From the Journals

Vadastuximab talirine gives big boost to AML remission


Key clinical point: For older patients with CD-33 positive AML, vadastuximab talirine plus a hypomethylating agent improves remission rates.

Major finding: The composite remission rate in patients treated with vadastuximab talirine and HMA therapy was 70%, compared with 17.8%-27.8% for patients treated with HMA therapy alone historically.

Study details: A prospective, phase 1 trial involving 53 elderly patients with CD33-positive AML at 14 treatment centers.

Disclosures: Seattle Genetics provided study funding and author compensation.

Source: Fathi AT et al. Blood. 2018 Jul 25. doi: 10.1182/blood-2018-03-841171.



For elderly patients with CD33-positive acute myeloid leukemia (AML), vadastuximab talirine in combination with a hypomethylating agent (HMA) improves remission rates, compared with HMA therapy alone, according to a phase 1 trial.

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More than half of the patients treated with combination therapy achieved deep remission, defined as a negative-flow cytometry test for minimal residual disease. Despite these promising results, hematologic toxicity concerns may limit future trials.

“Outcomes for patients with acute myeloid leukemia (AML) remain poor, particularly in older patients,” wrote Amir T. Fathi, MD, of the division of hematology and oncology at Massachusetts General Hospital Cancer Center, Boston, and his coauthors.

Many elderly patients currently receive hypomethylating agents HMAs as a form of low-intensity therapy, but associated remission rates are low. “The development of novel, well-tolerated therapies to enhance the efficacy of HMAs could meaningfully improve the standard of care for older patients with AML,” the investigators wrote in Blood. Vadastuximab talirine is a novel antibody therapy that targets CD33; preclinical data suggested that it could be an effective combination with HMA therapy.

The phase 1 trial involved 53 patients with newly diagnosed, CD33-positive AML and a median age of 75 years. Patients were naive to HMA therapy but could have previously received other low-intensity treatments. HMA therapy was administered first; either azacitidine (75 mg/m2 subcutaneous IV for 7 days) or decitabine (20 mg/m2 IV for 5 days), according to institutional standards. On the last day of HMA therapy, vadastuximab talirine (10 mcg/kg IV) was given. This protocol was repeated in 28-day cycles for up to four cycles. Patients who tolerated the combination and showed a clinical response were eligible to continue therapy.

The composite remission rate (CRc: complete remission and complete remission with incomplete blood count recovery) with combination therapy was 70%. Historically, HMA monotherapies have much lower composite remission rates (decitabine, 17.8%; azacytidine, 27.8%). Of all patients achieving remission, 51% tested negative by flow cytometry for minimal residual disease. Median overall survival was 11.3 months and median relapse-free survival was 7.7 months.

“Nevertheless, the increased response rate with the addition of vadastuximab talirine to HMAs was also associated with increased toxicity when compared to single-agent HMA therapy – indicative of the greater degree of myelosuppression,” the researchers wrote. The most common grade 3 or higher adverse events were thrombocytopenia (57%), febrile neutropenia (49%), anemia (45%), neutropenia (42%), and fatigue (15%).

The investigators stated that “the overall safety profile was similar for patients treated with vadastuximab talirine in combination with azacitidine versus decitabine (with the exception of incidence of febrile neutropenia).”

Following the encouraging results of this phase 1 trial, the CASCADE phase 3 trial was launched to again compare this combination with HMA monotherapy; however, the trial was halted early because of deaths in the combination arm. The investigators cited the need for stricter protocols to ensure safety during future trials.

“With such guidance and precaution, promising combinations for AML, a disease affecting predominantly older and more frail patients, may be more effectively studied so as to enhance our current suboptimal therapeutic options,” they wrote.

Seattle Genetics provided study funding and author compensation.

SOURCE: Fathi AT et al. Blood. 2018 Jul 25. doi: 10.1182/blood-2018-03-841171.

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