PS1051 FT-2102, AN IDH1 M INHIBITOR, INDUCES MUTATION CLEARANCE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS) TREATED IN PHASE 1 DOSE ESCALATION AND EXPANSION STUDY (2019)

Background: A marker chromosome (MC) is a fragmented chromosome whose origin cannot be identified from an existing autosomal or sex chromosome. Recently, MC was found to result from chromothripsis. Chromothripsis is a catastrophic phenomenon by which chromosomes are shattered into tens to hundreds of fragments, and half of the cases are related to TP53 gene mutation. MC is a relatively common abnormality and its incidence in acute myeloid leukemia (AML) is approximately 15%. Although AML with MC was reported to have a poor prognosis after intensive chemotherapy, the influence of MC on the outcome after allo-HSCT for AML is unclear. Aims: We evaluated the outcomes of AML patients with MC after allo-HSCT in comparison with other chromosomal abnormalities such as monosomal karyotype (MK), complex karyotype (CK) and existing sub-clone (SC). Methods: This retrospective analysis included 166 AML patients who received allo-HCT in our study group between 1990 and 2017. The median age of the patients at allo-HCT was 38 years old. The median follow-up period was 2.0 y.According to the revised Medical Research Council (rMRC) criteria for cytogenetic risk categories, 26 (15.7%), 104 (62.7%) and 36 (21.7%) patients were categorized as favorable-, intermediate- and adverse-risk, respectively. Results: MC was detected in 14 (8.4%) of 166 patients. Eleven (78.6%) had adverse-risk karyotypes. CK, MK and SC were observed in 26 (16.3%), 20 (12.0%) and 23 (13.9%) patients, respectively. The median age of AML with MC (AML/MC+, n = 14) and AML without MC (AML/MC-, n = 152) patients was similar (38.5 y vs 38 y, P = 0.812). Twelve AML/MC+ patients (85.7%) received allo-HCT at an advanced stage and 10 (71.4%) demonstrated primary induction failure. Compared with AML/MC- patients, AML/MC+ patients had a higher coexistence rate of CK (85.7% vs. 9.9%, p < 0.001), MK (78.6% vs. 5.9%, p < 0.001) and sub-clone (64.3% vs. 9.2%, p < 0.001). On univariate analysis, the 2-y overall survival (OS) and median survival period of AML/MC+ patients were poorer than those of AML/MC- patients (26.8% vs. 61.3% and 0.78 y vs. 4.9 y, p = 0.0126). The 2-y cumulated incidence of relapse (CIR) in AML/MC+ patients was higher than that in AML/MC- patients (80.4% vs. 37.2%, p < 0.01). To further investigate the impact of MC on the outcome after allo-HSCT, we compared AML patients with/without MC among those with an adverse-risk karyotype. The 2-y OS of adverse-risk AML/MC+ patients (n = 11) was lower than that of adverse-risk AML/MC- patients (n = 25) (9.1% vs 58.3%, p = 0.003). The median survival periods were 0.58 y and 4.0 y, and the 2-y CIR was 89.6% and 44.7% (p = 0.002), respectively. On the other hand, the 2-y OS of CK, MK and SC in adverse-risk AML patients was 33.2%, 26.9% and 34.7%, respectively. Based on our results, MC is the poorest factor after allo-HSCT, and we performed multivariate analysis for confirmation. In the multivariate analysis adjusted for donor, conditioning, disease stage before allo-HCT, CK, MK and SC, only MC was an independent poor risk factor for OS (HR 3.547, 95%CI: 1.46–8.63, p = 0.005) and CIR (HR 3.90, 95%CI: 1.47–10.33, p = 0.006) in adverse-risk AML patients. Summary/Conclusion: MC frequently coexists with other cytogenetic abnormalities. AML with MC has a poor outcome even after allo-HSCT compared with other chromosomal abnormalities.