AT ASH 2016

SAN DIEGO (FRONTLINE MEDICAL NEWS) – Call it “7+3+1”: an experimental induction regimen combining standard chemotherapy with an antibody drug conjugate induced rapid and deep remissions in a majority of patients with newly diagnosed acute myeloid leukemia in a small study.

Among 42 evaluable patients with previously untreated AML, the combination of cytarabine and an anthracycline (7+3, also known as 3+7), and the investigational antibody drug conjugate vadastuximab talirine was associated with a 60% complete remission (CR) rate, and 17% complete remission with incomplete recovery of platelets (CRi), reported Harry P. Erba, MD, PhD, of the University of Alabama at Birmingham, who discussed the findings in a video interview .

“In 1973, 43 years ago, the first paper was published on what we still continue to use as the initial therapy for a very aggressive cancer, acute myeloid leukemia,” he said at a briefing at the American Society of Hematology annual meeting.

“Nothing has been shown yet to be superior to that, despite four decades of clinical research,” he added.

Recent studies have suggested that depth of postinduction remissions, specifically being minimal residual disease (MRD)-negative, is associated with improved survival, he noted.

Vadastuximab talirine (33A, for short) is an antibody-drug conjugate targeted to CD33, which is expressed in approximately 90% of AML cells. The drug is designed to deliver a cytotoxic agent to myeloid leukemia cells.

As reported previously , 33A, in combination with a hypomethylating agent (decitabine or azacitidine) in 49 evaluable patients, was associated with a composite CR/CRi rate of 71%; the rates of CR/CRi were similar regardless of the partner agent used.

The overall response rate in that study was 76%, with responses seen among higher-risk patients, including remissions in 16 of 22 patients with underlying myelodysplasia, and in 15 of 18 patients with adverse cytogenetics.

Rapid complete remissions

In the phase Ib trial reported at ASH 2016 by Dr. Erba, adults aged 18-65 years with untreated primary or secondary AML (except acute promyelocytic leukemia) were enrolled.

The patients received 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m2 and daunorubicin 60 mg/m2) on days 1 and 4 of a 28-day treatment cycle. Patients were assessed for response on days 1 and 28 according to International Working Group Criteria.

Second induction regimens and postremission therapies were permitted at the investigators discretion, and did not include 33A.

The median patient age was 45.5 years. The patients had generally good performance status (Eastern Cooperative Oncology Group 0 or 1). In all, 17% of patients had secondary AML. In all, 12% had favorable cytogenetic risk disease, 50% had intermediate risk, and 36% had adverse risk. Ten percent of patients had NPM1 mutated disease, and 14% had FLT-3 mutations.

As noted, the composite CR/CRi rate was 76%, consisting of 60% CR and 17% CRI.

All five patients with favorable risk disease had a CR. The rate of CR/CRi was 86% among patients with intermediate-risk disease, and 60 for those with adverse-risk disease.

Of the 32 patients who achieved a CR or CRi, 94% did so after 1 cycle of therapy, and 25 were MRD negative, as evaluated by an independent laboratory using 10-color multi-parameter flow cytometry.

Treatment-related adverse hematologic events included febrile neutropenia (primarily grade 3) in 43% of patients, thrombocytopenia (mostly grade 4) in 38%, anemia (all grade 3) in 24%, and neutropenia (mostly grade 4) in 17%. Other treatment related events were similar to those seen with 7 + 3 alone, and included nausea, diarrhea, decreased appetite and fatigue, mostly grade 1 or 2. One patient had a grade 3 irreversible hepatic toxicity.

The death rate was 2%.

“What we felt we showed is that we were able to combine active doses of 33A with 7 + 3. The doses here were less than the doses used as a single agent, but all doses used in our phase 1b study, including lower doses that what we actually used here, showed complete remissions as a single agent.”

33A “added acceptable on-target myelosuppression. We saw platelet counts recovering to over 100,000, and neutrophils over 1,000 by about four-and-a-half to five weeks, which we felt was reasonable, and patients were able to go on to get post-remission therapy.

A randomized phase II trial comparing 33A and 7+3 to 7+3 alone is slated to launch in the first quarter of 2017.

Dr. Erba disclosed serving as a consultant to and receiving research funding from Seattle Genetics, which supported the study.