Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T): 2017 update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). DIAGNOSIS: MDS-RS is a lower risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥ 450 × 10(9)/L and large atypical megakaryocytes (similar to BCR-ABL1 negative MPN). MUTATIONS AND KARYOTYPE: Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations; with ASXL1/SETBP1 mutations adversely impacting survival. Cytogenetic abnormalities are uncommon in both diseases. RISK STRATIFICATION: Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-International Prognostic Scoring System (R-IPSS). Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic TREATMENT: Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs is uncertain.

Good riddance to the term "refractory anemia" in myelodysplastic syndromes.

The term "refractory anemia" was used in 1937 by Cornelius Parker Rhoads to describe patients whose anemia did not improve after treatment with liver extract or iron salts, and this term has been used to denote patients with certain subtypes of myelodysplastic syndromes (MDS) since the 1976 and 1982 French-American-British (FAB) classifications of acute leukemias and MDS. In 2016, the World Health Organization (WHO) proposed elimination of "refractory anemia" in a more general proposal for reclassification of myeloid neoplasia. A scandal relating to Dr. Rhoads' possibly unethical medical experiments on anemic patients in Puerto Rico in 1931 and a racially offensive letter he wrote during that period prompted an international incident and Congressional-level inquiry. This dark history, as well as continued terminological problems with refractory anemia, suggest that this hoary term has indeed worn out its usefulness. This article reviews the history of "refractory anemia" and evolution in its use over the past 80 years. Rhoads' personal history, the potentially confusing nature of "refractory anemia", and the fact that it is possible none of the 100 patients Rhoads described in 1937 actually had MDS all support the new WHO reclassification proposal to eliminate this term.

[Myelodysplastic syndrome classification]. / La classification des syndromes myélodysplasiques.

Myelodysplastic syndromes (MDS) are myeloid disorders with various clinical and biological presentations. The French-American-British (FAB-1982) classification included five categories basing on morphology and bone marrow blast count. Three criteria are taken into account: 1) the percentage of blasts in peripheral blood and bone marrow, 2) the percentage of ringed sideroblasts, and 3) the number of monocytes in peripheral blood. The World Health Organization classification (WHO 2001, 2008) modifies the FAB system by also taking cytogenetic characteristics and molecular biology into consideration. The last classification (WHO-2008) takes into account: 1) the number of peripheral cytopenia, 2) the percentage of blasts in peripheral blood and bone marrow, 3) the percentage of ringed sideroblasts, 4) the possible presence of Auer Rods, and 5) the detection of a cytogenetic abnormality (the isolated 5q deletion). The following subgroups are defined: refractory cytopenia with unilineage dysplasia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts, myelodysplastic syndrome unclassifiable and myelodysplastic syndrome with isolated del(5q).

Favorable outcome of patients who have 13q deletion: a suggestion for revision of the WHO 'MDS-U' designation.

To characterize bone marrow failure with del(13q), we reviewed clinical records of 22 bone marrow failure patients possessing del(13q) alone or del(13q) plus other abnormalities. All del(13q) patients were diagnosed with myelodysplastic syndrome-unclassified due to the absence of apparent dysplasia. Elevated glycosylphosphatidylinositol-anchored protein-deficient blood cell percentages were detected in all 16 with del(13q) alone and 3 of 6 (50%) patients with del(13q) plus other abnormalities. All 14 patients with del(13q) alone and 2 of 5 (40%) patients with del(13q) plus other abnormalities responded to immunosuppressive therapy with 10-year overall survival rates of 83% and 67%, respectively. Only 2 patients who had abnormalities in addition to the del(13q) abnormality developed acute myeloid leukemia. Given that myelodysplastic syndrome-unclassified with del(13q) is a benign bone marrow failure subset characterized by good response to immunosuppressive therapy and a high prevalence of increased glycosylphosphatidylinositol-anchored protein-deficient cells, del(13q) should not be considered an intermediate-risk chromosomal abnormality.

Diagnosis of acquired bone marrow failure syndrome during childhood using the 2008 World Health Organization classification system.

Distinguishing hypoplastic myelodysplastic syndrome from aplastic anemia (AA) is challenging. In the present study, Japanese and Chinese pediatric hematologists and pathologists conducted a joint review of bone marrow (BM) smears and trephine biopsies in 100 children with acquired BM failure syndrome, using the criteria proposed in the 2008 edition of the World Health Organization classification of hematopoietic and lymphoid tissues. The final consensus for the diagnoses of 100 children was AA in 29 patients, refractory cytopenia of childhood (RCC) in 58 patients, and refractory cytopenia with multilineage dysplasia (RCMD) in 13 patients. No significant differences between Japanese and Chinese children were found with regards to clinical and laboratory findings, or the distribution of diagnoses. Patients with RCC/RCMD showed milder disease severity and BM hypocellularity than those with AA. To establish the provisional entities for RCC, it is essential to prospectively compare the clinical outcomes between AA and RCC groups in a large number of patients.

Refractory cytopenia with unilineage dysplasia: analysis of prognostic factors and survival in 126 patients.

According to the revised WHO classification of 2008, dysplasia in > or = 10% of one bone marrow lineage and one cytopenia constitutes the low-risk category of unilineage cytopenia and unilineage dysplasia (UCUD). We retrospectively reclassified, according to WHO, low-risk MDS from our database and found 126 subjects with these features at diagnosis: 79 patients were categorized as refractory anemia (RA), 23 patients as refractory neutropenia (RN), and 24 as refractory thrombocytopenia (RT). We did not find differences between the three subgroups as regards sex, median age, and cytogenetic aberrations. Lower PMN count (0.8 x 10(9)/L) was observed in the RN category, as well as lower platelet count in the RT category (51 x 10(9)/L). Moreover, we found a lower rate of patients requiring RBC transfusions, during the disease course, in the RT category (45.8%) as compared to RA (62%) and RN (69%) groups (p = 0.05); a lower incidence of infections at diagnosis in the RT category (20.8%) compared to RA (32%) and RN (43%) categories (p = 0.03); and a higher incidence of hemorrhagic symptoms at diagnosis in the RT category (41.6%) and RN category (26%) as compared to the RA group (5%) (p = 0.001). Application of different scoring systems (Bournemouth and Spanish scores, WPSS) revealed a low OS in high-risk patients within the RT category, compared to RA and RN categories, although unlikely to reflect the consequences of low OS found in the former category. Statistically significant differences were also evidenced in the incidence of acute myeloid leukemia (AML) evolution and overall survival: 7/79 (8%) patients with the RA category evolved to AML in a median time of 89 months, whereas 4/23 (17%) of the RN category and 1/24 (4%) of the RT category experienced disease progression, in a median time of 33.8 and 12.8 months, respectively (p = 0.03). The RT category had a lower overall survival (15.9 months) as compared to RA (48.2 months) and RN (35.9 months) categories (p < 0.001). In conclusion, in our study, application of the revised 2008 WHO classification confirmed the importance of separating patients with unilineage dysplasia for prognostic disease assessment; from our results it seems that the RT category has a worse outcome.

Differences in the distribution of subtypes according to the WHO classification 2008 between Japanese and German patients with refractory anemia according to the FAB classification in myelodysplastic syndromes.

We reported the different clinical features between Japanese and German refractory anemia (RA) patients in FAB classification. We re-analyzed the clinical features by WHO classification revised in 2008. The frequencies of refractory cytopenia with unilineage dysplasia (RCUD) and myelodysplastic syndrome-unclassified (MDS-U) with pancytopenia in Japanese patients were higher than in German patients (p<0.001). Refractory cytopenia with multilineage dysplasia patients showed the most unfavorable prognosis in both countries. The higher frequencies of MDS-U with pancytopenia and RCUD in Japanese patients may influence the different clinical characteristics between Japanese and German FAB-RA patients.

Is refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T) a necessary or useful diagnostic category?

Both the 2001 World Health Organisation (WHO) classification of haematopoietic neoplasms and the 2008 WHO classification revision include a distinctive diagnostic category, refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T), to describe those rare patients who have both >or=15% ring sideroblasts and a sustained elevated platelet count. Recently, it has become clear that patients meeting WHO criteria for RARS-T have clonal JAK2(V617F) and MPL(W515) mutations at a similar rate to essential thrombocythaemia (ET). Given that the provisional classification of RARS-T as a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndrome, rather than as a form of MPN (i.e., ET), rests principally upon the presence of ring sideroblasts, which are a non-specific morphological finding, these new molecular results prompt reconsideration of the necessity for a distinctive RARS-T category. Here we review the historical developments that led up the definition of RARS-T as a disease entity, and we discuss conceptual understanding of RARS-T and arguments against continued use of RARS-T as a separate diagnostic category.

The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features.

The 2001 World Health Organization (WHO)-sponsored classification of hematopoietic tumors has, for the first time, clearly defined a group of rare myeloid neoplasms termed myelodysplastic/myeloproliferative diseases (MDS/MPDs). This group includes three main entities, chronic myelomonocytic leukemia, atypical chronic myeloid leukemia and juvenile myelomonocytic leukemia, and also several less well defined, 'unclassifiable' disorders with MDS/MPN-like features. In the upcoming fourth edition of the WHO fascicle, due out later this year, the term 'MPD' is replaced by 'myeloproliferative neoplasm (MPN)'. Accordingly, the term MDS/MPD is being replaced by 'MDS/MPN' that will be used in this review. Although much progress has been made in understanding the molecular pathogenesis of myeloid neoplasms, most of the diseases included in the group of MDS/MPN still remain 'clinicopathologically assigned'. In other words, they can only be accurately categorized by a careful multiparametric approach that is based on the integration of bone marrow and peripheral blood morphology with other laboratory and clinical findings. The current 'spotlight' review provides practical guidelines, which should allow for a reproducible classification of these uncommon neoplasms when encountered in clinical practice.

MPL W515 and JAK2 V617 mutation analysis in patients with refractory anemia with ringed sideroblasts and an elevated platelet count.

Discovery of a constitutively activating point mutation of the Janus kinase 2 (JAK2) receptor-associated tyrosine kinase in patients with polycythemia vera (PV) and other BCR/ABL-negative myeloproliferative disorders prompted many groups around the world to examine diverse subsets of patients with myeloid diseases for the prevalence of the JAK2 V617F mutation and its clinical and pathological associations.

Occurrence of the JAK2 V617F mutation in the WHO provisional entity: myelodysplastic/myeloproliferative disease, unclassifiable-refractory anemia with ringed sideroblasts associated with marked thrombocytosis.

The JAK2/V617F mutation has been noted in essential thrombocytemia. We investigated 19 cases with refractory anemia with ringed sideroblasts (RARS), including three RARS with thrombocytosis (RARS-T). Only the RARS-T patients showed this mutation. More cases need to be analyzed to determine the prevalence of the JAK2/V617F mutation in RARS-T.

Classification and scoring systems in myelodysplastic syndromes: a retrospective analysis of 311 patients.

The main objective of this study was to evaluate the role of the recent World Health Organization (WHO) classification for assessing prognosis in patients with myelodysplastic syndromes (MDS). To this effect, we analyzed the prognostic impact of the WHO and French-American-British (FAB) morphologic classifications and of four different scoring systems in a series of 311 patients with primary MDS diagnosed between October 1990 and June 2001. Both the FAB and WHO classifications identified groups with different prognoses (p<0.0001), those presenting refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS) showing the best prognosis. The WHO classification subdivided RA into RA with only red cell dysplasia, and refractory cytopenia with multilineage dysplasia (RCMD), and RARS into RARS plus refractory cytopenia with multilineage dysplasia and ringed sideroblast (RCMD-RS). In our population, we have shown that the two subtypes characterized by dysplasia affecting exclusively the erythroid population (RA and RARS) have a better prognosis, with a median survival of 122.2 and 81.9 months, respectively, than those with multilineage dysplasia (RCMD and RCMD-RS) with a median survival of 32.3 and 43.2 months, respectively. There were no significant differences in median survival comparing RA with RAS (p<0.95), or comparing RCMD with RSCMD (p<0.97). Besides, the four scoring systems discriminated our MDS patients in terms of survival, and an increase in prognostic capacity was achieved on adding the score to the morphological classifications. Risk scoring had a greater prognostic impact than the FAB and WHO classifications. Prognostic scoring systems may be an important tool for risk stratification in hematological practice, and add significance to morphological classification. Combined application of the WHO classification and score system is useful for improving the identification of patients with a poorer prognosis. The WHO classification establishes more homogeneous subcategories than the FAB classification and is also able to identify groups with different prognoses.

Difference in clinical features between Japanese and German patients with refractory anemia in myelodysplastic syndromes.

Several reports indicate that there might be differences in clinical features between Asian and Western myelodysplastic syndrome (MDS) cases. We analyzed refractory anemia (RA) in French-American-British (FAB) classification cases diagnosed in Japan and Germany to perform a more exact comparison between Asian and Western MDS types. In the first step, we analyzed agreement of morphologic diagnosis between Japanese and German hematologists. Blood and bone marrow slides of 129 patients diagnosed with FAB-RA, FAB-RA with ringed sideroblasts (RARS), or aplastic anemia were selected randomly and evaluated separately by each group. The agreements of diagnoses according to FAB and World Health Organization (WHO) classifications were 98.4% and 83.8%, respectively. Second, we compared clinical features between 131 Japanese and 597 German patients with FAB-RA. Japanese patients were significantly younger than German patients. Japanese patients had more severe cytopenias. However, prognosis of Japanese patients was significantly more favorable than that of German patients. Japanese patients had a significantly lower cumulative risk of acute leukemia evolution than did German patients. Frequency of WHO-RA in Japanese patients with FAB-RA was significantly higher than that in German patients. In conclusion, our results indicate that the clinical features of Japanese patients with FAB-RA differ from those of German patients.

The presence of clonal cell subpopulations in peripheral blood and bone marrow of patients with refractory cytopenia with multilineage dysplasia but not in patients with refractory anemia may reflect a multistep pathogenesis of myelodysplasia.

A clonal origin of hematopoiesis was studied by investigation of X-chromosome inactivation patterns (XCIP) in isolated granulocyte, CD14(+) and CD3(+) subpopulations obtained from bone marrow and peripheral blood of 36 female patients with primary myelodysplastic syndrome (MDS). Clonality was assessed by PCR amplification of polymorphic short tandem repeats of the human androgen receptor (HUMARA) gene and by investigation of silent polymorphism of iduronate sulphatase (IDS) or p55 genes. On the basis of results in a control group of 20 healthy age related females, a ratio of at least 9:1 between the two alleles was considered a significant marker of monoclonal hematopoiesis. Ten of the 11 patients with advanced forms of MDS (RAEB, RAEB-T, CMML) had clonal granulocytes and CD14(+) cells in peripheral blood. In patients with early disease, only 2 out of 11 patients (18%) with RA or RARS, according to WHO classification, had clonal granulocytes and CD14(+) cells in peripheral blood and bone marrow and 2 other patients with 5q-syndrome exhibited extremely oligoclonal granulocyte subpopulation in bone marrow. In contrast, we found clonal granulocytes in 12 out of 14 patients (86%) with refractory cytopenia with multilineage dysplasia (RCMD) and 8 of them simultanously exhibited clonal CD14(+) cells. Estimated 3 years survival of patients with early disease and clonal cell subpopulations was 61% as compared with 88% in patients without clonal hematopoiesis. Karyotype abnormalities were detected in 11 of the 25 females with early disease. Clonal patterns were present in 7 out of 8 patients with abberations diagnosed by routine cytogenetics, nevertheless, FISH revealed 5q deletion in 3 patients without signs of clonality in XCIP assay. No correlation was found between the presence of clonal subpopulations and the degree of telomere shortening in early MDS. Despite some limitations, the measurement of XCIP remains a sensitive tool for diagnosis of the first transforming mutation in the clonal development of MDS especially when combined with FISH and when an age related group is used to establish an appropriate allele ratio to exclude constitutional or acquired skewing. The occurrence of clonal cell subpopulations in most of the RCMD patients in contrast to RA may reflect a proposed multistep pathogenesis of MDS with dysplastic changes limited to erythropoiesis in early step and with subsequent development of multilineage dysplasia. The results also support the usefulness of separation of RCMD from 'pure' RA; however, a more complex insight combining different molecular techniques performed in a large number of patients is needed for refined classification of MDS on the basis of new molecular prognostic factors and for indication of more effective targeted therapy.