Prognostic Significance of the French-American-British (FAB) Morphologic Subclassification of “Acute Myeloid Leukemia, Not Otherwise Specified” in the 2008 WHO Classification: Analysis of 5,848 Newly Diagnosed Patients From HOVON, MRC/NCRI, SWOG, and MD Anderson Cancer Center
Authors: Walter Roland B. , Othus Megan , Burnett Alan K. , Löwenberg Bob , Kantarjian Hagop M. , Ossenkoppele Gert J. , Hills Robert K. , van Montfort Kees G.M. , Ravandi Farhad , Evans Anna , Pierce Sherry A. , Appelbaum Frederick R. , Estey Elihu H. 
Published: October 2019

Abstract
Abstract 540

Background:
The World Health Organization (WHO) classifies acute myeloid leukemia (AML) via genetic, immunophenotypic, biologic, and clinical features. Nevertheless, in the subgroup “AML, not otherwise specified (NOS)”, cases are subdivided based on morphologic criteria similar to those of the previous French-American-British (FAB) classification, but the clinical relevance of this practice is unknown. Assuming that part of a classification system's value derives from its clinical relevance, we used data from adults with newly diagnosed AML treated on trials conducted by the Dutch-Belgian Cooperative Trial Group for Hematology/Oncology (HOVON), the U.K. Medical Research Council/National Cancer Research Institute (MRC/NCRI), the U.S. cooperative group SWOG, and MD Anderson Cancer Center (MDA) to assess the prognostic significance of FAB in the WHO “AML, NOS” category.

Patients and Methods:
We reviewed information on patients with newly diagnosed AML other than acute promyelocytic leukemia receiving curative-intent treatment on HOVON (1987-2008), MRC/NCRI (1988-2010), or SWOG (1987-2009) protocols or at at MDA (2000-2011) and had information on FAB classification available. We used multivariate analyses to assess whether the FAB type was independently associated with early death (i.e. death within 28 days of initiation of chemotherapy or study registration), achievement of complete remission (CR), relapse-free survival (RFS), and overall survival (OS). The following pre-treatment covariates were used in the regression modeling: FAB category, age at diagnosis, white blood cell count, platelet count, bone marrow blast percentage, gender, performance status (0 vs. 1 vs. ≥2), karyotype (normal vs. abnormal), and treatment site.

Results:
After exclusion of patients with therapy-related neoplasms, AMLs with myelodysplasia-related changes, and leukemias with recurrent cytogenetic abnormalities but ignoring information on NPM1 and CEBPA, our cohort included 5,848 predominantly adult patients (median age: 54 years [range: 12–91 years] with “AML, NOS”. After multivariate adjustment, FAB M0 AML was independently associated with significantly lower likelihood of achieving CR and inferior RFS as well as OS as compared to FAB M1, M2, M4, M5, and M6 (FAB “M1-M6”), and inconclusive data regarding M7. Specifically, relative to patients with FAB M1-6, those with FAB M0 the hazard ratios (HRs) were 1.66 (95% confidence interval: 1.30–2.12) for achievement of CR (p<0.001), 0.86 (0.73–1.01) for RFS (p=0.068), and 0.82 (0.72–0.92) for OS (p=0.0013). In contrast, FAB M0 was not associated with risk of early death (HR: 1.01 [0.67–1.53], p=0.96). After exclusion of cases fitting the entity of “AML with mutated NPM1” (n=987) and cases with unknown NPM1 status (n=3,584), FAB M0 was no longer associated with worse outcome relative to other FAB subtypes in the remaining 1,277 patients, with HRs of 1.19 (0.75–1.91; p=0.46) for achievement of CR, 0.98 (0.74–1.31; p=0.89) for RFS, 0.91 (0.72–1.16; p=0.45) for OS, and 1.03 (0.35–3.03; p=0.95) for early death. Although data were limited by sample size, additional exclusion of cases fitting the provisional entity of “AML with mutated CEBPA” and cases with unknown CEBPA status did not further affect this result.

Conclusion:
In the 2008 WHO classification scheme, our data suggest that FAB subclassification of “AML, NOS” cases does not provide prognostic information if molecular data on the mutational status of NPM1 and CEBPA are available. This finding leads us to question the utility of continued use of the FAB system in this subset of AML patients.

Disclosures:
No relevant conflicts of interest to declare.