The MDS Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

Tosedostat: A potential treatment option for MDS after hypomethylating agent failure

Nov 30, 2020

Hypomethylating agents (HMAs) are standard of care for higher-risk patients with myelodysplastic syndromes (MDS), but fewer than half of patients treated with HMAs will achieve sustained responses. The treatment options for patients with MDS who are refractory to HMA-based therapy are very limited, and prognosis for patients with relapsed/refractory disease is poor.

Here, we summarize the results of a phase II study (NCT02452346) investigating the safety and efficacy of tosedostat, an oral aminopeptidase inhibitor, in patients with MDS after failure of HMA-based therapy, published by Sangmin Lee and colleagues in Leukemia and Lymphoma.1


The study cohort comprised 12 patients with MDS who were either refractory to, intolerant of, or relapsed after ≥ 4 cycles of decitabine- or azacitidine-based HMA treatment. Whilst very low- or low-risk patients, according to the revised International Prognostic Scoring System (IPSS-R), were initially permitted, the study was subsequently restricted to patients with IPSS-R high- or very high-risk MDS, 20–30% bone marrow (BM) blasts, or chronic myelomonocytic leukemia (CMML).

  • Tosedostat regimen: 120 mg orally, once daily for each 28-day cycle.
  • Azacitidine (75 mg/m2 on Days 1–5 of each cycle) was co-administered at the investigator’s discretion if, after two cycles, the patient had not responded to tosedostat.
  • Patients were permitted up to four cycles of tosedostat to achieve a response.
  • Response was assessed in the BM and peripheral blood.

Primary endpoints were:

  • Transfusion independence for patients with IPSS-R very low-, low-, and intermediate-risk disease,
  • Overall survival (OS) for patients with IPSS-R high-, or very high-risk disease.

Secondary endpoints were:

  • Overall response (complete and partial response, BM complete response, hematologic improvement),
  • Cytogenetic improvement,
  • Safety and tolerability,
  • Time to acute myeloid leukemia (AML) transformation.


Selected patient characteristics are shown in Table 1. A median of five cycles of therapy with hypomethylating agents (HMA) was received before study enrolment, and median time since last HMA treatment was 3.5 months (ten patients had received HMA treatment within 6 months before enrolment).

Table 1. Patient characteristics1

CMML, chronic myelomonocytic leukemia; HMA, hypomethylating agent; IPSS-R, revised International Prognostic Staging System.
*Three patients received both azacitidine and decitabine.


N = 12

Sex, male, n (%)

8 (67)

Median age, years (range)

73 (61–81)

IPSS-R risk classification, n (%)
   Very high

6 (50)
2 (17)
1 (8)
1 (8)
2 (17)

Prior HMA therapy*, n (%)

11 (92)
4 (33)

Seven patients had mutations in ≥ 1 of the following genes associated with poor OS in patients with MDS: ASXL1, ETV6, EZH2, RUNX1, and TP53. All patients with measurable molecular abnormalities had ≥ 2 of these mutations.


Patient outcomes are summarized in Table 2.

Table 2. Outcome data1

CR, complete response; HI, hematologic improvement; ORR, overall response rate; OS, overall survival; PD, progressive disease; SD, stable disease.


N = 12

ORR, n (%)

3 (25)
1 (8)
3 (25)

SD, n (%)

8 (67)

PD, n (%)

3 (25)

Median OS, months (range)
   For high- or very high-risk patients

15.6 (2.5–31.5)
15.9 (2.5–30.7)

One-year OS, %


Two-year OS, %


One patient was taken off the study due to progression to AML within 8 days of receiving tosedostat, and five patients who received azacitidine as well as tosedostat were taken off the study due to either progression (n = 3) or lack of response (n = 2). Four patients had dose interruptions (one due to rash and three due to thrombocytopenia).

Median OS was 15.6 months, and for seven patients (58%) OS was longer than 1 year; these patients received tosedostat for a median duration of 4.7 months (range, 21.1–11.4). Five of these patients later developed AML, four of whom received novel AML-directed therapy.

For one patient, a complete response was achieved and maintained for 5.8 months in total. This patient, classified as very high IPSS-R risk, received azacitidine in combination with tosedostat, and had a treatment duration of 11.4 months. Neutrophil, erythroid, and platelet responses were achieved for 4.9 months, 7.7 months, and 8.3 months, respectively.

Safety and tolerability

Overall, tosedostat was well tolerated, either alone or in combination with azacitidine. No patients discontinued treatment due to adverse events. Regarding cardiovascular adverse events, two patients experienced Grade 2 decreases in left ventricular ejection fraction, but no clinically significant congestive heart failure. Grade ≥ 3 non-hematologic toxicities were:

  • Hypokalemia (Grade 3; n = 1)
  • Shortness of breath (Grade 3; n = 1)
  • Febrile neutropenia (Grade 3; n = 1)
  • Rash (Grade 3; n = 1)
  • Syncope (Grade 3; n = 1)
  • Elevated gamma-glutamyl transpeptidase (GGT, Grade 3; n = 1)
  • Sepsis (Grade 4; n = 1)


Despite being limited by a small patient population, this study showed that tosedostat was well tolerated, both alone and in combination with azacitidine, in higher-risk patients with MDS who are refractory to, or relapse after, HMA therapy. Although the best response for most patients was stable disease, median OS (15.6 months) was superior to the < 6-month survival rate expected for this population. The prolonged survival may be influenced by the novel AML therapies received by some patients, but only limited conclusions can be drawn from this small patient population. Further studies to investigate the role of aminopeptidase inhibitors, and potential synergy with HMAs, in patients with relapsed/refractory MDS are warranted.

  1. Lee S, Desai P, Edirisinghe B, et al. Phase II study of the clinical efficacy and safety of tosedostat in patients with myelodysplastic syndromes (MDS) after failure of hypomethylating agent-based therapy. Leuk Lymphoma. 2020. Online ahead of print. DOI: 1080/10428194.2020.1832674