Presence of B‐cell precursors in bone marrow is a favorable independent prognostic factor for overall survival in patients with myelodysplastic syndromes
Authors: Konradin Metze, Suiellen C. Reis‐Alves, Irene G. H. Lorand‐metze
Journal: American Journal of Hematology (2016)

To the Editor: In their recent interesting publication, Chantepie et al. 1 reported a better survival of patients with acute myeloid leukemia (AML) when B-cell precursors (hematogones) could be detected in bone marrow (BM) during hematological recovery after chemotherapy. Myelodysplastic syndromes (MDS) are hemopoietic clonal disorders considered as “preleukemic.” A diagnostic hallmark of MDS is a reduced number of hematogones in BM 2, and it is hypothesized that this decrease is indicative of the degree of hemopoietic stem cell damage 3. Our aim was to find out whether the number of hematogones in BM could also be a prognostic factor for overall survival in MDS patients, comparing it with other well-known prognostic factors, such as the IPSS-R risk classification and the percentage of myeloid progenitors among BM cells. We analyzed this question in a cohort of 101 MDS patients comprising 64 males and 37 females with a median age of 64 years at diagnosis 4. According to the IPSS-R classification, 7 patients had a very high risk, 16 a high risk, 23 an intermediate risk, 37 a low risk, and 12 had a very low risk. In six cases the score could not be calculated as no cytogenetic data were available. Survival data were updated until May 2016. Patients were censored when receiving BM transplantation or chemotherapy. Median observation time was 48 months and 52 patients were alive at the end of this period. Diagnosis was based on clinical data, peripheral blood (PB) counts, BM cytology and histology as well as cytogenetics, according to the WHO 2008 criteria. Flow cytometry was performed at diagnosis using a panel of 4-color antibody combinations, analyzing antigen expression of myelomonocytic precursors and CD34+ cell subsets: CD64/CD14/CD45/HLA-DR; CD16/CD11b/CD45/CD13; CD13/CD117/CD45/CD34; CD19/CD10/CD45/CD34; and CD7/CD56/CD45/CD34. With this panel it was possible to evaluate up to 16 alterations 4, 5. In particular, we looked in granulocytic precursors for a decreased SSC, abnormal maturation pattern (in CD13/CD16 and CD11b/CD16 combinations) and expression of CD34 (>10% of the cells) in maturing cells. In monocytes, we searched for an increase in number, and increase in CD16+ cells, increase or loss of antigen expression, and abnormal expression of CD34 or CD56. Finally, we assessed in CD34+ cells an increase of total CD34+ cells, decrease of B-cell precursors (CD34+/CD19+/CD10+), an increase of myeloid progenitors (SSCint/CD13+/CD117+/CD34+), or abnormal expression of CD11b, CD7, or CD56 in CD34+ cells. B-cell precursors were not detectable in 54 patients. In the remaining cases, they ranged between 0.1% and 0.72%. There was a weak significant negative Spearman correlation between the percentage of these cells and age (r = −0.232 P = 0.022). We could not detect significant correlations between hematogones and the IPSS-R score, the number of aberrancies in the granulocytic lineage, or percentage of myeloid progenitors, but there were significant negative correlations with the number of monocytic aberrancies (r = −0.256; P = 0.012), the number of abnormalities of CD34+ cells (r = −0.206; P = 0.044), and the total number of aberrancies detected (r = −0.334; P = 0.0008). In the univariate Cox regression, the percentage of B-cell precursors was a significant favorable prognostic factor for overall survival (B = −6.220; P = 0.011). In the Kaplan–Meier curve, patients with detectable B-cell precursors in BM had a significant better overall survival (log-rank test: P < 0.001) than patients with undetectable CD34+/CD19+/CD10+ cells. After 5 years, 76.7% of the patients presenting BM hematogones at diagnosis were still alive, whereas this value dropped to 51.9% in patients without detectable B-cell precursors (Fig. 1). In a multivariate Cox regression model, the percentage of hematogones (B = −5.061; P =0.006), of myeloid progenitors (B = 0.191; P =0.02), and the IPSS-R score (B = 0.714; P < 0.001) remained in the final model, thus demonstrating that the percentage of B-cell precursors is an independent favorable prognostic factor in MDS patients. In order to estimate the clinical importance of the variable “hematogones” in the model, we calculated the relative Akaike weights (w) for different models according to the Akaike information criteria. The relative weight for the prognostic model based only on IPSS-R was 0.0179 and raised to 0.112 in a model containing IPSS-R and the percentage of myeloid precursors. The weight was even higher in a model based on IPSS-R and the percentage of B-cell precursors (w = 0.195), but the best model was achieved joining the variables “percentage of B-cell precursors,” “myeloid progenitors,” and the “IPSS-R score” (w = 0.675). These data indicate that the percentage of hematogones in BM at diagnosis adds important prognostic information independent from already well-known prognostic features for overall survival in MDS patients. This is in keeping with similar results found in the setting of hematological recovery after allogeneic BM transplantation, where the absence of B-cell precursors in BM on day +30 was associated with a higher non-relapse mortality, a higher frequency of acute graft-versus-host disease and infections 6. In normal individuals, there is a decrease of B-cell precursors, especially after the age 55 years, but these cells are even more decreased in patients with MDS compared to age-matched persons 5. All these data indicate that the number of B-cell precursors in BM is not only a good marker of a preserved immune function but also for the integrity of the hemopoietic stem cell. Kaplan–Meier plot showing survival benefit of MDS patients with detectable B cell precursors in bone marrow at diagnosis. Log rank test: P < 0.001. Konradin Metze1*, Suiellen C. Reis-Alves2, and Irene G. H. Lorand-metze2,3 1Department of Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil; 2Hematology/Hemotherapy Center, University of Campinas, Campinas, São Paulo, Brazil; 3Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil