Challenging the Adverse Label: Diverse Outcomes of ELN 2022 Adverse Cytogenetic Subgroups in Acute Myeloid Leukemia Patients Undergoing Allogeneic Hematopoietic Cell Transplantation in First Remission: On Behalf of the EBMT Acute Leukemia Working Party

Background: The presence of cytogenetic abnormalities continues to be an important factor in determining clinical outcomes for patients newly diagnosed with acute myeloid leukemia (AML). In the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), the frequency and prognostic value of different ELN 2022 adverse-risk karyotypes have not been studied. We aimed to evaluate, through the European Society for Blood and Marrow Transplantation (EBMT) database, the real-world implications of the AML ELN 2022 adverse cytogenetic risk classification on prediction of relapse and survival in patients receiving allo-HSCT in first complete remission (CR1), regardless of somatic mutation status.

Methods: This is a retrospective, registry-based, analysis with the approval of the EBMT Acute Leukemia Working Party. Adult patients aged more than 18 years with a diagnosis of AML who received an allo-HSCT between 2010-2022 in CR1, with an available full karyotype at diagnosis, classified as ELN 2022 adverse cytogenetic risk, were included.

Results: We identified 1735 allografted AML patients fulfilling the inclusion criteria. Most of these patients had de novo AML (67%), with a median age of 56 years (range: 18-78), and 52% were male. Patients received primarily reduced intensity conditioning (54%) and peripheral blood stem cells (88%) from matched sibling (24%), unrelated (57%), or haploidentical donors (17%). The most frequent ELN 2022 adverse-risk cytogenetic abnormalities were Group 1: monosomy 5, 7, or del5q without monosomy 17 or 17p abnormality and regardless of the other abnormalities (n= 514); Group 2: monosomy 17 or 17p abnormality and regardless of the other abnormalities (n=394); Group 3: CK not monosomal without additional adverse abnormalities (n=256); Group 4: t(v, 11q23) (n=213) without other adverse abnormalities; Group 5: CK and monosomal karyotype (MK) without other adverse abnormalities (n=178), followed by Group 6: abn 3q26 without other adverse abnormalities than t(9;22) (n=58); Group 7: t(6;9) without other adverse abnormalities (n=50); Group 8: t(9;22) without other adverse abnormalities (n=43); Group 9: monosomal without other adverse abnormalities (n=15); and Group 10: t(8;16) without other adverse abnormalities (n=14). By multiple correspondence analysis, independent categories of co-occurring cytogenetic abnormalities were identified, the first category includes monosomy 5, 7 and 17; the second category includes CK, 17p abnormality and del5q; the third includes adv3q26, t(6;9) and t(9;22); the fourth includes t(v, 11q23) and t(8;16).

Median follow up calculated by the reverse Kaplan-Meier method was 3 years. Overall, the 2-year relapse incidence (RI), leukemia-free survival (LFS) and overall survival (OS) were 43% (95% confidence interval (CI): 40-45%), 40% (95% CI: 38-43%), and 48% (95% CI: 45-50%), respectively. Outcomes were quite poor for patients in Group 2 with 2-year RI, LFS and OS of 62%, 22% and 25%, respectively, and Group 1: 43%, 38% and 47%, respectively. Notably, outcomes of patients with CK without additional adverse cytogenetic abnormalities were quite good with 2- year LFS and OS of 50% and 61% in the absence of MK and 48% and 55% in the presence of MK other than chr 5, 7, and 17. In multivariable analysis, compared to the group of complex karyotype without additional adverse abnormalities, LFS and OS were negatively affected by Group 2 abnormalities (hazard ratio [HR] 2.2 and 2.4, respectively), Group 1 abnormalities (HR 1.4 and 1.4, respectively) and Group 10 (HR 2 and 2.8, respectively) while OS was better in the presence of t(9;22) with a HR 0.43. Finally, RI was significantly decreased when using a mismatched related donor (predominantly haploidentical; HR 0.6) or unrelated donor (HR 0.83) compared to a matched related donor. OS was negatively affected by older age and LFS was improved when using a mismatched related donor (HR 0.8).

In conclusion, this large real-world study revealed a very poor outcome of allografted AML patients with monosomy 17 or 17p abnormalities and a poor outcome for those with monosomy 5, monosomy 7, and del5q. Outcomes were good for most other categories including CK with or without MK other than 5, 7, and 17 indicating that allo-HSCT can overcome the poor outcome of this ELN 2022 adverse cytogenetic risk.

Bazarbachi:Caribou: Honoraria; Biologix: Research Funding; Pfizer: Research Funding; Jansen: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria; Roche: Honoraria, Research Funding. Sicre De Fontbrune:Jazz Pharma: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Samsung: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding. Versluis:Novartis: Honoraria; Abbvie: Honoraria; Rigel: Membership on an entity's Board of Directors or advisory committees; ExcelThera: Membership on an entity's Board of Directors or advisory committees. Yakoub-Agha:Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Kite, a Gilead Company: Honoraria, Other: Travel Support. Forcade:Sobi: Speakers Bureau; Novartis: Other: Travel support, Speakers Bureau; Jazz: Speakers Bureau; GSK: Speakers Bureau; Gilead: Other: Travel support, Speakers Bureau; Astellas: Research Funding; Alexion: Other: Travel support, Speakers Bureau; Maat Pharma: Consultancy; Novartis: Consultancy; Sanofi: Other: Travel support, Speakers Bureau. Mohty:Amgen: Honoraria; BMS: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline Menarini: Honoraria; Novartis: Honoraria; GSK: Honoraria; Takeda: Honoraria; Pfizer: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Adaptive: Honoraria; MaaT Pharma: Current equity holder in publicly-traded company.