph.D.
As a monotherapy,
gilteritinib has significant overall survival improvements over salvage chemotherapy in relapse or refractory AML
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Focusing on the prevalence of FLT3-ITD or -ITK mutations in AML, tyrosine kinase inhibitors (TKIs) are a promising subset of targeted therapies that can be used as monotherapy or in combination. TKIs, like gilteritinib, bind to FLT3 at the ATPbinding site, preventing phosphorylation of FLT3 and another signaling protein STAT5.33 FLT3 receptors play a key role in stem cell proliferation, differentiation, and survival.29 A second-generation TKI, gilteritinib is more specific and more potent than first generation TKIs such as midostaurin. Gilteritinib was also the first FLT3 inhibitor to be approved as a monotherapy, showing improved survival over salvage chemotherapy in relapsed/ refractory AML. After decades of little to no advancement in AML treatments, the promise and approval of targeted therapies offers hope for a disease with typically poor outcomes. As a monotherapy, gilteritinib has significant overall survival improvements over salvage chemotherapy in relapse or refractory AML. In the ADMIRAL phase 3 clinical trial, 1-year overall survival of a gilteritinib monotherapy group was 37.1%, compared to 16.7% for the salvage chemotherapy group. Serious adverse effects included cytopenia (anemia, febrile neutropenia, thrombocytopenia), prolonged cardiac ventricular repolarization (9%), pancreatitis (5%), posterior reversible encephalopathy syndrome (1%), and differentiation syndrome (3%). Hemodynamic monitoring and dexamethasone, a standard treatment for differentiation syndrome in acute promyelocytic leukemia, was effective treatment for differentiation syndrome in this instance.29,34 Clinical trials are still underway to determine gilteritinib’s efficacy as a combination treatment with chemotherapeutic medicines. Lab studies with nude mice show a that in combination with low-dose arsenic trioxide (ATO), gilteritinib appears to induce cell apoptosis and inhibit proliferation.35 Gilteritinib stands out from other TKIs in that it offers multi-faceted benefits compared to similar medicines. Lestaurtinib and midostaurin, multitargeted TKIs approved for combination therapy with standard
chemotherapies, show no durable benefit as monotherapies. Similarly, sorafenib lacks enough clinical trial data to support its use as a monotherapy, and quizartinib, while showing positive results as a single agent, had short-lived effective responses.30 In a phase 1-2 open label trial (NCT02014558), 41% of relapse/refractory patients receiving >80mg/day gilteritinib showed a composite complete remission of AML, meaning the leukemia was no longer active and blood levels had normalized.35 Following decades of little to no advancement in the targeted therapies and testing techniques available for AML treatment, the shift forward began in April 2017 with the United States’ Food and Drug Administration (FDA) approval of midostaurin for FLT3-targeted treatment. The FDA then fast-tracked enasidenib in August of 2017, and the combination chemotherapeutic treatment daunorubicin plus cytarabine was approved only days later. In September of 2017, gemtuzumab ozogamicin, a chemotherapeutic treatment with a guiding monoclonal antibody targeting the CD33 antigen present on most AML cells, was reapproved in the UK and in the United States.7 The United States’ standard of care for AML patients has changed rapidly, while the UK lags behind. In the UK intensive chemotherapy remains the frontline treatment option according to the National Health Service (NHS), unless a patient is unfit for intensive chemotherapy.8 Given that the median age of diagnosis ranges from 67 to 70 years, an optimistic prognosis for median overall survival at five years is 10% for those fit enough to undergo intensive treatment. For older patients unfit for intensive chemotherapy, overall survival is a dismal 4 to 10 months.9 Targeted therapies offer less invasive treatment options with equal or better efficacy and prognosis.
Future Outlooks Since 2017, eight new FDA-approved drugs have been introduced to the AML treatment landscape - FLT3 inhibitors midostaurin and gilteritinib, IDH inhibitors ivosidenib and enasidenib, anti-
