Azacitidine Treatment For Patients With Myelodysplastic Syndromes and Acute Myeloid Leukemia Harboring Chromosome 3q Abnormalities
Authors: Wanquet Anne , Berthon Celine , Sebert Marie , Roux Clémence , Kulasekararaj Austin , Micol Jean-Baptiste , Itzykson Raphael , Thepot Sylvain , Recher Christian , Delaunay Jacques , Dreyfus Francois , Mufti Ghulam J. , Fenaux Pierre , Vey Norbert , Prebet Thomas 
Published: October 2019

Abstract

Background
Karyotype is one of the key prognosis factors in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Chromosome 3q abnormalities, including aberrant expression of EVI-1, represent a small subset of patients and are associated with a poor outcome in both MDS and AML patients treated with conventional treatment. Azacitidine is the current standard of care for high-risk MDS and is also active in AML. Given that AZA may provide responses in patients with poor chances of response to conventional treatment as patients with monosomy 7 and given the strong epigenetic modifications related to EVI-1 dysregulation, AZA may represent an interesting option for patients with 3q abnormalities. Therefore, we analyzed the outcome of patients with Chromosome 3q abnormalities treated with Azacitidine.

Patients and methods
This is a retrospective multicenter study. Patients were included if 1/ Diagnosis of MDS, CMML, or AML, including therapy related neoplasms 2/ harbored chromosome 3q abnormalities and/or EVI-1 overexpression by PCR 3/ received at least one cycle of azacitidine for either frontline or relapse treatment. Response was evaluated according IWG 2006 criteria. This cohort of patients was compared to 406 high risk MDS and AML patients without 3q abnormalities included in the French AZA compassional program.

Results
A total of 184 patients were analyzed. Median age was 64 years. According to WHO classification, patients presented RA/RCMD/RAEB-1 28% of cases, RAEB-2/CMML-2 31% of cases, and AML 41% of cases. Median bone marrow blast count was 15%. Cytogenetics were inv(3)/t(3;3) 22%, del(3q)/monosomy 3 26%, t(3q26;x) 20%, EVI-1 overexpression without 3q abnormality 14%, t(3q21;x) 4% and other 3q abnormalities 14%. 58% of patients had complex karyotype. Azacitidine was used frontline for 67% of patients, 33% being previously treated with intensive chemotherapy. Median number of cycle of azacitidine was 5 (1-33). Overall response rate was 47% (Complete or Partial response 27%). 31 patients (25% of patients younger than 70y) bridged to allogeneic transplantation. With a median follow-up of 16 months, median overall survival was 10.5 months. Younger age (below 65y, 13m vs 10m, p=0.052), low bone marrow blast count (below 20%, 13m vs 8m, p=0.001), presence of t(3q21;x) (74 vs 10 months, p=0.008), few cytogenetic abnormalities (below 3, 14m vs 9m, p=0.003), and use of Azacitidine frontline (13m vs 8 m, p=0.029) were associated with a better survival. Long term survival remains limited with a 3 years survival probability below 10%. Interestingly, baseline characteristics and prognosis of patients with EVI-1 overexpression without 3q cytogenetic abnormality were comparable with patients with 3q26 cytogenetic abberation. Then, we compared our cohort with MDS/AML patients without 3q abnormalities, their overall response rate was 30% (41% for HR MDS, 15% for AML, including 11% CR/PR), and median OS was 10.5 months (15 months for HR MDS and 7 months for AML). When we merged the 2 cohorts and performed multivariate analyses, presence of 3q abnormality had no prognosis impact on either response or survival.

Conclusion
Azacitidine seems to limit the dismal outcome associated with 3q abnormalities and thus represents a good alternative to conventional chemotherapy including for patients eligible for allogeneic transplantation. Moreover, our data showed that 3q group is heterogeneous with a favorable outcome for the small subset of patients with 3q21 abnormalities.

Disclosures:
Prebet: CELGENE: Honoraria. Off Label Use: Use of azacitidine in acute myeloid leukemia.