Lymphocytopenia predicts shortened survival in myelodysplastic syndrome with ring sideroblasts (<scp>MDS‐RS</scp>) but not in <scp>MDS</scp>/<scp>MPN‐RS‐T</scp>
Authors: Abhishek A. Mangaonkar, Faiqa Farrukh, Kaaren K. Reichard, Rhett P. Ketterling, Naseema Gangat, Aref Al‐Kali, Kebede Begna, Animesh Pardanani, Mrinal M. Patnaik, Ayalew Tefferi
Journal: American Journal of Hematology (2021)

More than 10 years ago, we described the association between absolute lymphocyte count (ALC) and survival in myelodysplastic syndromes (MDS) with1 or without2 del(5q); the latter study included 503 patients with non-del(5q) MDS and reported median survival of 18.5 months for patients with ALC < 1.2 × 109/L versus 26.6 months for those with ALC ≥ 1.2 × 109/L (p < .001);2 the prognostic contribution of ALC in the study was shown to be independent of the International Prognostic Scoring System (IPSS).3 In a subsequent larger study of 889 patients with primary MDS,4 we confirmed the prognostic relevance of ALC < 1.2 × 109/L, in the context of the revised IPSS (IPSS-R),5 although significance was borderline (p = .06).4 These observations were more recently confirmed by another retrospective study of 1023 patients from the Düsseldorf MDS-registry, which included therapy-related and del(5q) cases;6 ALC < 1.2 × 109/L was associated with shorter survival that was not accounted for by age or cytogenetic risk groups; however, significance was lost (p = .09) after accounting for bone marrow (BM) blast percentage and degree of cytopenias. Of note, the Düsseldorf study6 included 140 patients with MDS with ring sideroblasts (MDS-RS), with single lineage (SLD) or multilineage (MLD) dysplasia, and the prognostic relevance of ALC < 1.2 × 109/L was most apparent in MDS-RS-SLD.6 The objectives for the current study were to examine the prognostic relevance of lymphocytopenia (ALC < 1.0 or 1.2 × 109/L; Mayo Clinic reference range 0.95–3.07 × 109/L) in both MDS-RS and myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). After approval from the institutional review board, we queried the Mayo Clinic database for myeloid neoplasms to identify 147 patients who met the 2016 World Health Organization (WHO) diagnostic criteria for either MDS-RS (n = 71) or MDS/MPN-RS-T (n = 76).7 The main diagnostic criterion was the presence of at least 15% BM RS for both MDS-RS and MDS/MPN-RS-T, which in the case of MDS-RS also included patients with ≥ 5% BM RS in association with SF3B1 mutation. Additional required diagnostic criteria for both entities included the presence of < 5% BM blasts, < 1% peripheral blood (PB) blasts, and, for MDS/MPN-RS-T, presence of platelet count ≥ 450 × 109/L Exclusionary criteria included the presence of Auer rods, diagnostic criteria for MDS with isolated del(5q), t(3;3)(q21.3;q26.2), inv (3)(q21.3q26.2), BCR:ABL1, or other rearrangements of PDGFRA, PDGFRB, FGFR1, PCM1-JAK2.7 Conventional methods were used for cytogenetic and next-generation sequencing studies. Statistical analyses considered parameters at the time of diagnosis and were performed using JMP Pro 14.0.0 software package, SAS Institute, Cary, NC. Table 1 outlines presenting clinical and laboratory features, as well as postdiagnosis events, in 71 study patients with MDS-RS (median age 73 years, range 41–94; males 63%) and 76 with MDS/MPN-RS-T (median age 73 years, range 49–93; males 61%). IPSS-R risk distributions for MDS-RS were 34% very low, 59% low, 4% intermediate, 3% high, and 0% very high; the corresponding figures for MDS/MPN-RS-T were 29%, 62%, 3%, 3%, and 2%. SF3B1, JAK2, and ASXL1 mutation frequencies were 100%, 1%, and 11%, respectively, for MDS-RS and 92%, 30%, and 20%, respectively, for MDS/MPN-RS-T. Comparison of patients with MDS-RS versus MDS/MPN-RS-T revealed the former with lower absolute neutrophil count (ANC; median 3 vs. 4.6 × 109/L; p = .002) and the latter with higher absolute monocyte count (AMC; median 0.4 vs. 0.5 × 109/L; p = .05), but otherwise similar ALC (median 1.6 vs. 1.6 × 109/L; p = .4), degree of anemia (hemoglobin <10 g/dL in 65% vs. 67%; p = .8) and IPSS-R cytogenetic and overall risk distribution (p = .3 and .8, respectively). Median follow-up for living patients with MDS-RS was 2.1 years and for those with MDS/MPN-RS-T was 2.8 years. During follow-up, 46 (65%) deaths and 2 (2.8%) leukemic transformations were documented in MDS-RS and 36 (47%) deaths and 2 (2.6%) leukemic transformations in MDS/MPN-RS-T. Overall survival data were similar between MDS-RS (median 5.4 years) and MDS/MPN-RS-T (median 5.6 years; Figure 1A; p = .98). 45 (92) N evaluated = 49 13 (30) N evaluated = 43 12 (17) N evaluated = 72 2 (3) N evaluated = 72 1(2) N evaluated = 61 The prevalence of ALC < 1.0 × 109/L and ALC <1.2 × 109/L was 24% (n = 17) and 31% (n = 22), respectively, in MDS-RS and 20% (n = 15) and 29% (n = 22), respectively, in MDS/MPN-RS-T. In univariate analysis, the detrimental impact of ALC < 1.0/1.2 × 109/L on survival was evident in MDS-RS (p < .001/.001; Figure 1B) but not in MDS/MPN-RS-T (p = .3/.4; Figure 1C). Considering the higher strength of survival segregation at ALC cutoff of 1.0 (hazard ratio [HR] 4.3; 95% confidence interval [CI] 2.1–8.8) versus 1.2 (HR 2.9; 95% CI 1.5–5.6), further survival analysis in MDS-RS was performed using the ALC cutoff of 1.0 × 109/L; we should also note that the ROC analysis determined optimal ALC cutoff level was 1.1 × 109/L, but we chose the 1.0 × 109/L as the clinically more consistent cutoff level for "lymphocytopenia," considering the institutional ALC reference range of 0.95–3.07 × 109/L. As outlined in Table 1, MDS-RS patients with ALC < 1 × 109/L, compared to their counterparts with higher ALC, were more likely to display neutropenia, severe anemia, thrombocytopenia, and lower absolute monocyte count, whereas the distribution of age, sex, and cytogenetic risk categories were similar between the two groups. On multivariable analysis, the prognostic impact of ALC <1.0 × 109/L (p < .001) eclipsed that of IPSS-R (p = .16). On the other hand, age as a continuous variable (p = .04), hemoglobin < 10 g/dL (p = .04; HR 1.9, 95% CI 1.02–3.6), IPSS-R cytogenetic risk profile (p = .04; intermediate vs. very good/good HR 4.9; 95% CI 1.6–14.6) retained significance in a multivariable model that included ALC < 1,0 × 109/L (p < .001; HR 4.3, 95% CI 2.0–9.1). No other variable, including those that clustered with ALC < 1.0 × 109/L (Table 1), showed additional significance. The number of leukemic events was too low to allow assessment of leukemia-free survival. The current study confirms the special relevance of MDS-RS on previously reported associations between ALC and survival in primary MDS, as was astutely pointed out by Silzle et al.,6 in the latter study, the authors analyzed 721 patients with primary MDS and were able to demonstrate a significant association between ALC < 1.2 × 109/L and reduced survival among 42 patients with MDS-RS-SLD (p < .001; median survival 62 vs. 155 months), but not among other low-risk WHO-defined subcategories, including MDS-RS-MLD (p = .3), MDS-SLD (p = .3), MDS-MLD (p = .4), and MDS del(5q) (p = .2). Whether or not these observed significance levels would have changed had they used an ALC cutoff of 1 × 109/L remains to be followed up by the authors; of note, in the current study, a significant association was also apparent for ALC < 1.2 × 109/L in MDS-RS (p = .001). The current study did not distinguish between MDS-RS-SLD and MDS-RS-MLD because of sample size restriction; however, the significant association between ALC < 1.0 × 109/L (p < .001) and reduced survival in MDS-RS remained intact during multivariable analysis that accounted for thrombocytopenia (platelet count < 100 × 109/L; p = .15), neutropenia (ANC < 1.8 × 109/L; p = .5), and anemia (hemoglobin < 10 g/dL; p = .04). Importantly, we show that the survival impact of lymphocytopenia might not hold true in the context of MDS/MPN-RS-T, which otherwise shares morphologic (RS ≥ 15%) and molecular (SF3B1 mutation) similarities to MDS-RS; in this regard, the exclusion of patients with platelet count > 450 × 109/L in MDS-RS or those with JAK2V617F in MDS/MPN-RS-T did not alter the influence of ALC < 1.0 × 109/L on survival (p values <.001 and .7, respectively). Whether or not lymphocytopenia in MDS-RS constitutes a component of a clone-intrinsic defect in the effective hematopoiesis or additionally contributes to myeloid-lineage cytopenias remains to be clarified. The latter possibility suggests a potentially salutary effect for immune modulation as a treatment option, as in the case of lenalidomide treatment-associated modulation of the BM immune microenvironment in MDS.8 Regardless, the observation from the current study argues for the inclusion of ALC in future prognostic models for MDS-RS. Authors declare no conflicts of interest in relation to the manuscript. For original data, please contact mangaonkar.abhishek@mayo.edu or tefferi.ayalew@mayo.edu.