Clinical Features of Complex Karyotype in Newly Diagnosed Acute Myeloid Leukemia

Introduction: Acute myeloid leukemia (AML) with complex karyotype (CK), which is defined as ≧3 chromosome abnormalities, has a poor prognosis. In a few reports, CK-AML was classified into typical CK-AML and atypical CK-AML (Mrózek, et al. Leukemia 2019; Leung, et al. Am J Hematol 2019; Schoch, et al. Genes Chromosomes Cancer 2005). The former was defined as CK including monosomy of chromosome 5, 7 and 17 or deletion of 5q, 7q and/or 17p and the latter was defined as CK without those abnormalities. Although it has been reported that patients with typical CK-AML had lower complete remission (CR) rates and shorter overall survival (OS) than those for patients with atypical CK-AML, the clinical features of CK-AML in Japanese patients have remained unclear.

Patients and methods: Hokkaido Leukemia Net (HLN) is a regional prospective cohort study registering cases of newly diagnosed AML from affiliated hospitals covering Hokkaido, the northern most island of Japan. We retrospectively analyzed CK-AML cases registered in HLN between April 2010 and December 2021. Survival of patients with CK-AML was compared to that of patients with normal karyotype (NK) AML. We excluded acute promyelocytic leukemia (APL) patients. The definition of CK was based on the 2017 European LeukemiaNet (ELN) criteria. This study was conducted in accordance with the Helsinki Declaration and was approved by the institutional review boards.

Results: CK-AML patients accounted for 13.8% (N=115) and NK-AML patients accounted for 41.5% (N=346) of the 834 AML patients. The characteristics of patients with CK-AML were as follows: age 17 to 91 (median 67); male 69 (60.0%), female 46 (40.0%); typical CK-AML 77 (67%), atypical CK-AML 38 (33.0%). In typical CK-AML patients, 49, 39, and 28 patients had monosomy or deletion of chromosomes 5, 7 and 17, respectively (Figure A). There were no significant differences between patients with typical CK-AML and those with atypical CK-AML in median age (68 years vs 66.5 years, P=0.338), white blood cell count at diagnosis (3600/μL vs 4700/μL, P=0.217), percentage of bone marrow blast cells at diagnosis (43.8% vs 58.4%, P=0.106), percentage of patients who received intensive chemotherapy (46.8% vs 63.2%, P=0.155), percentage of patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) (22.0% vs 26.3%, P=0.813), CR rate (47.8% vs 59.5%, P=0.310), relapse rate (42.9% vs 57.1%, P=0.589) and primary induction failure (PIF) rate (64.7% vs 56.8%, P=0.529). Regarding the degree of karyotype complexity, patients with typical CK-AML had larger numbers of chromosome abnormalities than did patients with atypical CK-AML (median, 9 vs 4 abnormalities; P<0.001). In AML subtypes, patients with typical CK-AML included a significantly larger percentage of AML patients with myelodysplasia-related changes (AML-MRC) than did patients with atypical CK-AML (48.1% vs 21.1%, P=0.008). Two-year OS rates in patients with typical CK-AML, patients with atypical CK-AML and patients with NK-AML were 7.1%, 34.6% and 50.8% respectively. Median OS of patients with typical CK-AML was 143 days (95% CI: 106-183), which was significantly inferior to that of patients with atypical CK-AML (median OS of 369 days, 95% CI: 63-751, P=0.009). In patients with typical CK-AML, patients with monosomy 17 or deletion of 17p had significantly shorter OS than that for patients without such abnormalities (105 days vs 165 days, P=0.033) (Figure B). Additionally, typical CK-AML patients without monosomy 17 or deletion of 17p had shorter OS than that of patients with atypical CK-AML, though the difference was not statistically significant (165 days vs 369 days, P=0.078).

Conclusion: This retrospective analysis showed that a poor prognosis group of CK-AML could be further stratified into typical CK-AML and atypical CK-AML. Patients with typical CK-AML had a worse prognosis than that for patients with atypical CK-AML in a Japanese cohort. Patients with monosomy 17 or deletion of 17p had significantly shorter OS than that for other typical CK -AML patients. This extremely poor prognostic group of CK-AML patients with monosomy 17 or deletion of 17p can be identified without genetic testing and long survival has not been achieved by the current treatment strategy including allo-HSCT. A large percentage of AML cases with TP53 mutation located on chromosome 17 contributes to the refractory and/or relapse nature of the disease in this category.

Kondo:Alexion Pharma: Honoraria; PharmaEssentia Japan: Honoraria; Chugai Pharmaceutical: Honoraria. Iyama:Alexion Pharmaceuticals: Honoraria, Research Funding; MSD: Research Funding; Otsuka: Honoraria, Research Funding; SymBio Pharmaceuticals: Honoraria, Research Funding; Astellas: Honoraria; CSL Behring: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Meiji Pharma: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Sanofi: Honoraria, Research Funding. Teshima:Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Chugai: Research Funding; Astellas: Research Funding; TEIJIN PHARMA: Research Funding; Fuji Pharma: Research Funding; NIPPON SHINYAKU: Research Funding; Janssen: Other: Manuscript preparation; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Manuscript preparation, Research Funding; Luca Science Inc.: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Kyowa Kirin: Honoraria, Research Funding.