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2966 Phase II Clinical Study of the Clinical Efficacy and Safety of Tosedostat in Patients with Myelodysplastic Syndromes (MDS) after Failure of Hypomethylating Agent-Based Therapy

Myelodysplastic Syndromes—Clinical Studies
Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Poster II
Sunday, December 10, 2017, 6:00 PM-8:00 PM
Bldg A, Lvl 1, Hall A2 (Georgia World Congress Center)

Sangmin Lee, MD1, Pinkal Desai, MD, MPH2, Bianca Edirisinghe3*, Samantha Pianello4*, Jack W. Singer, MD5, Michael Samuel, MD6*, Ellen K Ritchie, MD6 and Gail J. Roboz, MD7

1Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY
2Weill Cornell Medical College, New York, NY
3Columbia University, New York
4Weill Cornell Medicine, New York
5CTI Biopharma, Seattle, WA
6Weill Cornell Medicine, New York, NY
7Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY


The prognosis for myelodysplastic syndromes (MDS) patients who fail to respond or lose their response to hypomethylating agents is dismal and there is a compelling unmet medical need for novel therapeutic strategies for these patients. Tosedostat is an oral inhibitor of members of the M1 and M17 classes of aminopeptidases that includes the Zn2+-dependent aminopeptidases. Prior studies of tosedostat in acute myeloid leukemia (AML) demonstrated that it is well tolerated, and has activity in refractory and relapsed AML patients. This study aims to evaluate the efficacy of tosedostat in MDS patients refractory to hypomethylating agents.


We designed a phase II study of tosedostat in patients with MDS who have relapsed after or refractory to at least 4 cycles of azacitidine or decitabine. Treatment consisted of tosedostat at 120mg orally once daily every 28 days. After two cycles of tosedostat, azacitidine (75mg/m2 for 5 days subcutaneous or intravenously) could be added to tosedostat at the investigator’s discretion. The primary endpoint was overall survival. Secondary objectives included hematological improvements, overall response, and cytogenetic response according to the 2006 IWG criteria, safety and tolerability of tosedostat, and time to AML transformation. Adverse events (AEs) were assessed and graded according to the CTCAE v4.03 criteria.


A total of 12 patients were enrolled from February 2015 to March 2016. Median age was 73 years old (69-81), with 8 males and 4 females. By IPSS-R, 7 patients were classified as very high risk, 2 patients were high risk, one patients was intermediate risk, and two patients were low risk. Patients received a median of 5 prior cycles of hypomethylating agents (4-33) prior to study entry. Patients received a median of 4 cycles of tosedostat (1-13), and 5 patients received azacitidine in addition to tosedostat. Median azacitidine cycles were 2 (1-3). Of 11 evaluable patients, one patient achieved CR, 8 patients had stable disease, and two patients had disease progression. Median overall survival was 14.5 months (2.5-23.7 months). The patient who achieved CR had very high IPSS-R risk at baseline, previously achieved hematologic response to azacitidine prior to relapse, and also achieved neutrophil response for 4.9 months, erythroid response for 7.7 months, and platelet response for 8.3 months. The only grade 4 adverse event occurred as sepsis in one patient. The grade 3 non-hematologic adverse events were syncope (8%), elevated GGT (8%), shortness of breath (8%), hypokalemia (8%), rash (8%), and febrile neutropenia (8%). Adverse events attributable to tosedostat were increased BNP (grade 1, 42%), decreased ejection fraction (grade 2, 33%), rash (grade 3, 8%), decline in performance status (grade 2, 8%), fatigue (grade 1, 8%), prolonged QTc (grade 1, 8%), hypomagnesemia (grade 1, 8%), and loose stool (grade 1, 16%).


Tosedostat is well tolerated in patients with MDS, as single agent and in combination with azacitidine. The MDS patients on this study had significantly longer median overall survival than typically predicted for patients who have failed or progressed after hypomethylating agents. Tosedostat therefore warrants further clinical investigation in MDS in this difficult to treat population.

Disclosures: Desai: Agios: Other: Ad Board; Argenx: Other: Ad Board. Singer: CTI Biopharma: Employment, Equity Ownership. Ritchie: Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, Speakers Bureau; Novartis: Consultancy, Other: Research funding to my institution, and travel, Speakers Bureau; Pfizer: Consultancy, Other: Research funding to my institution; Astellas Pharma: Other: Research funding to my institution; Bristol-Myers Squibb: Other: Research funding to my institution; NS Pharma: Other: Research funding to my institution. Roboz: Cellectis: Research Funding; AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy.

*signifies non-member of ASH