AUTHORS
Dimitrios Kotsos, MD, MSc, Patrycja L. Gradowska2, Thomas Pabst, MD3, Johan A. Maertens, MD4, Markus G. Manz, MD5, Bjorn Gjertsen, MD, PhD6, Soren Lehmann, MD, PhD7, Andrea Lenartova8, Bart J. Biemond, MD, PhD9, Olivier Spertini, MD10, Janine van Elssen, MD, PhD11, Lisanne Beugelink12, Peter JM Valk, PhD13, Gert J. Ossenkoppele, MD14, Bob Lowenberg, MD,PhD15, Gerwin A. Huls, MD, PhD16, Marc Raaijmakers, MD17, Jurjen Versluis Sr, MD, PhD18
AFFILIATIONS
1 Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
2 Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands, HOVON Foundation, Rotterdam, Netherlands
3 Department of Medical Oncology, University Hospital, Inselspital, Bern, Switzerland, Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland
4 University Hospital Gasthuisberg, Leuven, Belgium
5 Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland, University Hospital Zurich, Zurich, Switzerland
6 Centre for Myeloid Blood Cancer CMYC, University of Bergen, Bergen, Norway, Haukeland University Hospital, Bergen, Norway
7 Karolinska University Hospital, Stockholm, Sweden
8 Oslo University Hospital, Oslo, Norway
9 Amsterdam UMC, Cancer Center Amsterdam, University of Amsterdam, Amsterdam, Netherlands
10 Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois), University of Lausanne (UNIL), Lausanne, Switzerland
11 GROW institute for Oncology and developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
12 Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
13 Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
14 Amsterdam UMC, Cancer Center Amsterdam, University of Amsterdam, Amsterdam, Netherlands
15 Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
16 University Medical Center, University Groningen, Groningen, Netherlands
17 Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
18 Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
ABSTRACT
Introduction
The 2022 European LeukemiaNet (ELN) recommendations define morphologic remission response categories for acute myeloid leukemia (AML), including complete response (CR), CR with partial hematologic recovery (CRh), and CR with incomplete hematologic recovery (CRi). Recent studies report inferior outcomes for patients achieving CRh or CRi compared to CR, but determinants of worse outcomes remain unclear. We assessed the impact of hematological recovery in remission after intensive induction treatment on outcomes and the impact of consolidation treatment.
Methods
Newly diagnosed AML patients aged 18-65 years who were treated with two cycles of 7+3 induction chemotherapy in two HOVON-SAKK-Nordic clinical trials (HO102 and HO132) and achieved a morphologic remission after cycle 2 were included. Genetic risk stratification was performed according to ELN2022 criteria. Measurable residual disease (MRD) was measured after cycle two with flow cytometry and/or deep sequencing–based detection of NPM1 or FLT3-ITD. Response categories were hierarchically assigned with neutrophil count ≥1.0 ×109/L and platelet count ≥100 ×109/L for CR, ≥0.5 ×109/L and ≥50 ×109/L for CRh, <0.5 ×109/L and/or <50 ×109/L for CRi. Overall survival (OS) and relapse-free survival (RFS) were estimated using Kaplan-Meier, and cumulative incidence (CI) of relapse (CIR) and non-relapse mortality (NRM) were estimated, with NRM and relapse treated as respective competing events (Gray’s test). OS and RFS for the overall cohort were calculated from post–cycle 2 remission assessment and from the time of start of consolidation for the analysis of impact of consolidation. Consolidation included allogeneic hematopoietic cell transplantation (allo-HCT) and chemo-based treatment. Multivariable Cox (OS/RFS) and Fine-Gray (CIR/NRM) models were adjusted for trial, age, baseline white blood cell (WBC) count, sex, AML clinical ontogeny, ELN2022 risk, WHO status, no. of cycles to remission, and MRD.
Results
Among 1,299 patients achieving morphologic remission after 2 cycles of intensive induction, 926 (71%) had CR, 195 (15%) CRh, and 178 (14%) CRi. Patients in CRi were older and were more often classified as adverse-risk (CR 27%, CRh 39%, CRi 48%). MRD assessment was available in 69% of CR, 57% of CRh, and 39% of CRi patients. Among evaluable patients, MRD positivity was similar across response categories (CR 30%, CRh 29%, CRi 29%). Median follow-up was 102 months (IQR: 85-120).
OS was reduced in CRh and CRi patients (5-year OS: 54±4% and 47±4% vs. 62±2% in CR, respectively), which was significantly different in multivariable analysis for CR vs CRi (p=0.02). Similarly, 5-year RFS was reduced in CRi patients (41±4% vs 52±2% in CR; p=0.001), but not in CRh (47±4%; p=0.35). Worse OS and RFS for CRi patients was primarily driven by increased CI of NRM (5-year 25±3%) compared to CR and CRh (9±1% and 14±2%, p<0.001 and p=0.01, respectively). CIR were 40±2%, 39±4%, and 34±4% for CR, CRh, and CRi subgroups.
Of 1,299 patients, 1,162 proceeded to consolidation therapy, consisting of chemo-based consolidation (CR: 44%, CRh: 30%, CRi: 11%) or allo-HCT (CR: 47%, CRh: 61%, CRi: 71%). CRi patients who did not proceed to consolidation had high 6-month CI of NRM, which was not observed for CRh and CR (CRi: 41±9%, CRh 0%, CR 3±2%). Among patients receiving chemo-based consolidation, 5-year OS was 71±2% for CR, 60±6% for CRh, and 44±11% for CRi, and RFS 57±2%, 50±7%, and 24±10%. In multivariable analysis, RFS was significantly inferior only in CRi patients compared to CR (HR 1.89, 95%CI 1.09-3.30; p=0.02), driven by higher relapse (HR 2.22, 95%CI 1.38-3.60; p=0.001) with no difference in NRM. Among allo-HCT recipients, 5-year OS and RFS were similar across CR, CRh, CRi categories (55±2%, 55±5%, 54±4% and 50±3%, 51±5%, 52±4%, respectively). Multivariable analysis indicated a non-significant increased CI of NRM after allo-HCT for CRi patients compared to CR (HR 1.51, 95%CI 0.98-2.31, p=0.06).
Conclusion
AML patients in CRi after intensive induction chemotherapy have inferior OS, driven by NRM in the overall cohort and by increased CIR after chemo-based consolidation. Allo-HCT may overcome the adverse prognostic impact of incomplete hematologic recovery. These findings suggest that hematologic recovery status should be incorporated into consolidation decision-making.
DISCLOSURES
Dimitrios Kotsos, MD, MSc: No relevant conflicts of interest to declare.