General AML

New data from phase II trial of SY-1425 combined with azacitidine in newly diagnosed, unfit patients with AML

On the 24th October 2019, the company announced the updated clinical data of a phase II trial NCT02807558 evaluating the efficacy of SY-1425 (a first in-class selective retinoic acid receptor alpha (RARα)) combined with azacitidine for the treatment of newly diagnosed, unfit patients with acute myeloid leukemia (AML).1 The data was presented at the 5th European School of Haematology (ESH) International Conference Acute Myeloid Leukemia, Estoril, PT.2  

Patient population1  
  • Patients were enrolled if they were newly diagnosed with AML (excluding promyelocytic leukemia patients) and if they were ineligible for standard intensive chemotherapy
  • Forty newly diagnosed patients with AML were evaluated for safety
  • Thirty-five patients were assessed for efficacy with the following biomarkers:
    • Thirteen were positive for RARα
    • Twenty-two were negative for RARα
    • 4/35 patients were positive for interferon regulatory factor 8 (IRF8)
  • Median age was 76 years

All patients received intravenous or subcutaneous administration of azacitidine (75 mg/m2) for seven days, then oral administration of SY-1425 (6 mg/m2/day), that was divided into two doses for each 28-day cycle.

  • Majority of responses were observed in the first assessment. Response assessments were done on Day 1 of Cycle 1, 2, 4, and then every third cycle
  • 82% (9/11) of patients that were RARα-positive demonstrated prolonged transfusion independence3
  • Duration of response was up to 334 days for RARα-positive patients vs 168 days for RARα-negative patients
    • 3/8 patients achieved a lasting response beyond the data cut-off of seven months
  • Patients who were positive for IRF8 and negative for RARα (n= 4) achieved CR/Cri rate of 0%

Table 1. Responses of biomarker stratified patients

Best IWG Response

RARα/IRF8 Positive n (%)

RARα Positive n (%)

Response Evaluable




9 (53)

8 (62)


8 (47)

8 (62)


7 (41)

7 (54)


3 (18)

3 (23)


3 (18)

3 (23)


1 (6)

1 (8)

CR, complete response; CRc, cytogenetic CR; CRi, CR with incomplete hematologic recovery; CRm, molecular CR (minimal residual disease negative by flow cytometry or molecular techniques); ORR, overall response rate. As defined by revised International Working Group (IWG) criteria

  • The SY-1425 and azacitidine combination was well tolerated with no observed incidence of increased toxicities, in comparison to either SY-1425 or azacitidine alone
  • Myelosuppression rates such as neutropenia, were comparable to treatment with azacitidine alone
  • The most common grade 3 or higher adverse events (AEs) were thrombocytopenia (25%), anemia (23%), and febrile neutropenia (23%)
  • Most non-hematologic AEs were low grade with nausea (38%), decreased appetite (38%), constipation (33%), fatigue (33%), and peripheral edema (30%)
  • Myelosuppression rates, such as neutropenia, were equal to that observed in single-agent azacytidine treatment

The authors concluded that in comparison to treatment with SY-1425 or azacitidine alone, combination treatment demonstrated increased efficacy, an acceptable tolerability safety profile with a high CR rate (54%), and prompt onset of action in newly diagnosed, RARα-positive, unfit patients with AML. Response rates in patients that were negative for RARα were comparable to response rates with single-agent azacitidine. This trial shows promising results in RARα-positive patient population and warrants further evaluation.

  1. SYROS. Syros Announces New Data from Phase 2 Trial of SY-1425 in Combination with Azacitidine Demonstrating High Response Rates, Rapid Onset of Action and Favorable Tolerability Profile in RARA-Positive Newly Diagnosed Unfit AML Patients [Accessed November 07 2019]
  2. De Botton S et al. SY-1425, a Potent and Selective RARα Agonist, in Combination with Azacitidine Demonstrates High Response Rates and a Rapid Onset of Clinical Responses
    in RARA-Positive Newly Diagnosed Unfit AML. Abstract 16081. Poster presented at European School of Haematology; October 24-26, 2019; Estoril, PT
  3. Kahl K.L. MJH Life Sciences. SY-1425 Combination Shows Promise in Acute Myeloid Leukemia Subgroup [Accessed November 07 2019]
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