General AML|TP53|DNMT3A|TET2

Azacitidine in MDS and AML patients with early post-transplant relapse – oral abstract in AML at SOHO 2017

The fifth Annual Meeting of the Society of Hematologic Oncology (SOHO) took place at the Westin Galleria in Houston, Texas, between 13th–16th September 2017 and the AML Global Portal is delighted to give an overview on the key abstracts in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS).

On 13th September 2017, there was a session dedicated to MDS and it was co-chaired by Pierre Fenaux from the Saint-Louis Hospital, University Paris 7 and Guillermo Garcia-Manero from The University Texas MD Anderson Cancer Center, Houston, Texas.

During this session, abstract MDS-204 titled “Outcomes and Mutational Analysis of a Prospective Phase II Trial of Azacitidine in Patients with MDS and AML With Early Post-Transplant Relapse” was presented by Janghee Woo from the Seattle Cancer Care Alliance, Seattle.

In patients with MDS and AML, post-transplant relapse is a major cause of treatment failure. Janghee Woo, reported results from a prospective phase II trial which aimed to assess the potential benefit of post-transplant use of hypomethylating agent, azacitidine, on the prevention and treatment of relapse in patients with MDS and AML.

In this phase II study, 39 AML and MDS patients who relapsed within 100 days of undergoing allogenic Hematopoietic Cell Transplant (HCT) from related and un-related donors were included. Patients were administered 75/mg/m2/day for 7 days, every 28 days. The primary endpoint of the study was 6 months Overall Survival (OS).

  • Overall Response Rate (ORR); 30.7% (12/39)
    • Complete Remission (CR); 3/39
    • Partial Remission (PR); 9/39
  • 6-months OS; 64% 

The phase II trial also aimed to identify mutational patterns associated with post-HCT relapse, response to azacitidine and post-relapse survival. The mutational profile of bone marrow samples obtained at pre-HCT diagnosis, Post-HCT relapse and during azacitidine treatment were analyzed.

  • At the time of relapse, commonly mutated genes include, TP53 (47%), TET2 (33%), and DNMT3A (14%)
  • TP53 mutations associated significantly with poor responsiveness to azacitidine (Odds Ratio [OR] = 3.08, P = 0.04) and poor survival (HR = 3.04, P = 0.02)

In summary, the results of the study demonstrate the “efficacy of azacitidine in controlling disease progression in patients with MDS and AML who relapse after transplant”.

Abstract:

Context: Post-transplant relapse remains a major cause of treatment failure in patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Understanding of the biology of relapse and response to azacitidine treatment remains limited. Objective: To determine the benefit of the post-transplant use of azacitidine for the treatment of relapse in patients with MDS or AML, and identify mutational patterns associated with response to azacitidine and post-relapse survival. Design: We conducted a prospective trial in 39 patients with MDS or AML who relapsed within 100 days of transplant from related or unrelated donors. Treatment consisted of 5-azacitidine, 75 mg/m2 /day for 7 days, administered every 28 days, starting within 2 weeks of documentation of relapse, unless there was no evidence of response, the disease progressed or toxicity occurred. We determined the frequency and chronology of gene mutations using a targeted 54 gene panel on paired serial bone marrow samples. To identify the mutations derived from recipient clones, we compared the bone marrows at relapse to bone marrows obtained prior to transplant. Main Outcomes Measures: The primary endpoint was 6- month overall survival. Secondary endpoints included the response rate by International Working Group criteria. Results: At 6 months, 25 of 39 patients (64%) were alive, and 12 of 39(30.7%) had responded to azacitidine, 3 achieving a complete remission(CR), and 9 a partial remission(PR). The 2-year OS was 25%. The 2-year OS in patients achieving CR/PR at 6 months was 71%. The most commonly mutated genes at the time of relapse included TP53 (48%), TET2 (33%) and DNMT3A (14%). These mutations persisted through the course of transplant from pre-transplant. Mutations in TP53 were significantly associated with poor responsiveness to azacitidine (OR 3.08, 95%CI 1.1e9.0, p¼0.04) and inferior survival (HR 3.04, 95%CI 1.3e5.8, p¼0.02). Clones with TP53 mutations mostly remained unchanged throughout treatment. Conclusions: The present results show efficacy of azacitidine in controlling disease progression in patients with MDS or AML who relapse after transplant. The mutational analysis provides a molecular basis for the clinical observations with azacitidine, a lesser likelihood of eradication of the underlying malignancy containing those mutations and progressive clonal evolution during treatment.

References
  1. Woo J. et al. Outcomes and Mutational Analysis of a Prospective Phase II Trial of Azacitidine in Patients with MDS and AML With Early Post-Transplant Relapse. Clinical Lymphoma, Myeloma, and Leukemia. 2017 Sep; 17(suppl 2):S348–S349. DOI: http://dx.doi.org/10.1016/j.clml.2017.07.173