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Specialty Pharmacy Continuum • September/October 2020
CLINICAL
AML Rx Evolves With Growing List of Options In acute myeloid leukemia (AML), newer options, such as a FLT3 inhibitor for relapsing-remitting disease and several therapies for patients who are ineligible for intensive chemotherapy, are pushing out old standards, according to data recently presented at the 2020 virtual annual meetings of the American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA). After decades of little progress, the options in AML are evolving quickly. ADMIRAL Trial: Long-Term Survivors New data from the phase 3 ADMIRAL trial presented at ASCO show that in a subset of patients who achieved an overall survival (OS) of 18 months or longer after treatment with the FLT3 inhibitor gilteritinib (Xospata, Astellas), the median duration of complete response (CR) has not been reached (abstract 7514).
Extended gilteritinib is feasible because it has been well tolerated despite substantial initial rates of cytopenias, Dr. Perl said, noting that the most common grade 3 or higher adverse events (AEs) occurring during the first 12 months of gilteritinib therapy were febrile neutropenia (45%), anemia (40%) and thrombocytopenia (23%). After 12 months, the incidences of
improve OS in older AML patients who are ineligible for more intensive chemotherapy regimens. One of the trials, called VIALE-A, was presented as a latebreaker at EHA (abstract LB2601). The other, VIALE-C, was presented at ASCO (abstract 7511). In VIALE-A, investigators enrolled 433 treatment-naive AML patients who were not eligible for intensive chemotherapy based on an age greater than 75 years or the presence of comorbidities, such as heart failure, lung dysfunction or poor performance status. The patients were randomly assigned, in a 2:1 ratio, to receive azacitidine combined with either venetoclax or placebo. To improve tolerability, they used a ramp-up schedule of venetoclax in the first cycle. Median OS, a co-primary end point with CR, was 14.7 months in the
These new data from
ADMIRAL confirm a
persistent mortality benefit at 24 months (20% vs. 14%). In VIALE-A, the rate of CR or CR plus partial hematologic recovery was
66.4% with venetoclax versus 28.3% without it.
In the trial, 371 patients with FLT mutation–positive AML were randomly assigned to receive gilteritinib or standard therapy. When the trial results were published last year (N Engl J Med 2019;381[18]:1728-1740), gilteritinib had demonstrated an OS advantage (9.3 vs. 5.6 months; P<0.001), but the new data show very long periods of disease control, particularly in patients who continued to take gilteritinib. The focus of this analysis was on the 63 patients who had survived at least 18 months, reported Alexander E. Perl, MD, an associate professor of medicine at the University of Pennsylvania, in Philadelphia. Of the 35 patients who underwent hematopoietic cell transplant (HCT), 25 (71%) remained on gilteritinib after transplant. Of the 28 patients who did not undergo HCT, 15 (54%) have received gilteritinib for at least 18 months, and some remain on this therapy.
these AEs decreased to 8%, 10% and 0%, respectively, he added. When the ADMIRAL trial was published, Dr. Perl said the OS benefit coupled with the drug’s greater tolerability established gilteritinib as a standard for treatment of FLT3-positive relapsingremitting AML. These new data from ADMIRAL confirm a persistent mortality benefit at 24 months (20% vs. 14%). Dr. Perl associated the improved longterm survival with the ongoing remissions, improvement in the proportion of patients receiving HCT and post-HCT administration of gilteritinib.
Phase 3 Venetoclax Data Broaden Role in Older Patients With AML Two phase 3 studies have expanded the evidence that venetoclax (Venclexta, AbbVie/Genentech) can be combined with other well-tolerated agents to
venetoclax arm versus 9.6 months in the placebo arm. Venetoclax reduced the risk for death by 34% (hazard ratio [HR], 0.66; P<0.001) reported Courtney DiNardo, MD, an associate professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, in Houston. The rate of CR or CR plus partial hematologic recovery (CRh) was 66.4% with venetoclax versus 28.3% without it (P<0.001). Venetoclax also was favored for the combined end point of CR plus CR with incomplete blood count recovery (CRi) in the FLT3-positive patients (72% vs. 36%; P=0.021) as well as in the IDH1/2-positive patients (75% vs. 11%; P<0.001). Several grade 3 or higher cytopenias, including neutropenia (42% vs. 29%) and febrile neutropenia (42% vs. 19%) were more common in the group receiving venetoclax. Gastrointestinal events
also were more common in patients receiving venetoclax, but most were grade 2 or lower, and no early deaths were associated with the combination. Tumor lysis syndrome (TLS), which has been associated with venetoclax in the past and is the reason that a rampup strategy is used when this drug is started, was not a significant issue in this study. Although there were three cases of minor TLS, no patient required a modified course of venetoclax. An inhibitor of the B-cell lymphoma-2 (or BCL-2) protein, venetoclax is approved in combination with azacitidine or decitabine, another hypomethylating agent, for the types of patients enrolled in the VIALE-A trial. It also is approved in combination with low doses of cytarabine, which was the focus of VIALE-C. In VIALE-C, 211 patients were randomly assigned in a 2:1 ratio to receive oral venetoclax plus a low dose of subcutaneous cytarabine or low-dose cytarabine alone. As in VIALE-A, venetoclax was initiated in a ramp-up strategy in the first cycle. In both groups, 20 mg/m2 of cytarabine was administered on the first 10 days of each 28-day cycle. For the primary end point of OS, venetoclax plus cytarabine was superior to cytarabine alone (8.4 vs. 4.1 months; HR, 0.70; P=0.04), according to investigator Andrew Wei, MBBS, PhD, an adjunct associate professor at the Australian Centre for Blood Diseases at Monash University, in Melbourne. Several secondary end points also favored venetoclax in combination with low-dose cytarabine, including CR/CRh (48% vs. 15%) and CR/CRi (48% vs. 13%). The median event-free survival was nearly twice as long in the group receiving both venetoclax and cytarabine (4.9 vs. 2.1 months). Grade 3 or higher neutropenia was twice as common with the combination (49% vs. 18%), but Dr. Wei called the safety profile of the combination “tolerable and manageable.” He concluded that these data support this combination as an option for newly diagnosed AML patients who are unfit for intensive chemotherapy.
5-Year Data With CPX-351 Support Survival Benefit Five-year data with CPX-351 (Vyxeos, Jazz), a liposomal encapsulation of cytarabine and daunorubicin, confirm a long-time OS benefit in newly diagnosed patients with high-risk or secondary AML. An OS benefit in this phase 3 trial of CPX-351 versus 7+3 chemotherapy was reported earlier (J Clin Oncol 2018;36:2684-2692), but these updated
