6 minute read
The Evolving Role and Development of New Targeted Therapies
Anna Love, M.B.S., Ph.D.
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
Acute myeloid leukemia (AML)
CD33 monoclonal antibody-chemotherapy conjugate gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib, and the BCL-2 inhibitor venetoclax. 38 Targeted treatments are not limited to a singular medicine for a singular mutation, but also a particular combination of treatments for a given leukemic subtype.
For elderly patients who are unfit for aggressive chemotherapy, DNA-hypomethylating agents may be an appropriate and well-tolerated approach. Initial studies with decitabine as a frontline treatment produced unremarkable results, but a new series of developments has shown that decitabine, a hypomethylating agent, in combination with venetoclax, a BCL-2 inhibitor, results in high rates of complete remission in both frontline settings and modest effects in relapse settings. 39 For relapse/refractory patients, the median overall survival was 3 months with a 6- month overall survival rate of 24%. Objective response rate was 24% in patients with diploid/ intermediate-risk cytogenetics, 27% in patients with IDH1 or IDH2 mutations, 50% in patients with RUNX1 mutations, and 15% in patients with adverse cytogenetics. Even though results are modest, combination venetoclax and lowintensity chemotherapy is a relatively safe and well-tolerated alternative therapy option, especially beneficial for patients with IDH1, IDH2 or RUNX1 mutations. 38
For patients with chromosomal translocations that result in oncogenic fusion proteins, like PML-RARA, AML1-ETO, MLL-fusions, and CBFBMYH11, a broader class of drugs targeting DNA damage repair may be the new frontier of AML treatment. These DNA damage repair drugs may also treat single point mutations, such as FLT3 and NPM1. 40 As is the nature of targeted therapies, DNA repair is likely to be useful as a monotherapy for only a subset of AML patients with underlying DNA repair defects like secondary leukemias or complex karyotypes. 41
As of this report, there are currently 29 treatment clinical trials for adult AML covering combination therapy, cell transplant, marrow transplants, and open- and closed-label trials. The phase 3 VIALE-A trial has shown positive results with combination azacitidine and venetoclax, while the SIERRA phase 3 trial showed a highly effective conditioning agent in Iomab-B prior to stem cell transplant compared to traditional chemotherapy conditioning. 42,43 In June 2020, the ASTRAL-1 phase 3 trial ended without meeting its end goal. The trial compared guadecitabine, a DNA hypomethylating agent, to AML patients’ therapy of choice for patients were considered unfit for intensive chemotherapy. ASTRAL-2 and ASTRAL-3 trials are still underway.
Leukemic disease being so incredibly complex to map and having limited viable treatment options has created a chasm between the volume of data collected on the disease and the comprehensive information gleaned from it. While the clinical case is that targeted treatments are on the rise, certain co-occurrences lead to better prognosis, and while the treatment landscape is finally changing, the truth for AML patients is that leukemia is a devastating diagnosis. Decades of treatment stagnation has cost countless patient lives. The onus is on researchers and healthcare providers to identify this gap and move to close it rapidly. For many patients, standard AML therapy has, to date, failed to provide cures. For elderly patients with comorbidities contraindicative of intensive chemotherapies, few low-toxicity treatment options are available, leaving them with salvage therapies or palliative care. The absence of viable options speaks to the urgency for new treatments. 36 While the clinical case is that targeted treatments are on the rise, certain co-occurrences lead to better prognosis, and while the treatment landscape is finally changing, the truth for AML patients is that leukemia is a devastating diagnosis
