Treatment and outcomes for chronic myelomonocytic leukemia compared to myelodysplastic syndromes in older adults
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Prior studies have investigated patients' characteristics, treatments, and outcomes for older adults with myelodysplastic syndromes, but most failed to distinguish chronic myelomonocytic leukemia. Recognizing potentially important differences between the diseases, we undertook a population-based comparison of baseline characteristics, treatments, and outcomes between older adults with chronic myelomonocytic leukemia and myelodysplastic syndromes. The patients' data were obtained from Surveillance Epidemiology and End Results registry data from 2001-2005, linked to Medicare claims. Baseline characteristics, treatment (red blood cell transfusions, hematopoietic growth factors, hypomethylating agents, chemotherapy or transplantation), progression to acute myeloid leukemia, and overall survival were compared using bivariate techniques. Multivariate logistic regression estimated differences in treatments received. Cox proportional hazard models estimated the effects of chronic myelomonocytic leukemia relative to myelodysplastic syndromes on progression-free survival. A larger proportion of patients with chronic myelomonocytic leukemia (n=792), compared to patients with myelodysplastic syndromes (n=7,385), failed to receive any treatment (25% versus 15%; PKeywords:
Chronic myelomonocytic leukemia
Background: Recently, 3 types of monocytes have been characterized by immunophenotyping in chronic myelomonocytic leukemia (CMML). Increase in monocytes in bone marrow (BM) may also be found in myelodysplastic syndromes (MDS). In a previous study using multiparameter flow cytometry to study BM myeloid precursors in MDS we found monocyte increase in 21% of the patients, with similar frequencies in RAEB and low risk MDS, but this was associated with a worse overall survival. Aims: to study the phenotypic characteristics of BM myelomonocytic precursors and CD34 + progenitors in CMML and compare them with findings observed in MDS. Methods we studied cases of CMML and low risk MDS entering our Laboratory in 2018. Bone marrow (BM) was collected at the diagnostic work‐up. Diagnosis and classification of the cases was made by WHO 2016 criteria based on peripheral blood counts, BM morphology and cytogenetics. Cases of transitory peripheral cytopenias presenting normal results were used as controls. Immunophenotyping of BM cells was made with and 8‐color platform according to Euroflow. A minimum 300000 cells were acquired. Results: We examined 24 cases of MDS (age 27‐88 years), and 19 CMMLs (age 55‐90 years) which were compared with 12 controls (age 25‐79 years). Concerning immunophenotypic features, SSC of granulocytic precursors/SSC of lymphocytes <6 was seen in 10 MDS and in 9 LMMC cases. Abnormal antigen expression in granulocytic precursors was observed in 11/23 MDS (0 alterations = 12, 1 = 5 and 2 = 6) and 11/17 CMML (0 alterations = 7, 1 = 7 and 2 = 5). Total monocytes were increased in all CMMLs but also in 15 cases of MDS, with similar proportions of classical monocytes (median 94.7% and 93.1% respectively), but increase in monocytes in CMML was mostly dependent on increase in classical monocytes, while in MDS both classical and non‐classical forms increased. Myeloid CD34 + progenitors were >2% in 4 cases of CMML but in none of the MDS cases. Total lymphocytes increased in MDS, but decreased in CMML. In these later, the decrease was more prominent in mature B‐cells, but occurred also in T CD4 + cells. Summary/Conclusion: Immunophenotyping of BM in CMML discloses several abnormalities of monocytic but also of granulocytic precursors, similar to MDS. Besides, decrease in lymphoid cells is similar to what has been described in juvenile myelomonocytic leukemia but different from those seen in low risk MDS.
Chronic myelomonocytic leukemia
Immunophenotyping
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Chronic myelomonocytic leukemia
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Chronic myelomonocytic leukemia
Immunophenotyping
Myeloproliferative Disorders
Juvenile myelomonocytic leukemia
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Chronic myelomonocytic leukemia is similar to but a separate entity from both myeloproliferative neoplasms and myelodysplastic syndromes, and shows either myeloproliferative or myelodysplastic features. We ask whether this distinction may have a molecular basis. We established the gene expression profiles of 39 samples of chronic myelomonocytic leukemia (including 12 CD34-positive) and 32 CD34-positive samples of myelodysplastic syndromes by using Affymetrix microarrays, and studied the status of 18 genes by Sanger sequencing and array-comparative genomic hybridization in 53 samples. Analysis of 12 mRNAS from chronic myelomonocytic leukemia established a gene expression signature of 122 probe sets differentially expressed between proliferative and dysplastic cases of chronic myelomonocytic leukemia. As compared to proliferative cases, dysplastic cases over-expressed genes involved in red blood cell biology. When applied to 32 myelodysplastic syndromes, this gene expression signature was able to discriminate refractory anemias with ring sideroblasts from refractory anemias with excess of blasts. By comparing mRNAS from these two forms of myelodysplastic syndromes we derived a second gene expression signature. This signature separated the myelodysplastic and myeloproliferative forms of chronic myelomonocytic leukemias. These results were validated using two independent gene expression data sets. We found that myelodysplastic chronic myelomonocytic leukemias are characterized by mutations in transcription/epigenetic regulators (ASXL1, RUNX1, TET2) and splicing genes (SRSF2) and the absence of mutations in signaling genes. Myelodysplastic chronic myelomonocytic leukemias and refractory anemias with ring sideroblasts share a common expression program suggesting they are part of a continuum, which is not totally explained by their similar but not, however, identical mutation spectrum.
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Chronic myelomonocytic leukemia
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Hypomethylating agents (HMAs) are the standard of care for myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). HMA treatment failure is a major clinical problem and its mechanisms are poorly characterized. We performed RNA sequencing in CD34+ bone marrow stem hematopoietic stem and progenitor cells (BM-HSPCs) from 51 patients with CMML and MDS before HMA treatment and compared transcriptomic signatures between responders and nonresponders. We observed very few genes with significant differential expression in HMA non-responders versus responders, and the commonly altered genes in non-responders to both azacitidine (AZA) and decitabine (DAC) treatments were immunoglobulin genes. Gene set analysis identified 78 biological pathways commonly altered in non-responders to both treatments. Among these, we determined that the γ-aminobutyric acid (GABA) receptor signaling significantly affected hematopoiesis in both human BM-HSPCs and mice, indicating that the transcriptomic signatures identified here could serve as candidate biomarkers and therapeutic targets for HMA failure in MDS and CMML.
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The hazard ratio and median survival time are the routine indicators in survival analysis. We briefly introduced the relationship between hazard ratio and median survival time and the role of proportional hazard assumption. We compared 110 pairs of hazard ratio and median survival time ratio in 58 articles and demonstrated the reasons for the difference by examples. The results showed that the hazard ratio estimated by the Cox regression model is unreasonable and not equivalent to median survival time ratio when the proportional hazard assumption is not met. Therefore, before performing the Cox regression model, the proportional hazard assumption should be tested first. If proportional hazard assumption is met, Cox regression model can be used; if proportional hazard assumption is not met, restricted mean survival times is suggested.风险比（hazard ratio，HR）和中位生存时间是生存分析时的常规分析和报告指标。本文简要介绍了HR和中位生存时间的关系以及比例风险假定在这两者之间的作用，分析了检索出的58篇文献中的110对风险比和中位生存时间比的差异，并通过实例阐明了产生这种差异的原因。结果表明，在不满足比例风险假定时，Cox回归模型计算得到的风险比是不合理的，且与中位生存时间之比不等价。因此，在使用Cox回归模型前，应先进行比例风险假定的检验，只有符合比例风险假定时才能使用该模型；当不符合比例风险假定时，建议使用限制性平均生存时间。.
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Prior studies have investigated patients' characteristics, treatments, and outcomes for older adults with myelodysplastic syndromes, but most failed to distinguish chronic myelomonocytic leukemia. Recognizing potentially important differences between the diseases, we undertook a population-based comparison of baseline characteristics, treatments, and outcomes between older adults with chronic myelomonocytic leukemia and myelodysplastic syndromes. The patients' data were obtained from Surveillance Epidemiology and End Results registry data from 2001-2005, linked to Medicare claims. Baseline characteristics, treatment (red blood cell transfusions, hematopoietic growth factors, hypomethylating agents, chemotherapy or transplantation), progression to acute myeloid leukemia, and overall survival were compared using bivariate techniques. Multivariate logistic regression estimated differences in treatments received. Cox proportional hazard models estimated the effects of chronic myelomonocytic leukemia relative to myelodysplastic syndromes on progression-free survival. A larger proportion of patients with chronic myelomonocytic leukemia (n=792), compared to patients with myelodysplastic syndromes (n=7,385), failed to receive any treatment (25% versus 15%; P
Chronic myelomonocytic leukemia
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