The clinical outcomes of reclassified erythroleukemia (erythroid/myeloid) as myelodysplastic syndrome (MDS) per 2017 WHO guideline compared to MDS
Authors: Omar Alkharabsheh, Aref Al‐Kali, Salwa Saadeh, Rong He, David Viswanatha, Patricia Greipp, Kaaren Reichard, Mithun Shah, Naseema Gangat, Mrinal Patnaik, William Hogan, Mark Litzow, Hassan Alkhateeb, Phuong L. Nguyen
Journal: American Journal of Hematology (2018)

Prior to 2017, the diagnosis of acute erythroid leukemia (AEL): erythroid/myeloid subtype or erythroleukemia had depended on enumerating bone marrow (BM) blasts as a percentage of nonerythroid cells when erythroid precursors exceeded 50%.1In 2017, the WHO classification of hematolymphoid neoplasms proposed that BM blasts be enumerated as a percentage of all nucleated cells, regardless of the quantity of erythroid precursors. Many cases previously diagnosed as AEL would henceforth be classified as myelodysplastic syndrome (MDS) if the marrow blasts, calculated as a percentage of all nucleated cells, are less than 20%. For those patients diagnosed with AEL prior to 2017, how might this change have affected their outcome. Moreover, despite the 2017 WHO revised definition of AEL,2 the potential effects of a prominent erythroid compartment (>50%) remain uncertain. Other investigators have suggested that calculating the BM blasts as a percentage of the nonerythroid cells instead of the total nucleated cells might allow for more accurate or granular prognostication.3 In this study, in an attempt to determine whether or not the 2017 WHO position on counting BM blasts as a percentage of all nucleated cells might have affected patient outcomes, those patients previously classified as AEL but now re-classified as MDS according to the 2017 criteria were compared to cases of MDS with comparable BM blasts. We conducted a retrospective review in two databases at the Mayo Clinic (October 1993–March 2016). The first database included patients with MDS, and the second was for acute myeloid leukemia (AML), erythroid/myeloid subtype (M6a by FAB). For both groups, all patients had a BM core biopsy and aspirate performed at diagnosis. Both aspirate smears and core biopsy sections were reviewed by our hematopathologists; whenever possible, blast identification and quantification were derived from the BM aspirate smears. In cases of “dry” tap or hemodilute aspirate sampling, the core biopsy sections were used. Data extraction from the patient's records included complete blood count (CBC) at diagnosis, BM blast percentage, conventional cytogenetics, date of diagnosis, date of death or date of last follow up for alive patients. Appropriate institutional review board approval was obtained. Over the same time period, MDS cases with excess blasts (MDS-EB) were identified to serve as the comparator arm. After exclusion of all therapy-related myeloid neoplasms (t-MN), the AEL were re-classified according to the 2017 WHO criteria into three groups: MDS-EB, AML-NOS and pure erythroid leukemia (PEL). This process of reclassification was based on calculating the BM blast as a percentage of all nucleated marrow cells. If the blast count was <20%, the case was reclassified as MDS-EB. If the blasts ≥20%, the case was re-classified as AML-NOS. Lastly, cases with 80% immature erythroid precursors or more and with 30% proerythroblasts or more were classified as PEL. There were no cases with WHO-defined recurrent genetic abnormalities. The two groups were matched by BM blast percentages to compare the baseline characteristics and estimate survival differences. Overall survival (OS) was estimated using the Kaplan-Meier method and compared by the log-rank test. Data analysis was done by using the JMP v13 software. Patients who underwent blood or marrow transplantation (BMT) were censored for overall survival at day 0 of BMT. Fifty eight cases of AEL were identified. Eight cases (14%) fulfilled the criteria for t-MN and were subsequently excluded from analysis. When the BM blasts were calculated as a percentage of all nucleated cells, 11 cases (22%) were reclassified as AML-NOS; their median overall survival (mOS) was 6.4 months. Twenty eight cases (56%) had 5-19% BM blasts, so these were re-classified as MDS and their mOS 12.8 is months. Of these MDS cases, 3 (10%) were MDS-EB1 and 25 (90%) were MDS-EB2. Lastly, seven cases (14%) fulfilled the diagnostic criteria of PEL, and their mOS was 3.9 months. Of note, PEL cases often had complex karyotypes. Among these three re-classified groups, there was a trend toward better OS for the MDS as compared to AML-NOS and PEL (mOS 12.8 vs. 6.4 months, respectively), but the difference did not reach statistical significance (P = 0.1) (see Supporting Information Material). The 28 cases previously diagnosed as erythroleukemia but reclassified as MDS were next compared to the MDS-EB matched cohort. The re-classified erythroleukemia group (BM blast percentages range from 5 to 18; median blast is 11%) had worse cytopenia and a higher BM blast percentage as compared to the comparator MDS-EB group. This led to statistically significant (P = .03) higher R-IPSS scores in the reclassified erythroleukemia group, but the cytogenetic categories were comparable between the two groups (see Supporting Information Material). With respect to outcome, there was no statistically significant difference in mOS between the two groups (14.9 months in the former erythroleukemia and 15.7 months in the comparator MDS-EB, P = .9) (Figure 1). The former erythroleukemia group received intensive therapy including more BMT as compared to the comparator MDS-EB group (P < .001). After censoring for BMT, there was no statistically significant difference in survival between the two groups (mOS 15.5 vs. 12.1 months, P = .4). To investigate the effect of erythroid predominance in MDS-EB, the former erythroleukemia cases: all with ≥50% erythroid precursors and re-classified as to MDS with >50% erythroid precursors: were compared to the matched comparator MDS cohort. No statistically significant difference in overall survival was detected (14.9 vs. 15.8 months, P = .9) (see Supporting Information Material). Because massive parallel sequencing became routine clinical laboratory practice only in the last 2 years of the period covered by this retrospective study, a very small number of cases was subjected to such analysis. FLT3 status is known in seven cases of the former erythroleukemia and was positive in one case only. In this study, when patients previously diagnosed with erythroleukemia were re-classified as MDS according to the 2017 WHO criteria and compared to other patients with MDS-EB, no observed differences in OS were detected between the two groups. This observation remained after censoring for BMT. At the same time, this study did identify several different clinical and pathologic characteristics among those patients previously diagnosed as AEL in comparison to those patients diagnosed with MDS and matched by their BM blast percentages. The former was more cytopenic; their BM blast percentages when calculated as a percentage of all BM nucleated cells were higher; and they tended to have higher R-IPSS scores. It should be noted that although matched according to their BM blast counts, the two groups differed in one fundamental way: While those cases formerly classified as AEL had >50% erythroid precursors, those in the comparator MDS group did not. The published literature appeared mixed on the significance—if any—of erythroid prominence in MDS and AML. In a multi-institutional study, Margolskee et al. suggested that erythroid richness in AML imparted no effect on patient overall survival.4However, others have reported clinical, cytogenetic and molecular genetic features more akin to high-grade MDS among those AML with >50% erythroid cells.5Despite the current WHO position on BM blast enumeration, the value of counting BM blasts as a percentage of nonerythroid cells may not be so easily dismissed yet. In a large study of over 3000 patients with MDS including 465 patients with erythroid hyperplasia, Arenillas et al. found that calculating BM blasts as a percentage of nonerythroid cells allowed for greater prognostic accuracy.6 Our retrospective study, although limited by the small number of AEL cases, found that slightly over half of those patients previously diagnosed as AEL at our institution would be reclassified as MDS-EB-1 or -2 in the current WHO classification schema. When compared to MDS-EB, there was no apparent difference in OS. Molecular profiling to explore patterns of gene mutations may help determine whether or not this particular group of myeloid neoplasms with erythroid predominance may be associated with a specific molecular signature and prognostic risk stratification. The authors disclose no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.