What Is the Prognostic Relevance of Responses Less Than a CR(Sub-CR) to Initial AML Treatment?

Context: Achievement of CR has long been one of the goals of AML treatment. Over the years, less stringent criteria for defining CR (sub-CR) have been developed to incorporate patients in clinical trials and to facilitate regulatory approvals. In both the intensive and non-intensive up-front treatment scenarios, sub-CR responses are associated with inferior outcomes compared to those achieving true CR. However, it is not clear whether sub-CR response comprises a prognostic factor independent of the underlying disease biology.

Design: Retrospective single center study

Patients and methods: 363 AML patients CR or sub-CR response between Jan 2019 to Jan 2023 were included. Sub-CR responses included CRi, CRh, and MLFS per ELN 2022. Univariate and multivariable logistic regression models were conducted to assess the association between clinical variables and CR/sub-CR response. Kaplan-Meier curves were generated for EFS and OS, and differences were tested using the log-rank test. All statistical analyses were performed using the EZR software (a modified version of R commander (version 1.5.4)).

Objectives:Primary objective: To identify predictors of sub-CR response.

Secondary objectives: To compare EFS and OS between CR and sub-CR patients, in both overall population and AML subgroups

Results: Among the 363 patients, 227 patients achieved CR, and 136 sub-CR. Sub-CR responses included CRi/h(75) and MLFS(61). By UVA, sub-CR response was associated with secondary AML(OR: 2.801(95%CI[1.70 - 4.63]); p<0.0001), adverse cytogenetics(OR: 5.008[1.36 - 18.35]; p 0.02), intermediate cytogenetics(OR: 6.5[1.92 - 22.03]; p 0.02), ELN adverse risk(OR: 5.95[3.2 - 11.1]; p<0.001), ELN intermediate risk(OR: 2.11[1.07 - 4.15]; p<0.0001), unmutated NPM1 (OR: 1.96[1.23 - 3.13]; p 0.02), MDS-related mutations(OR: 4.49[2.84 - 7.09]; p<0.0001) and non-intensive treatment (OR: 8.612[4.98 - 14.87]; p<0.001). On MVA, sub-CR responses were associated with non-intensive treatment (OR: 6.273 [3.46 - 11.35]; p<0.0001), ELN adverse risk (OR: 3.033 [1.49 - 6.18]; p 0.0073) and MDS-related mutations (OR: 2.757[1.57 - 4.83]; p 0.0004).

The 24 month-EFS was inferior(p<0.0001) in patients with sub-CR (33.5% [25.2 - 41.7]) compared those with a CR (58.1% [51.1 - 64.5]). Similarly, 24-month OS was inferior in the sub-CR group (45.3% [36.3 - 53.9] (sub-CR) vs 67.5% [60.6 - 73.5] (CR); p<0.0001). This difference persisted after censoring for transplant (HSCT) (26.4% [17.6 - 36.1] (sub-CR) vs 54.6% [45.9 - 62.6] (CR); p<0.0001).

The inferior OS of the sub-CR group was seen in ELN favorable (24-month OS: 56.2%(sub-CR) vs 84.3%(CR); p 0.008) and intermediate risk (24-month OS: 52.9%(sub-CR) vs 64.9%(CR); p-0.02), but not in adverse risk (24-month OS: 39.8%(sub-CR) vs 52.3%(CR); p-0.187). Inferior OS of sub-CR was observed in intensively treated patients (24-month OS:52.7%(sub-CR) vs 71.7%(CR); p-<0.0001), but not in non-intensively treated patients (24- month OS: 37.6%(sub-CR) vs 22.5%(CR); p-0.149).

When MRD status was considered, we did not observe a significant difference in the 24-month OS between sub-CR and CR, whether MRD negative (24-month OS: 56.6%(sub-CR) vs 67.7%(CR); p-0.06) or positive (24-month OS: 40.3%(sub-CR) vs 62.95(CR); p-0.08). In patients who underwent HSCT, there was no significant difference in the 24-month OS between sub-CR and CR (64%(sub-CR) vs 72.4%(CR); p-0.0504) whereas a difference was noted in the non-transplanted population (31.6%(sub-CR) vs 62.5%(CR); p-<0.0001).

Conclusions: We conclude that sub-CR responses in AML reflect both underlying disease biology and type of treatment administered. Sub-CR responses were more common in patients with adverse pre-treatment characteristics (ELN adverse risk and MDS-related mutations), and in non-intensively treated patients. In these subgroups, a sub-CR response did not confer inferior survival. In contrast, sub-CR response was associated with inferior survival in intensively treated patients and in favorable/intermediate risk AML. The OS effects of sub-CR response were MRD independent in our hands, and HSCT appeared to be able to overcome the negative OS impact of sub-CR status.

Chan:Servier Pharmaceuticas LLC: Research Funding. Gupta:GSK: Consultancy, Honoraria, Other: support for attending meetings and/or travel; Sumitomo Pharm: Consultancy; BMS/Celgene: Consultancy, Other: Participation on a data safety or advisory board; Incyte: Consultancy, Other: Participation on a data safety or advisory board; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Constellation: Consultancy; Sierra Oncology: Consultancy, Other: Participation on a data safety or advisory board; CTI Biopharma: Consultancy, Other: Participation on a data safety or advisory board; Pfizer: Consultancy, Other: Participation on a data safety or advisory board; Daiichi Sankyo: Consultancy, Other: Participation on a data safety or advisory board; Roche: Membership on an entity's Board of Directors or advisory committees. Richard-Carpentier:Pfizer: Honoraria, Other: Advisory Board Participation; BMS: Other: Advisory Board Participation; AbbVie: Honoraria, Other: Advisory Board Participation; Astellas: Honoraria, Other: Advisory Board Participation; Taiho: Honoraria, Other: Advisory Board Participation. Schimmer:Medivir AB: Research Funding; Novartis: Consultancy; BMS: Research Funding; Jazz: Consultancy; Otsuka Pharmaceuticals: Consultancy; UHN: Patents & Royalties: DNT cells; Takeda: Consultancy, Research Funding. Yee:Astex: Other: research support; Forma Therapeutics: Other: research support; F. Hoffmann-La Roche: Other: research support; Genentech: Other: research support; Geron: Other: research support; Gilead Sciences: Other: research support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: research support; Bristol Myers Squibb/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Taiho Pharma: Membership on an entity's Board of Directors or advisory committees; Taiho Pharma: Honoraria. Maze:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma Essentia: Research Funding; Takeda: Research Funding; Kronos Bio: Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy.