Thirty of 32 complete remissions were achieved with only one round of chemotherapy. This means 4 weeks in the hospital rather than 6 to 8 weeks, and this is important to patients.— Harry P. Erba, MD, PhD
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The investigational CD33-directed antibody-drug conjugate vadastuximab talirine yielded high overall and complete response rates when combined with standard “7+3” chemotherapy for patients newly diagnosed with acute myeloid leukemia.1 Results from this phase Ib study were presented at the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition by Harry P. Erba, MD, PhD, of the University of Alabama at Birmingham.
“We saw preliminary evidence of added activity, and we are hoping that the deep remissions we saw will translate to a real benefit for the patient,” Dr. Erba said at a press briefing.
“Standard induction therapy for newly diagnosed acute myeloid leukemia (AML) has not changed in 30 years,” he noted. Induction therapy with cytarabine and daunorubicin (7+3 chemotherapy) results in a high number of complete responses, but most patients are either resistant to initial treatment or relapse after initial response. Recently, clearance of minimal residual disease after initial treatment has been associated with improved long-term outcomes. There is a need to identify treatments that will enhance minimal residual disease negativity and therefore improve outcomes.
Vadastuximab talirine (also known as 33A) is a CD33-directed antibody conjugated to two molecules of a pyrrolobenzodiazepine dimer (anti-tumor natural property). CD33 is expressed on the blast cells of 90% of cases of AML; therefore, it represents “a promising target for therapy, regardless of genetic or mutational heterogeneity,” Dr. Erba added. “We hypothesized that 33A combined with 7+3 could induce minimal residual disease–negative remissions and result in reduced relapse rates and improved survival.”
Dr. Erba and colleagues evaluated the safety and antileukemic activity of escalating doses of vadastuximab talirine in combination with 7+3 for patients younger than 65 years of age (median age, 45.5 years) with newly diagnosed AML. Most patients had intermediate (50%) or adverse (36%) cytogenetic risk factors, and 17% had secondary AML.
Vadastuximab talirine was given on days 1 and 4 concomitantly with 7+3 induction therapy (cytarabine at 100 mg/m2/d and daunorubicin at 60 mg/m2/d). The investigators assessed response (per International Working Group criteria) and minimal residual disease (by multiparametric flow-cytometric assay) on day 28.
In the ongoing phase Ib study, 42 patients have been treated. Four received 10+10 mg/kg of vadastuximab talirine, and 38 patients received 20+10 mg/kg. Patients showed no evidence of increased mortality (30- mortality rate 2%), and the rates of nonhematologic adverse events were similar to those expected with standard chemotherapy alone.
The main treatment-related toxicities, essentially all grades 1 or 2, included nausea (17%), diarrhea (7%), fatigue (14%), and decreased appetite (7%). Hematologic toxicities, however, were common. “Virtually all patients developed grade 4 neutropenia and thrombocytopenia, but the development of grade 3/4 cytopenias following 7+3 alone is expected,” he said.
The overall response rate was 76%, with a 60% rate of complete remissions, defined as recovery of neutrophils to ≥ 100,000/µL and recovery of platelets to ≥ 100,000/µL. The remainder of responses were complete remissions with incomplete platelet count recovery.
“The response rate was lower among patients with adverse karyotypes (60%), although the results compare favorably to historical controls,” he said. All five patients with favorable karyotypes achieved complete remissions.
Although the response rates may not be dissimilar to what would be expected with 7+3 alone, he acknowledged, the responses were rapid. “Thirty of 32 complete remissions were achieved with only one round of chemotherapy. This means 4 weeks in the hospital rather than 6 to 8 weeks, and this is important to patients.”
Minimal Residual Disease
There were 32 complete remissions, and 25 of these patients were considered to be minimal residual disease–negative by a sensitive 10-color multiparameter flow-cytometry technique, developed by Dr. Brent Wood’s laboratory at the University of Washington, he added. Dr. Erba called this finding “an impressive degree of minimal residual disease negativity” and suggested it could surpass that achieved with 7+3 alone.
Dr. Erba made this prediction based on comparing this rate with the minimal residual disease negativity rate seen in Southwest Oncology Group (SWOG) 0106, the phase III trial of 7+3 plus or minus gemtuzumab ozogamicin on day 4 of induction therapy.2 He compared the SWOG 0106 cohort with his phase Ib patients who would have been eligible for the SWOG study (ie, those younger than age 60 without secondary AML). Both studies evaluated minimal residual disease using the flow-cytometry assay from Dr. Wood’s laboratory.
“We found that 73% of our patients achieved minimal residual disease-negative complete remissions, compared to 54% in the SWOG study,” he said. “While this kind of comparison must be interpreted with great caution, we actually do think it’s a very important signal, especially given the fact we compared minimal residual disease using the same flow-cytometry assay has been proven over the years. Does this translate into better outcomes? We don’t know yet.”
Further Study Planned
Dr. Erba concluded: “I think we can safely give vadastuximab talirine in combination with 7+3 chemotherapy. The next question to answer is whether it improves long-term disease-free survival. There’s much reason to be hopeful that such an investigation will provide positive results.”
A randomized controlled trial will evaluate 7+3 with and without vadastuximab talirine. Researchers are also continuing to explore the efficacy and safety of a single dose of the drug on day 1 of treatment in the phase IB study. ■
Disclosure: Dr. Erba has served as a consultant for Sunesis, Novartis, ARIAD, Amgen, Seattle Genetics, Incyte, Celgene, Pfizer, Daiichi Sankyo, and Janssen; has received research funding from Amgen, Seattle Genetics, Millennium Pharmaceuticals, Celator, Janssen, Agios, Astellas, and Juno; and has served on the speakers bureau and/or data and safety monitoring board for Novartis, Incyte, Celgene, Janssen, and Glycomimetics.
1. Erba HP, Levy MY, Vasu S, et al: A phase 1b study of vadastuximab talirine in combination with 7+3 induction therapy for patients with newly diagnosed acute myeloid leukemia. 2016 ASH Annual Meeting. Abstract 211. Presented December 3, 2016.
2. Petersdorf SH, Kopecky KJ, Slovak M, et al: A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 121:4854-4860, 2013.
In these initial studies, vadastuximab appears to be at least as good as, and maybe better than, gemtuzumab ozogamicin. It is certainly a route for bringing an anti-CD33 monoclonal antibody back to market in AML.— Mikkael A. Sekeres, MD, MS
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