Navigating Myelodysplastic and Myelodysplastic/Myeloproliferative Overlap Syndromes.

Myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPNs) are clonal diseases that differ in morphologic diagnostic criteria but share some common disease phenotypes that include cytopenias, propensity to acute myeloid leukemia evolution, and a substantially shortened patient survival. MDS/MPNs share many clinical and molecular features with MDS, including frequent mutations involving epigenetic modifier and/or spliceosome genes. Although the current 2016 World Health Organization classification incorporates some genetic features in its diagnostic criteria for MDS and MDS/MPNs, recent accumulation of data has underscored the importance of the mutation profiles on both disease classification and prognosis. Machine-learning algorithms have identified distinct molecular genetic signatures that help refine prognosis and notable associations of these genetic signatures with morphologic and clinical features. Combined geno-clinical models that incorporate mutation data seem to surpass the current prognostic schemes. Future MDS classification and prognostication schema will be based on the portfolio of genetic aberrations and traditional features, such as blast count and clinical factors. Arriving at these systems will require studies on large patient cohorts that incorporate advanced computational analysis. The current treatment algorithm in MDS is based on patient risk as derived from existing prognostic and disease classes. Luspatercept is newly approved for patients with MDS and ring sideroblasts who are transfusion dependent after erythropoietic-stimulating agent failure. Other agents that address red blood cell transfusion dependence in patients with lower-risk MDS and the failure of hypomethylating agents in higher-risk disease are in advanced testing. Finally, a plethora of novel targeted agents and immune checkpoint inhibitors are being evaluated in combination with a hypomethylating agent backbone to augment the depth and duration of response and, we hope, improve overall survival.

The importance of evaluating specific myeloid malignancies in epidemiological studies of environmental carcinogens.

INTRODUCTION: Although myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN) - including chronic myeloid leukemia (CML) - and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are largely clinically distinct myeloid malignancies, epidemiological studies rarely examine them separately and often combine them with lymphoid malignancies, limiting possible etiological interpretations for specific myeloid malignancies. METHODS: We systematically evaluated the epidemiological literature on the four chemical agents (1,3-butadiene, formaldehyde, benzene, and tobacco smoking, excluding pharmaceutical, microbial and radioactive agents, and pesticides) classified by the International Agency for Research on Cancer as having sufficient epidemiological evidence to conclude that each causes "myeloid malignancies." Literature searches of IARC Monographs and PubMed identified 85 studies that we critically assessed, and for appropriate subsets, summarized results using meta-analysis. RESULTS: Only two epidemiological studies on 1,3-butadiene were identified, but reported findings were inadequate to evaluate specific myeloid malignancies. Studies on formaldehyde reported results for AML and CML - and not for MDS or MPN - but reported no increased risks. For benzene, several specific myeloid malignancies were evaluated, with consistent associations reported with AML and MDS and mixed results for CML. Studies of tobacco smoking examined all major myeloid malignancies, demonstrating consistent relationships with AML, MDS and MPN, but not with CML. CONCLUSIONS: Surprisingly few epidemiological studies present results for specific myeloid malignancies, and those identified were inconsistent across studies of the same exposure, as well as across chemical agents. This exercise illustrates that even for agents classified as having sufficient evidence of causing "myeloid malignancies," the epidemiological evidence for specific myeloid malignancies is generally limited and inconsistent. Future epidemiological studies should report findings for the specific myeloid malignancies, as combining them post hoc - where appropriate - always remains possible, whereas disaggregation may not. Furthermore, combining results across possibly discrete diseases reduces the chances of identifying important malignancy-specific causal associations.

The risk of tuberculosis in cancer patients is greatest in lymphoma and myelodysplastic syndrome/myeloproliferative neoplasm: a large population-based cohort study.

Patients with cancer are at high risk for tuberculosis (TB). This study combined the Israeli databases of cancer and TB and examined the development of TB among all newly diagnosed cancer cases from 1993 to 2013. Patients were classified into groups according to their different malignancies. Among 495,335 cancer patients, 335 developed TB following cancer diagnosis. The cumulative incidence of TB following cancer diagnosis was highest among MDS/MPN (148.8/100,000 patients) and lymphoma (154.1/100,000 patients) (p = .023). The HR of TB following cancer among hematologic patients was 2.51 (p < .001), relative to patients with in situ carcinomas/skin cancer and highest among MDS/MPN and lymphoma patients (2.74, p = .012 and 2.70, p < .001, respectively). Among lymphoma patients, a significant increased HR was found only among NHL patients (2.72, p < .001). The limitations include lack of information regarding risk factors for TB and of anti-cancer treatments. In conclusion, these data may encourage a heightened awareness for TB among patients with a background of lymphoma and MDS/MPN.

Turning the tide in myelodysplastic/myeloproliferative neoplasms.

Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) are aggressive myeloid malignancies recognized as a distinct category owing to their unique combination of dysplastic and proliferative features. Although current classification schemes still emphasize morphology and exclusionary criteria, disease-defining somatic mutations and/or germline predisposition alleles are increasingly incorporated into diagnostic algorithms. The developing picture suggests that phenotypes are driven mostly by epigenetic mechanisms that reflect a complex interplay between genotype, physiological processes such as ageing and interactions between malignant haematopoietic cells and the stromal microenvironment of the bone marrow. Despite the rapid accumulation of genetic knowledge, therapies have remained nonspecific and largely inefficient. In this Review, we discuss the pathogenesis of MDS/MPN, focusing on the relationship between genotype and phenotype and the molecular underpinnings of epigenetic dysregulation. Starting with the limitations of current therapies, we also explore how the available mechanistic data may be harnessed to inform strategies to develop rational and more effective treatments, and which gaps in our knowledge need to be filled to translate biological understanding into clinical progress.

Epidemiología de la leucemia mieloide crónica en España y sus posibles implicaciones terapéuticas / Epidemiology of chronic myeloid leukemia in Spain and its possible therapeutic implications

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Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001-12.

Descriptive epidemiological information on myeloproliferative neoplasms (MPNs) and myelodysplastic (MDS)/MPNs is largely derived from single institution and European population-based studies. Data obtained following adoption of the World Health Organization classification of haematopoietic neoplasms and JAK2 V617F mutation testing are sparse. Using population-based data, we comprehensively assessed subtype-specific MPN and MDS/MPN incidence rates (IRs), IR ratios (IRRs) and relative survival (RS) in the United States (2001-12). IRs were highest for polycythaemia vera (PV) (IR = 10·9) and essential thrombocythaemia (ET) (IR = 9·6). Except for ET and mastocytosis, overall IRs were significantly higher among males (IRRs = 1·4-2·3). All evaluable MPNs were associated with lower IRs among Hispanic whites than non-Hispanic whites (NHWs), with the exception of BCR-ABL1-positive chronic myeloid leukaemia (CML), chronic eosinophilic leukaemia (CEL) and juvenile myelomonocytic leukaemia. Except for CEL, Asians/Pacific Islanders had significantly lower MPN IRs than NHWs. ET, MPN-unclassifiable and CEL IRs were 18%, 19% and 60% higher, respectively, among blacks than NHWs. Five-year RS was more favourable for younger (<60 years) than older individuals and for women compared with men, except for PV at older ages. RS was highest (>90%) for younger PV and ET patients and lowest (<20%) for older chronic myelomonocytic leukaemia and atypical BCR-ABL1-negative CML patients. Varying MPN and MDS/MPN incidence patterns by subtype support distinct aetiologies and/or susceptible populations. Decreased survival rates as compared to that expected in the general population were associated with every MPN subtype, highlighting the need for new treatments, particularly among older individuals.

Coverage and accuracy of myeloproliferative and myelodysplastic neoplasms in the Finnish Cancer Registry.

Background Registration of haematological malignancies presents specific challenges, and a wide range of data is required to ensure case ascertainment and proper classification of these diseases. We studied the data quality of myeloproliferative and myelodysplastic neoplasms in the Finnish Cancer Registry (FCR), comparing information with hospital discharges. Material and methods Hospital discharges (HILMO) in 2007-2013 including diagnostic codes of myeloproliferative and myelodysplastic neoplasms were extracted. Patients were individually linked to the FCR database for all haematological malignancies registered in 1953-2013. Coverage and accuracy of the FCR and agreement between registers was estimated. Results In total 5289 individuals were retrieved from two registers. Of these, 1406 were common, 1080 only found in the FCR and 2803 only in the HILMO. Coverage of myeloproliferative and myelodysplastic neoplasms in the FCR was 47.0% (95% CI 45.7-48.4%). Almost one quarter of the registrations in the FCR was based on a death certificate only. The accuracy of diagnosis was 51.4% (95% CI 49.4-53.3%), but it varied substantially by disease category. Kappa statistic for agreement between registers was excellent (0.83, 95% CI 0.80-0.85) for common cases. 7.6% of cases in the HILMO was registered as leukaemias in the FCR. Conclusions More than half of the patients found in the HILMO were entirely missing from the FCR. However, some of the diagnoses in HILMO may be preliminary and this represents the maximal number of missing cases. Cancer registers benefit from supplementary data sources, such as hospital discharges, to increase coverage and accuracy of register data on haematological malignancies.

Neoplasias mieloproliferativas crónicas con cromosoma Filadelfia negativo y neoplasias linfoides concurrentes / Concurrent lymphoid and Philadelphia chromosome-negative myeloproliferative neoplasms

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[Incidence of haematological neoplasms in Castilla y León, Spain]. / Estudio de incidencia de las neoplasias hematopoyéticas en Castilla y León.

BACKGROUND AND OBJECTIVE: We aimed to assess the incidence of haematological neoplasms (HNs) in Castilla y León (2,5 million inhabitants) and its distribution by age, gender and histological type. PATIENTS AND METHOD: The epidemiological profile based on the described variables of the 10,943 HNs diagnosed during a 10-years period was analyzed, compared with other studies. RESULTS: The overall age-adjusted incidence was 29.4 cases/10(5) inhabitants-year, with some geographical differences. The mean age was 67.3 years, with a turning point between the 6th-7th decades of life from which there was a very significant increase of incidence. Two relevant facts where simultaneous with advancing age: decreased lymphoid neoplasms incidence and increased low degree neoplasms incidence. Lymphoid low degree neoplasms accounted for half of the registered processes, showed the greatest preference for male and reached the mode before the rest of neoplasms. Myeloid neoplasms incidence (9.5) was higher than that reported in other European registries, specially compared to southern European countries, opposite to lymphoid neoplasms incidence (20.0). CONCLUSIONS: A higher myeloid neoplasms incidence and lower lymphoid one than expected was observed. The turning point of incidence is between the 6th-7th decades of life, with a preference for male that decreases with age. There is an increased incidence of HNs in the area where a higher density of potentially polluting facilities is concentrated.

I walk the other line: myelodysplastic/myeloproliferative neoplasm overlap syndromes.

Patients with the myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) overlap, including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN-unclassifiable (MDS/MPN-U), and refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T), often present with findings of both dysplasia and marrow proliferation, occupying the border region of two seemingly divergent camps. Historically, these disorders which have been lumped with either MDS or MPN have represented a minority, or been excluded all together, from the development of prognostic models and clinical trials. Therefore, Food and Drug Administration approved therapies specifically for overlap subtypes are lacking. More recently, the revolution in molecular genetics has led to discovery of mutations enacting pathways that result in the distinct biology and presentation of the overlap syndromes. Additionally, these recurrent genetic lesions have a prognostic value and are potential therapeutic targets, which might ultimately improve patient outcomes by reducing disease-related symptoms and complications and by prolonging survival.

Clinical significance of SF3B1 mutations in Korean patients with myelodysplastic syndromes and myelodysplasia/myeloproliferative neoplasms with ring sideroblasts.

Somatic mutations in the SF3B1 gene, a gene encoding the splicing factor 3B subunit 1, were recently reported in myelodysplastic syndromes (MDS), particularly in the presence of ring sideroblasts (RS). The authors investigated the prevalence and clinical significance of SF3B1 mutations in Korean patients with myeloid neoplasms with RS. The study subjects were 43 Korean patients with myeloid neoplasms. Twenty-nine patients (67 %) had 15 % or more RS (high-count RS [HC-RS]), and 14 (33 %) had RS less than 15 % (low-count RS [LC-RS]). Molecular genetic tests were performed to detect SF3B1 mutations by direct sequencing on bone marrow samples of the patients. SF3B1 mutations were detected in 55 % (16/29) of the HC-RS group: 3 RARS (3/3), 8 RCMD (8/16), 3 RARS-t (3/4), 1 RAEB (1/4), and 1 MDS-U (1/1). All mutations were previously reported mutations with K700E being the most common (63 % of mutation-positive cases). On the other hand, none (0 %) of the LC-RS group had SF3B1 mutation. The patients with SF3B1 mutations had higher platelet counts (p = 0.023), higher proportions of RS (p = 0.003), and lower proportions of bone marrow blasts (p = 0.026) than those without SF3B1 mutations. SF3B1 mutations showed a favorable survival implication (p = 0.025), but not in multivariate analysis (p = 0.178). This study confirmed that SF3B1 mutation is highly specific to the HC-RS phenotype in Korean patients with myeloid neoplasms with similar frequencies and distributions in previous findings and is associated with distinct hematologic features.

Survival of European patients diagnosed with myeloid malignancies: a HAEMACARE study.

Population-based information on the survival of patients with myeloid malignancies is rare mainly because some entities were not recognized as malignant until the publication of the third revision of the International Classification of Diseases for Oncology and World Health Organization classification in 2000. In this study we report the survival of patients with myeloid malignancies, classified by updated criteria, in Europe. We analyzed 58,800 cases incident between 1995 to 2002 in 48 population-based cancer registries from 20 European countries, classified into HAEMACARE myeloid malignancy groupings. The period approach was used to estimate 5-year relative survival in 2000-2002. The relative overall survival rate was 37%, but varied significantly between the major groups: being 17% for acute myeloid leukemia, 20% for myelodysplastic/myeloproliferative neoplasms, 31% for myelodysplastic syndromes and 63% for myeloproliferative neoplasms. Survival of patients with individual disease entities ranged from 90% for those with essential thrombocythemia to 4% for those with acute myeloid leukemia with multilineage dysplasia. Regional European variations in survival were conspicuous for myeloproliferative neoplasms, with survival rates being lowest in Eastern Europe. This is the first paper to present large-scale, European survival data for patients with myeloid malignancies using prognosis-based groupings of entities defined by the third revision of the International Classification of Diseases for Oncology/World Health Organization classifications. Poor survival in some parts of Europe, particularly for treatable diseases such as chronic myeloid leukemia, is of concern for hematologists and public health authorities.

Incidence, survival and prevalence of myeloid malignancies in Europe.

BACKGROUND: The Surveillance of Rare Cancers in Europe (RARECARE) project aims at increasing knowledge of rare cancers in Europe. This manuscript describes the epidemiology of myeloid malignancies (MMs), taking into account the morphological characterisation of these tumours. METHODS: We used data gathered by RARECARE on cancer patients diagnosed from 1995 to 2002 and archived in 64 European population-based cancer registries, followed up to 31st December 2003 or later. RESULTS: The overall annual crude incidence of MMs was 8.6 per 100,000. Acute myeloid leukaemia (AML) and myeloproliferative neoplasms (MPN) were most common, with incidence rates of 3.7 and 3.1 per 100,000 year respectively, followed by 1.8 for myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MD/MPN) and 0.1 for histiocytic and dendritic cell neoplasms (HDCN). The 5-year relative survival rate ranged from 18% for chronic myelomonocytic leukaemia, 19% for AML, 29% for MDS and 44% for chronic myeloid leukaemia to relatively favourable rates for MPN (62%) and HDCN (83%). Total number of new cases of MMs in the EU27 is estimated at 43,000 annually, total number of prevalent cases (1st January 2008) at 189,000 cases. CONCLUSION: MMs form a large variety of rare entities with specific characteristics. Collection of detailed information (immunophenotype, genetic abnormalities, molecular data and clinical data) and an up-to-date classification system is essential for their surveillance, especially now that more and more targeted therapies are being introduced.

Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project.

Changing definitions and classifications of hematologic malignancies (HMs) complicate incidence comparisons. HAEMACARE classified HMs into groupings consistent with the latest World Health Organization classification and useful for epidemiologic and public health purposes. We present crude, age-specific and age-standardized incidence rates for European HMs according to these groupings, estimated from 66,371 lymphoid malignancies (LMs) and 21,796 myeloid malignancies (MMs) registered in 2000-2002 by 44 European cancer registries, grouped into 5 regions. Age-standardized incidence rates were 24.5 (per 100,000) for LMs and 7.55 for MMs. The commonest LMs were plasma cell neoplasms (4.62), small B-cell lymphocytic lymphoma/chronic lymphatic leukemia (3.79), diffuse B-cell lymphoma (3.13), and Hodgkin lymphoma (2.41). The commonest MMs were acute myeloid leukemia (2.96), other myeloproliferative neoplasms (1.76), and myelodysplastic syndrome (1.24). Unknown morphology LMs were commonest in Northern Europe (7.53); unknown morphology MMs were commonest in Southern Europe (0.73). Overall incidence was lowest in Eastern Europe and lower in women than in men. For most LMs, incidence was highest in Southern Europe; for MMs incidence was highest in the United Kingdom and Ireland. Differences in diagnostic and registration criteria are an important cause of incidence variation; however, different distribution of HM risk factors also contributes. The quality of population-based HM data needs further improvement.

CTLA-4 +49A>G polymorphism of recipients of HLA-matched sibling allogeneic stem cell transplantation is associated with survival and relapse incidence.

Conflicting observations have been reported about the role of CTLA-4 gene polymorphisms in the clinical outcome of allogeneic hematopoietic stem cell transplantation (HSCT). We have investigated three polymorphisms of the CTLA-4 gene (-318C>T, +49A>G, CT60G>A) in 133 donor/recipient pairs who underwent HLA-matched sibling donor HSCT for hematological malignancies. We found no association of the clinical outcome of the HSCT with either recipient or donor -318C>T and CT60G>A polymorphisms. At variance, we found a significant association of donor +49A>G G/G genotype with longer overall survival (OS; log-rank test, P = 0.04), and the number of +49A>G G-alleles in the recipient with longer OS (P = 0.027), longer disease-free survival (P = 0.036) and reduced relapse rate (P = 0.042). However, only recipient +49A>G polymorphism was retained as independent prognostic factor in a multivariate analysis, suggesting that the expression of CTLA-4 on the cells of recipient may be relevant for the clinical outcome of HSCT.

Risks of myeloid malignancies in patients with autoimmune conditions.

Autoimmune conditions are associated with an elevated risk of lymphoproliferative malignancies, but few studies have investigated the risk of myeloid malignancies. From the US Surveillance Epidemiology and End Results (SEER)-Medicare database, 13 486 myeloid malignancy patients (aged 67+ years) and 160 086 population-based controls were selected. Logistic regression models adjusted for gender, age, race, calendar year and number of physician claims were used to estimate odds ratios (ORs) for myeloid malignancies in relation to autoimmune conditions. Multiple comparisons were controlled for using the Bonferroni correction (P<0.0005). Autoimmune conditions, overall, were associated with an increased risk of acute myeloid leukaemia (AML) (OR 1.29) and myelodysplastic syndrome (MDS, OR 1.50). Specifically, AML was associated with rheumatoid arthritis (OR 1.28), systemic lupus erythematosus (OR 1.92), polymyalgia rheumatica (OR 1.73), autoimmune haemolytic anaemia (OR 3.74), systemic vasculitis (OR 6.23), ulcerative colitis (OR 1.72) and pernicious anaemia (OR 1.57). Myelodysplastic syndrome was associated with rheumatoid arthritis (OR1.52) and pernicious anaemia (OR 2.38). Overall, autoimmune conditions were not associated with chronic myeloid leukaemia (OR 1.09) or chronic myeloproliferative disorders (OR 1.15). Medications used to treat autoimmune conditions, shared genetic predisposition and/or direct infiltration of bone marrow by autoimmune conditions, could explain these excess risks of myeloid malignancies.

Mixed myeloproliferative and myelodysplastic disorders.

When the French-American-British (FAB) classification system was first devised in the 1970s for the myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) was included in the FAB MDS classification schema. It always appeared out of place, however, at least when compared with the other FAB MDS categories, as CMML clearly has some features of a myeloproliferative disorder. Yet CMML also did not fit well with the traditional four myeloproliferative disorders. In the 1990s there was ongoing discussion about distinguishing a proliferative type of CMML versus a dysplastic type of CMML, based primarily on the total white blood cell count. In 2001 the World Health Organization reclassified most of the hematologic malignancies, creating a new category of mixed myelodysplastic/myeloproliferative diseases. Finally, CMML has an appropriate home, along with other disorders that seem to fit quite well in this "mixed" category.