SAN FRANCISCO—Tosedostat in combination with cytarabine or decitabine induced complete remission (CR)/CR with incomplete blood count recovery (CRi) rates of 53% in older patients newly diagnosed with acute myeloid leukemia (AML)/high-risk myelodysplastic syndrome (MDS), results of a randomized open-label phase 2 trial (Abstract 3690) reported at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition.

Tosedostat, an oral aminopeptidase inhibitor, was delivered predominantly as outpatient therapy, noted Raya Mawad, MD, of the Clinical Research Division, Fred Hutchinson Cancer Research Center and University of Washington in Seattle, WA.

The study randomly assigned 34 patients 60 years of age or older with untreated AML and intermediate or high-risk cytogenetics or high-risk MDS 1:1 to oral tosedostat 120 mg/day days 1 to 21 with either 5 days of cytarabine 1 g/m2/day (17 patients) or decitabine 20 mg/m2/day (17 patients) delivered intravenously every 35 days for up to 3 cycles.

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Following a protocol amendment, 8 patients received tosedostat 180 mg/day continuously, and those with favorable-risk AML was eligible. Patients obtaining a CR/CRi after 3 cycles could receive up to 2 additional cycles.

Median age of the patients was 70 years (range 60-83). Twenty-nine patients (85%) had AML; 5 (15%) had MDS RAEB-2. By European Leukemia Net criteria, 19 patients (56%) had cytogenetics with intermediate-risk; 14 (41%), adverse-risk; and 1 (3%), favorable-risk, while 7 (21%) had normal cytogenetics and were FLT3-positive. Fifteen patients (44%) had secondary AML/MDS or an antecedent hematologic disorder.

At a median follow-up of 11.2 months (range 0.5-22.3), 14 patients (41%) had achieved a CR and 4 (12%), a CRi; 5 patients had adverse risk AML and 4 patients had FLT3-ITD-positive AML. Of 18 patients with CR/CRi, 11 received HCT, 6 deferred NCT, and 1 died of sepsis in CRi on day 133. An average of 2 cycles was required for maximal response; 9 patients required 3 cycles; 4 patients required 2 cycles; and 5 patients had 1 cycle.

Median overall survival (OS) was 11.5 months (95% confidence interval [CI] 5.2-16.7), with 27 patients (79%) alive at 4 months. Responders had a median OS of 16.7 months compared with 6.1 months for nonresponders.

Fourteen patients (41%) failed treatment and 2 (6%) were not evaluable.

Grade 3 or 4 hematologic adverse events (AEs) were febrile neutropenia (16 patients, 47%), fever (3 patients, 9%), pneumonia (11 patients, 32%), sepsis (7 patients, 21%), and DIC (2 patients, 6%). No grade 3 or 4 nonhematologic toxicities were observed.

“Although similar efficacy was seen with cytarabine or decitabine, grade 3 to 4 febrile neutropenia and infections were more common with cytarabine,” Dr. Savage noted.

Of the 7 patients who died within 4 months of starting therapy, 4 died of sepsis, 1 died during cycle 2, and 3 patients died on subsequent salvage treatments.

One patient with myeloproliferative disease and splenomegaly died of splenic infarction on day 15; 1 of AML after electively stopping treatment after cycle 1; and 1 died at the age of 83 during cycle 2 of an unknown cause. Eleven patients (32%) were treated completely as outpatients and required no hospitalization.

This approach may warrant further study in a controlled trial, Dr. Savage concluded.


  1. Mawad, Raya, MD, et al. “3690 A Randomized Phase II Study of Tosedostat in Combination with Either Cytarabine or Decitabine in Newly Diagnosed Older Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome.” ASH 2014. Oral Presentation. December 8, 2014.