Red Blood Cell Alloimmunization in Korean Patients With Myelodysplastic Syndrome and Liver Cirrhosis
2019; 39(2): 218-222
Ann Lab Med 2022; 42(3): 299-305
Published online May 1, 2022 https://doi.org/10.3343/alm.2022.42.3.299
Copyright © Korean Society for Laboratory Medicine.
Departments of 1Hematology and Oncology and 2Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 3Hematopathology Division, Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA; 4Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
Correspondence to: Akriti G Jain, M.D.
Department of Hematology and Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Myelodysplastic syndrome (MDS) is a diverse hematological malignancy with a wide spectrum of presentations and implications. Treatment strategies for patients with MDS heavily rely on prognostic scoring systems, such as the revised international prognostic scoring system (IPSS-R). Bone marrow fibrosis (BMF) has been identified as an independent risk factor for poor survival in patients with MDS, irrespective of the IPSS-R risk category. However, BMF is not widely included in scoring systems and is not always considered by clinicians when making treatment decisions for patients. In this review, we discuss the available literature about the presentation and prognosis of patients with MDS and concurrent BMF. The prognostic impact of BMF should be factored in when deciding on transplant candidacy, especially for intermediate-risk patients.
Keywords: Myelodysplastic syndrome, Bone marrow fibrosis, International prognostic scoring system, Allogeneic stem cell transplantation
The stromal microenvironment of the bone marrow (BM) comprises structural fibrils that provide connective tissue structure and support for hematopoietic progenitor cells. Reticulin and collagen type I/III are the most common BM fibers . BM biopsy sections can be assessed for the presence of these stromal fibers to evaluate the extent of fibrosis using a silver impregnation technique called Gomori’s stain . A pathological increase in BM fibrosis (BMF) reportedly has both clinical and prognostic significance in various hematological malignancies. In chronic myeloid leukemia and multiple myeloma, BMF portends decreased responsiveness to most commonly used treatments [3, 4]. In primary myelofibrosis (PMF), the higher the fibrosis grade, the poorer the prognosis . In patients with essential thrombocythemia, increased reticulin fibrosis predicts an increased risk of thrombosis, major bleeding, and transformation into myelofibrosis, and in patients with polycythemia vera, it is associated with worse outcomes .
Myelodysplastic syndrome (MDS) is a heterogenous hematological malignancy with a wide spectrum of clinical presentations. MDS is characterized by dysplasia in one or more BM cell lineages and/or ineffective erythropoiesis. In 1981, Sultan,
The risk stratification scale of the revised international prognostic scoring system (IPSS-R) for MDS ranges from very low risk to very high risk . The IPSS-R utilizes cytogenetics, BM blasts, and laboratory parameters, including Hb, platelets, and absolute neutrophil count (ANC), at diagnosis . BMF is not included in the IPSS-R for determining the risk category and prognosis. In addition, the clinical relevance of BMF was not recognized in the 2008 WHO classification . The 2016 WHO classification identified MDS-F as an unclassified MDS subtype . Moderate to severe BMF in
While the pathophysiology of BMF is not well understood, some theories suggest increased cytokine production from megakaryocytes and platelets, which reportedly are higher in patients with BMF . Cytokine transforming growth factor-β has been suggested to be a potent stimulator of fibroblast collagen synthesis . Other cytokines implicated in the pathophysiology of BMF include platelet-derived growth factor, calmodulin, and basic fibroblast growth factor . Spliceosome and RAS pathway mutations have been implicated in the pathogenesis of BMF in patients with MDS . However, it is clear that the BMF seen in MDS is a reactive process and that the fibroblasts present in the BM responsible for the fibrosis are not monoclonal . We describe patients with MDS with BMF and their diagnosis, management, and prognosis.
Before 2005, the BMF grading was subjective, and pathologists used various grading systems . In 2001, Steensma,
There are two types of fibers that contribute to BMF. While an increase in reticulin fibers has a limited association with the severity of the underlying malignancy, collagen fibers are strongly linked with abnormal blood counts and poor outcomes . Reticulin fibrosis is frequently reversed after therapeutic intervention, while collagen fibrosis is less likely to alleviate with therapy . Trichrome stain for collagen fibrosis is not commonly used for MDS-F as it is often, though not always, correlated with reticulin fibrosis (≥MF-2). Fig. 1 shows peripheral blood and BM findings in a patient with MDS-F. BMF is often associated with dry tap which could hinder morphologic assessment of dysplasia. Careful examination of peripheral blood and the slides from bone marrow touch imprint would be helpful.
In a study on the clinical significance of moderate to severe BMF in patients with therapy-related (t-)MDS, Fu,
In a study conducted at our institution by Melody,
It is imperative to recognize cytogenetic and mutational profiles that can help in BMF prognosis assessment. Cytogenetic features of MDS-F include monosomy 7 [9, 16, 28]. Complex or other unique cytogenetic features have been reported [7, 9, 16, 28-32]. Fu,
Patients with MDS with substantial BMF are treated using similar strategies as those without fibrosis. Supportive care, immunomodulatory agents, hypomethylating agents, induction chemotherapy, and/or alloSCT can be used. Fu,
AlloSCT is the only potentially curative treatment for MDS. However, alloSCT is associated with a high mortality rate and hence is generally offered only to patients with high- and very-high-risk MDS. As noted before, BMF is not considered when IPSS-R is used to score the prognostic risk, but if BMF accompanies rapidly progressing MDS, alloSCT should be considered. Table 1 lists studies that comparatively investigated the outcomes of patients with MDS-F that underwent alloSCT and MDS patients without BMF. In a study in 721 MDS patients who underwent alloSCT, Kroger,
The most important implication of BMF in MDS patients is its impact on their prognosis in terms of survival as well as progression. Table 2 compares outcomes of patients with MDS-F with those of patients with MDS. Fu,
When the IPSS-R prognostic criteria were first established, BMF was considered a potential factor for determining the prognostic risk. However, it was discounted as an additive factor for predicting survival in MDS because of its low prevalence and discrepancies in the evaluation of the degree of BMF across institutions. We presented evidence that BMF is a poor prognostic variable, even if it is observed during the course of disease. It is recommended that BMF be integrated into currently used risk classification/stratification systems. The presence of moderate to severe BMF in patients with MDS should be accounted for when considering transplantation as a potential treatment strategy in patients with intermediate-risk disease. Future directions include further improving our understanding of the underlying pathobiology of BMF and assessing the impacts of treatments in patients with MDS-F.
Jain AG wrote the manuscript. Zhang L reviewed the manuscript and contributed to the images for the manuscript. Bennet JM and Komrokii R critically reviewed and corrected the manuscript.
Jain AG, Zhang L, and Bennett JM do not have any conflicts of interest to report. Komroji R does not have any conflicts significant for this review. Komroji R: BMSCelgene: Consultancy, Membership on an entity’s Board of Directors or Advisory Committees and Speakers Bureau, Jazz: Consultancy and Speakers Bureau, Novartis: Consultancy, Honoraria and Membership on an entity’s Board of Directors or Advisory Committees, AbbVie: Consultancy, Acceleron: Consultancy, PharmaEssentia: Membership on an entity’s Board of Directors or Advisory Committees, Taiho Oncology: Membership on an entity’s Board of Directors or Advisory Committees, Geron: Consultancy.