[Allogeneic hematopoietic stem cell transplantation for the treatment of acute myeloid leukemia with primary thrombocytosis: three cases report and literatures review].
Zong X P,Tang L,Cen J N,Chen S N,Sun A N,Wu D P
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi
To investigate the characteristics of the essential thrombocythemia (ET) cases transformed to the acute myeloid leukemia (AML) and the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of this disease. The clinical and laboratory characteristics of 3 ET cases before and after transformation and after allo-HSCT were retrospectively analyzed, meanwhile the related literatures were reviewed and discussed. Case 1 was a male patient of 44 years old, whose PLT was 500×10(9)/L when firstly diagnosed ET. After 3 years the disease progressed into myelodysplastic syndrome (MDS) while WT1 expression increased from 77 (first visit) to 13 171 copies/10 000 ABL copies, at the same time chromosome changed dramatically. During the period of decitabine treatment the disease processed into AML. Case 2 was a male of 58 years old whose PLT was 2 100×10(9)/L when firstly diagnosed ET. The disease progressed to AML after 9 years, whose WT1 expression increased from 130 (first visit) to 3 222 copies/10 000 ABL copies, and he relapsed shortly after intensive chemotherapy. Case 3 was a male of 60 years old whose PLT was 900×10(9)/L when firstly diagnosed ET. The disease progressed to AML after 5 years, whose WT1 increased from 56 (first visit) to3 696 copies/10 000 ABL copies. Moreover leukemia spread to central nervous system (CNS) during chemotherapy. Before allo-HSCT, cases 1 did not achieve remission; case 2 relapsed after a short time of remission and case 3 transferred to CNS leukemia. All of the 3 cases underwent allo-HSCT successfully, and they all achieved completely remission, whose chromosome and gene mutation recovered negative. At the same time, CNS leukemia of case 3 disappeared. The median WT1 decreased to 50 copies/10 000 ABL copies. There was no severe complication during the median time of 5 months after allo-HSCT. The patients transformed to AML had poor prognosis, allo-HSCT was the only method that can cure the disease now.
[Acquired aplastic anemia developing myelodysplastic syndrome/acute myeloid leukemia: clinical analysis of nineteen patients and literatures review].
Ma Li,Li Xingxin,Zhang Jing,Shao Yingqi,Nie Neng,Huang Zhendong,Ge Meili,Zheng Yizhou,Qu Dongxia,Shi Jun
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi
OBJECTIVE:To analyze the clinical features of clonal evolution of acquired aplastic anemia (AA) into myelodysplastic syndrome/acute myeloid leukemia (AML) and review of literatures. METHODS:AA developing MDS/AML patients between December 1994 and December 2011 enrolled into this study to analyze their clinical characteristics. RESULTS:During the median follow-up of 49(15-97) months, 19 patients evolved to MDS/AML, of whom 10, 8 and 1 were from VSAA, SAA and NSAA subgroups, respectively. The median G-CSF therapy was 270(29-510) days. There were monosomy 7 in 11(57.9%) of 19 patients with AA evolved to MDS/AML. The median AA evolved to MDS/AML was 33(11-88) months. The median MDS/AML transformation in responders (54.2 months) was significantly longer than of non-responders (25.7 months, P<0.01). CONCLUSION:AA patients could evolved into MDS/AML concomitant with abnormal karotype and worse prognosis.
Therapy-related myelodysplastic syndrome.
Candelaria Myrna,Dueñas-Gonzalez Alfonso
Expert opinion on drug safety
INTRODUCTION:Myelodysplastic syndrome (MDS) is a heterogeneous clonal disorder characterized by deregulation of apoptosis, dysplastic features in hematopoietic precursors, peripheral blood cytopenias and an increased risk for transformation to acute leukemia. Roughly 20% of MDS are therapy related (t-MDS), and this is considered an independent adverse prognostic factor. AREAS COVERED:This review based on a comprehensive literature search provides an overview on the main features of t-MDS, including its epidemiology, risk factors, molecular pathogenesis, prognostic classifications and therapy. EXPERT OPINION:Increasing evidence points out that the most important event in t-MDS is genetic alterations in hematopoietic stem precursor cells, however, ineffective hematopoiesis may also result from abnormalities in the bone marrow microenvironment. Thus, novel views onto the processes of t-MDS are needed such as the osteohematology concept. On the other hand, the number of people living with and beyond cancer is increasing worldwide; thus, most emphasis should be placed on preventing secondary malignancies such as t-MDS. From this review, it becomes clear that we are in urgent need not only to deepen our understanding of the leukemogenesis mechanisms induced by exposure to chemotherapy and radiation but also to translate this knowledge into clinical strategies aimed at risk reduction.
An increased percentage of myeloid CD34+ bone marrow cells stratifies intermediate IPSS-R myelodysplastic syndrome patients into prognostically significant groups.
Chen-Liang T-H,Casado-Prieto A M,Campos-Rodríguez V,Hurtado A M,Amigo M L,García-Malo M D,Vicente V,Ortuño F J,Jerez A
International journal of laboratory hematology
INTRODUCTION:The Revised International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes (MDS) has established an intermediate category where a disease-modifying intervention is a matter of debate. Flow cytometry allows us to determine a fraction of immature myeloid cells in a semiautomated procedure. The aim of this study, mirroring IPSS-R study inclusion criteria, was to test whether bone marrow (BM) CD34+My percentage has independent prognostic value in the MDS setting. METHODS:BM CD34+My cells were quantified, at diagnosis, selecting CD34+/CD45+/CD11b±/CD13+. Patients were excluded when receiving treatment for altering the natural course of the disease and when IPSS-R could not be calculated due to the lack of metaphases. Finally, Cox analyses were performed, on a series of 260 patients, for overall survival (OS) and time to acute myeloid leukemia (AML) transformation. RESULTS:By analyzing ROC curves, the most accurate prognostic variable, regarding blasts by cytology and CD34+ by cytometry, was the percentage of blasts by microscopy. The percentage of CD34+My in BM showed an AUC of 0.767 and 0.576 for time to AML transformation and OS, respectively. When performing a multivariate regression including the IPSS-R and the percentage of BM CD34+My cells >1%, both factors predicted for a shorter time to AML transformation. In addition, CD34+My percentage successfully stratified the intermediate IPSS-R category into two prognostic groups with a relative risk of 5.73 (95% CI [1.2-27.8]; P = .03). CONCLUSION:We found that BM CD34+My percentage has an independent value concerning the IPSS-R, especially relevant for the prediction of transformation to AML and within the intermediate group.
Outcome of patients with low-risk and intermediate-1-risk myelodysplastic syndrome after hypomethylating agent failure: a report on behalf of the MDS Clinical Research Consortium.
Jabbour Elias J,Garcia-Manero Guillermo,Strati Paolo,Mishra Asmita,Al Ali Najla H,Padron Eric,Lancet Jeffrey,Kadia Tapan,Daver Naval,O'Brien Susan,Steensma David P,Sekeres Mikkael A,Gore Steven D,Dezern Amy,Roboz Gail J,List Alan F,Kantarjian Hagop M,Komrokji Rami S
BACKGROUND:The hypomethylating agents (HMAs) azacitidine and decitabine are most commonly used to treat patients with higher-risk myelodysplastic syndromes (MDS). To the authors' knowledge, the prognosis of patients with low-risk and intermediate-1-risk MDS by the International Prognostic Scoring System (IPSS) after HMA failure has not been explored comprehensively. METHODS:The clinical characteristics and treatment outcome of 438 patients with low-risk and intermediate-1-risk MDS who were treated with HMAs were retrospectively analyzed. RESULTS:Using the International Working Group response criteria, the overall objective response to HMA was 35% with a median of 6 cycles of HMA administered, and the median response duration was 7 months. Only 7% of patients had disease that transformed into acute myeloid leukemia while receiving therapy. Of the 290 patients who were evaluable at the time of HMA failure, 77% remained in the lower-risk disease categories. On multivariate analysis, baseline neutropenia, intermediate-risk and poor-risk baseline karyotype, and lack of response to HMA were found to be independently associated with a higher risk of disease progression. With a median follow-up of 16 months, the median transformation-free survival and overall survival (OS) after HMA failure were 15 months and 17 months, respectively. On multivariate analysis, only The University of Texas MD Anderson Global Scoring System was found to be independently predictive of outcome, with patients with higher-risk categories having poor transformation-free survival (hazards ratio [HR], 1.5; P = .003) and OS (HR, 1.8; P = .002). The administration of salvage therapy was independently associated with better OS only (HR, 0.8; P = .01). CONCLUSIONS:Outcomes of patients with lower-risk MDS after HMA failure are poor and the treatment of these patients remains an unmet medical need. OS is a reasonable primary endpoint for clinical studies targeting this population.
Thol F,Heuser M,Ganser A
Myelodysplastic syndrome (MDS) encompasses a heterogeneous group of diseases originating in hematopoietic stem cells and is characterized by inefficient hematopoiesis and dysplastic changes in the bone marrow. In peripheral blood patients show anemia (mostly macrocytic), frequently accompanied by neutropenia and thrombocytopenia. Thus, clinically the patients suffer from fatigue (anemia), increased bleeding (thrombocytopenia) and infectious complications (neutropenia). Approximately one quarter of MDS patients develop acute myeloid leukemia (AML) in the course of the disease, which is characterized by a 20 % or more increase of blasts in the bone marrow. The estimated overall survival as well as the risk for AML transformation can be calculated with the international prognostic scoring system (IPSS) as well as the revised IPSS score (IPSS-R). Novel sequencing methods (e.g. next generation sequencing) allow the detection of recurrent gene mutations in MDS patients. Genes of the splicing machinery as well as genes involved in epigenetic regulation (e.g. ASXL1 and TET2) are most frequently mutated in MDS. Therapy is selected based on the patient risk profile (IPSS). Allogeneic stem cell transplantation is a curative approach for high risk patients (i.e. IPSS int-2 and higher) with a good performance status and a biological age below 70 years. Otherwise, high risk patients are treated with demethylating agents (e.g. decitabine and azacitidine). Low risk patients (IPSS low and int-1) mainly receive supportive therapy including iron chelation. An exceptional position is presented by MDS with an isolated 5q deletion as it can be treated with lenalidomide with good success. Enrolling patients in clinical trials is strongly recommended to improve the prospects of this disease.
The prognostic impact of mutations in spliceosomal genes for myelodysplastic syndrome patients without ring sideroblasts.
Kang Min-Gu,Kim Hye-Ran,Seo Bo-Young,Lee Jun Hyung,Choi Seok-Yong,Kim Soo-Hyun,Shin Jong-Hee,Suh Soon-Pal,Ahn Jae-Sook,Shin Myung-Geun
BACKGROUND:Mutations in genes that are part of the splicing machinery for myelodysplastic syndromes (MDS), including MDS without ring sideroblasts (RS), have been widely investigated. The effects of these mutations on clinical outcomes have been diverse and contrasting. METHODS:We examined a cohort of 129 de novo MDS patients, who did not harbor RS, for mutations affecting three spliceosomal genes (SF3B1, U2AF1, and SRSF2). RESULTS:The mutation rates of SF3B1, U2AF1, and SRSF2 were 7.0 %, 7.8 %, and 10.1 %, respectively. Compared with previously reported results, these rates were relatively infrequent. The SRSF2 mutation strongly correlated with old age (P < 0.001), while the mutation status of SF3B1 did not affect overall survival (OS), progression-free survival (PFS), or acute myeloid leukemia (AML) transformation. In contrast, MDS patients with mutations in U2AF1 or SRSF2 exhibited inferior PFS. The U2AF1 mutation was associated with inferior OS in low-risk MDS patients (P = 0.035). The SRSF2 mutation was somewhat associated with AML transformation (P = 0.083). CONCLUSION:Our findings suggest that the frequencies of the SF3B1, U2AF1, and SRSF2 splicing gene mutations in MDS without RS were relatively low. We also demonstrated that the U2AF1 and SRSF2 mutations were associated with an unfavorable prognostic impact in MDS patients without RS.
Hypocellular myelodysplastic syndrome with myelofibrosis in acute myeloid leukemia transformation: A case report.
Song Kui,Xu Xiaojun,Li Min
Primary myelodysplastic syndrome (MDS) with myelofibrosis is a rare hematological disorder that should be classified as a distinct subgroup of MDS. Treatment of MDS with myelofibrosis remains problematic and the prognosis is poor in these patients, particularly following transformation into acute myeloid leukemia (AML). The current study presents the case of a 28-year-old male diagnosed with MDS associated with myelofibrosis, together with hypocellular bone marrow features. Following induction chemotherapy consisting of mitoxantrone and cytarabine, the patient achieved complete remission, but developed severe myelofibrosis. The patient relapsed and the disease transformed into AML 12 months later. However, the extent of the myelofibrosis was markedly alleviated upon administration of a FLAG regimen that consisted of fludarabine, cytarabine and granulocyte colony-stimulating factor during the AML transformation. After one course of the FLAG regimen, the patient achieved a second complete remission. As there was no suitable donor for hematopoietic stem cell transplantation (HSCT), the patient relapsed and succumbed shortly after. In conclusion, MDS with fibrosis is an aggressive disease, but the degree of myelofibrosis may not be associated with the progression of hypocellular MDS, and allogeneic HSCT remains a potentially curative option for affected patients.
Updated recommendations on the management of gastrointestinal disturbances during iron chelation therapy with Deferasirox in transfusion dependent patients with myelodysplastic syndrome - Emphasis on optimized dosing schedules and new formulations.
Nolte Florian,Angelucci Emanuele,Breccia Massimo,Gattermann Norbert,Santini Valeria,Vey Norbert,Hofmann Wolf-Karsten
Myelodysplastic syndromes (MDS) are oligoclonal hematopoietic disorders characterized by peripheral cytopenias with anemias being the most prevalent feature. The majority of patients will depend on regular transfusions of packed red blood cells (PRBC) during the course of the disease. Particularly patients with MDS and low risk for transformation into acute myeloid leukemia and low risk of early death will receive PRBC transfusions on a regular basis, which puts them at high risk for transfusional iron overload. Transfusion dependence has been associated with negative impact on organ function and reduced life expectancy. Recently, several retrospective but also some prospective studies have indicated, that transfusion dependent patients with MDS might benefit from consequent iron chelation with regard to morbidity and mortality. However, low treatment adherence due to adverse events mainly gastrointestinal in nature is an important obstacle in achieving sufficient iron chelation in MDS patients. Here, we will summarize and discuss the existing data on Deferasirox in low risk MDS published so far and provide recommendations for optimal management of gastrointestinal adverse events during iron chelation aiming at improving treatment compliance and, hence, sufficiently removing excess iron from the patients.
Validation of the Lower-Risk MD Anderson Prognostic Scoring System for Patients With Myelodysplastic Syndrome.
Komrokji Rami,Ramadan Hanadi,Al Ali Najla,Corrales-Yepez Maria,Zhang Ling,Padron Eric,Lancet Jeffrey,List Alan
Clinical lymphoma, myeloma & leukemia
The International Prognostic Scoring System (IPSS) is the most widely used tool for risk assessment and treatment decisions for myelodysplastic syndrome (MDS). Several new models have been proposed to identify a subset of lower-risk patients with MDS who are experiencing inferior than expected outcomes. We validated the Lower-Risk MD Anderson Risk Model (LR-MDAS) in 1288 lower-risk patients with MDS by the IPSS. On the basis of the LR-MDAS, 228 patients (17%) were in category 1, 730 patients (57%) were in category 2, 315 patients (25%) were in category 3, and 15 patients (1%) were in an unknown category. The median overall survival for the corresponding LR-MDAS categories was (1) 109 months (95% confidence interval [CI], 82-137), (2) 56 months (95% CI, 58-73), and (3) 29 months (95% CI, 24-35) (P < .005). Overall, 25% of patients were upstaged to category 3. LR-MDAS refined prognostic value among very low-, low-, and intermediate-risk Revised IPSS. The rate of acute myeloid leukemia transformation according to LR-MDAS was 15%, 18%, and 29% for categories 1, 2, and 3, respectively (P < .005). Our data validate the prognostic value of the LR-MDAS model, but the utility of it as a treatment decision tool should be studied prospectively.
Inflammation-related genes S100s, RNASE3, and CYBB and risk of leukemic transformation in patients with myelodysplastic syndrome with myelofibrosis.
Hong Minghua,Wu Junqing,Ma Lifeng,Han Xiaoping,Lu Ting,Wang Zhaoming,Zhao Jing,Liu Lizhen,Fu Huarui,Huang Weijia,Zheng Weiyan,He Jingsong,Wei Guoqing,Wang Huanping,Chen Zhimei,Huang He,Cai Zhen,Guo Guoji,Sun Jie
Myelodysplastic syndrome with myelofibrosis (MDS-MF) has been associated with an inferior prognosis compared with MDS without MF. However, MDS-MF is not listed independently as a subtype of MDS, and its clinical and genetic characteristics remain poorly understood. We retrospectively compared 53 patients with MDS-MF (44 MF grade 1/MF; 9 MF grade 2-3/MF) and 31 with de novo MDS without MF (MDS). The leukemic transformation risks of both MDS-MF and MDS-MF were increased compared with the MDS group. To identify the potential mechanisms responsible for the leukemic transformation of MDS-MF, we performed single-cell sequencing for one MDS-MF patient before and after leukemic transformation to explore the variations in gene expression levels. In addition to upgraded expression levels of acute myeloid leukemia-related genes during leukemic transformation, expression levels of some inflammation-related genes (such as S100s, RNASE3, and CYBB) were also increased, and inflammation-related pathways were up-regulated. These results suggest that inflammation-related genes and pathways may play an important role in the leukemic transformation of MDS-MF.
The incidence, risk factors, and survival of acute myeloid leukemia secondary to myelodysplastic syndrome: A population-based study.
Ye Xingnong,Chen Dan,Zheng Yan,Wu Cai,Zhu Xiaoqiong,Huang Jian
To determine the incidence, risk factors, and relative survival of acute myeloid leukemia (AML) secondary to myelodysplastic syndrome (MDS) in the Surveillance, Epidemiology, and End Results (SEER) database. Retrospective analysis of all patients with new MDS onset in the SEER-18 database from 2001 to 2013. We identified 36 558 patients with primary MDS. The rate of secondary AML (sAML) was 3.7% among patients 40 years or younger and 2.5% among those older than 40 (P = .039). The median transformation interval was significantly shorter for the younger group (4.04 vs 13.1 mo; P < .001). For both age groups, median overall and cancer-specific survival were significantly longer for patients who did not develop sAML. Although the younger patients survived longer than the older patients, sAML development had a more negative effect on the survival of younger patients. Female sex, age, and World Health Organization (WHO) type MDS with single lineage dysplasia (MDS-SLD) were associated with a decreased risk of sAML for older but not younger patients. Among older patients with MDS, a married status, Black race, female sex, shorter time to sAML, and WHO type MDS-SLD or MDS with ringed sideroblasts were favorable prognostic factors for survival. In the SEER database, the rate of sAML among patients with MDS is lower than that in previous reports, but these patients still have worse survival. Risk assessment should include clinical and demographic factors.
The Effects of Human BDH2 on the Cell Cycle, Differentiation, and Apoptosis and Associations with Leukemia Transformation in Myelodysplastic Syndrome.
Yang Wen-Chi,Lin Sheng-Fung,Wang Shu-Chen,Tsai Wan-Chi,Wu Chun-Chieh,Wu Shih-Chi
International journal of molecular sciences
Iron overload is related to leukemia transformation in myelodysplastic syndrome (MDS) patients. Siderophores help to transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. Using qRT-PCR, we analyze mRNA expression in the bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients with normal BM. Elevated mRNA expression in BM is observed in MDS patients ( = 187 vs. 43, normal BM; = 0.009), and this is related to ferritin levels. Patients with higher expression show a greater risk of leukemia progression (15.25% vs. 3.77%, lower expression; = 0.017) and shorter leukemia-free-survival (medium LFS, 9 years vs. 7 years; = 0.024), as do patients with a ferritin level ≥350 ng/mL. Additionally, we investigate the mechanisms related to the prognostic ability of BDH2 by using BDH2-KD THP1. The cell cycle analysis, surface markers, and special stain studies indicate that BDH2-KD induces differentiation and decreases the growth rate of THP1 cells, which is associated with the retardation of the cell cycle. Moreover, many genes, including genes related to mitochondrial catabolism, oncogenes, tumor suppressor genes, and genes related to cell differentiation and proliferation influence BDH2-KD THP1 cells. Herein, we demonstrate that BDH2 is involved in cell cycle arrest and the inhibition of differentiation in malignant cells. Furthermore, the high BDH2 expression in MDS patients could be suggestive of a poor prognostic factor. This study provides a foundation for further research on the roles of BDH2 and iron metabolism in the pathogenesis of MDS.
Characterization of myelodysplastic syndromes progressing to acute lymphoblastic leukemia.
Martins Filipe,Kruszewski Michael,Scarpelli Ilaria,Schoumans Jacqueline,Spertini Olivier,Lübbert Michael,Blum Sabine
Annals of hematology
Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases, with a variable probability of transformation into acute leukemia, which is, in the vast majority of cases, of myeloid lineage. Nevertheless, rare cases of acute lymphoblastic leukemia in patients with previously diagnosed MDS have been reported. We describe a series of 3 cases of MDS/CMML marked with evolution to acute lymphoblastic leukemia (ALL) and provide a comprehensive review of the 49 cases documented in the literature so far. These sporadic events have only been published as single-case reports or small series to date. Such atypical cases emphasize the possibility of major phenotypic switches arising at the leukemic stem cell (LSC) and/or early progenitor levels, as a consequence of epigenetic and genomic events driving these changes in the bone marrow niche.
Incorporation of somatic panels for the detection of haematopoietic transformation in children and young adults with leukaemia predisposition syndromes and with acquired cytopenias.
Noy-Lotan Sharon,Krasnov Tanya,Dgany Orly,Jeison Marta,Yanir Asaf D,Gilad Oded,Toledano Helen,Barzilai-Birenboim Shlomit,Yacobovich Joanne,Izraeli Shai,Tamary Hannah,Steinberg-Shemer Orna
British journal of haematology
Detection of somatic mutations may help verify the diagnosis of myelodysplastic syndrome (MDS) in patients with persistent cytopenias or with MDS-predisposition syndromes, prior to the development of overt leukemia. However, the spectrum and consequences of acquired changes in paediatric patients have not been fully evaluated, and especially not in the context of an underlying syndrome. We incorporated a targeted next-generation-sequencing panel of 54 genes for the detection of somatic mutations in paediatric and young adult patients with inherited or acquired cytopenias. Sixty-five patients were included in this study, of whom 17 (26%) had somatic mutations. We detected somatic mutations in 20% of individuals with inherited MDS-predisposition syndromes, including in patients with severe congenital neutropenia and Fanconi anaemia, and with germline mutations in SAMD9L. Thirty-eight per cent of children with acquired cytopenias and suspected MDS had somatic changes, most commonly in genes related to signal transduction and transcription. Molecularly abnormal clones often preceded cytogenetic changes. Thus, routine performance of somatic panels can establish the diagnosis of MDS and determine the optimal timing of haematopoietic stem cell transplantation, prior to the development of leukaemia. In addition, performing somatic panels in patients with inherited MDS-predisposition syndromes may reveal their unique spectrum of acquired mutations.
Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level.
Myelodysplastic syndromes (MDS) frequently progress to acute myeloid leukemia (AML); however, the cells leading to malignant transformation have not been directly elucidated. As progression of MDS to AML in humans provides a biological system to determine the cellular origins and mechanisms of neoplastic transformation, we studied highly fractionated stem cell populations in longitudinal samples of patients with MDS who progressed to AML. Targeted deep sequencing combined with single-cell sequencing of sorted cell populations revealed that stem cells at the MDS stage, including immunophenotypically and functionally defined pre-MDS stem cells (pre-MDS-SC), had a significantly higher subclonal complexity compared to blast cells and contained a large number of aging-related variants. Single-cell targeted resequencing of highly fractionated stem cells revealed a pattern of nonlinear, parallel clonal evolution, with distinct subclones within pre-MDS-SC and MDS-SC contributing to generation of MDS blasts or progression to AML, respectively. Furthermore, phenotypically aberrant stem cell clones expanded during transformation and stem cell subclones that were not detectable in MDS blasts became dominant upon AML progression. These results reveal a crucial role of diverse stem cell compartments during MDS progression to AML and have implications for current bulk cell-focused precision oncology approaches, both in MDS and possibly other cancers that evolve from premalignant conditions, that may miss pre-existing rare aberrant stem cells that drive disease progression and leukemic transformation.
Higher-risk myelodysplastic syndromes with del(5q): does the del(5q) matter?
Gorshein Elan,Weber Urs M,Gore Steven
Expert review of hematology
: Myelodysplastic Syndrome (MDS) represents a group of cancers characterized by abnormal blood cell formation and maturation, leading to various degrees of cytopenias and potential transformation to acute myeloid leukemia. Deletion of the long arm of chromosome 5 (del(5q)) is the most common clonal chromosomal anomaly in MDS, yet the population in this disease subtype is quite heterogeneous. This manuscript analyzes literature on high-risk MDS with del(5q) abnormalities.: The paper will review outcomes with lenalidomide among high-risk MDS patients with del(5q). It will discuss the implications of harboring gene mutations, and share the data for allogeneic hematopoietic stem cell transplantations in this setting. Finally, the report evaluates the risk of disease progression in these patients.: Improved characterization of MDS has enhanced our understanding of patients with anomalies involving del(5q). Emerging literature is exploring combination therapy beyond lenalidomide, and next-generation sequencing may identify secondary mutations that could be an additional avenue for treatment.
Myelodysplastic syndrome transformed into B-lineage acute lymphoblastic leukemia: A case report.
Zhu Ye-Jing,Ma Xiang-Yu,Hao Yun-Liang,Guan Yun
World journal of clinical cases
BACKGROUND:Myelodysplastic syndromes (MDSs) are a group of hematological diseases caused by expansion of an abnormal clone of hematopoietic stem cells. Primary MDS is a potentially premalignant clonal disorder that may progress to overt acute leukemia in 25%-50% of cases. However, most of these cases evolve into acute myeloid leukemia and rarely progress to acute lymphoblastic leukemia (ALL). Thus, transformation of MDS into B-cell ALL is rare. CASE SUMMARY:A 58-year-old man was admitted to the hospital for reduced blood cell counts. Based on all the test results and the World Health Organization diagnosis and classification, the patient was finally diagnosed with ring-shaped sideroblastic MDS with refractory hemocytopenia due to multilineage dysplasia. We used red blood cell transfusions and other symptomatic support treatments. After 4 years, the patient felt dizziness, fatigue, and night sweats. We improved bone marrow and peripheral blood and other related auxiliary examinations. He was eventually diagnosed with B-lineage acute lymphocytic leukemia (MDS transformation). CONCLUSION:The number of peripheral blood cells, type of MDS, proportion of primitive cells in bone marrow, and number and quality of karyotypes are all closely related to the conversion of MDS to ALL.
Myelodysplastic syndrome transforming to atypical chronic myeloid leukemia shows changes in its mutation allele frequency and acquisition of new mutations.
Leukemia research reports
Although acute transformation to acute myeloid leukemia represents a well-established form of disease progression in myelodysplastic syndromes (MDS), the progressive development of proliferative features with a phenotypic shift to a myelodysplastic/myeloproliferative neoplasm such as chronic myelomonocytic leukemia developing from a prior MDS has also been observed. However, transition from a MDS to an atypical chronic myeloid leukemia negative (aCML) is exceptionally rare. Herewith we report one such case, describing its clinical, morphologic and molecular correlates. The observed molecular progression which paralleled the phenotypic shift, partially elucidates the pathogenetic mechanisms involved in this rare type of disease progression.
Tumor genetic alterations and features of the immune microenvironment drive myelodysplastic syndrome escape and progression.
Montes Paola,Bernal Mónica,Campo Laura N,González-Ramírez Amanda Rocío,Jiménez Pilar,Garrido Pilar,Jurado Manuel,Garrido Federico,Ruiz-Cabello Francisco,Hernández Francisca
Cancer immunology, immunotherapy : CII
The transformation and progression of myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML) involve genetic, epigenetic, and microenvironmental factors. Driver mutations have emerged as valuable markers for defining risk groups and as candidates for targeted treatment approaches in MDS. It is also evident that the risk of transformation to sAML is increased by evasion of adaptive immune surveillance. This study was designed to explore the immune microenvironment, immunogenic tumor-intrinsic mechanisms (HLA and PD-L1 expression), and tumor genetic features (somatic mutations and altered karyotypes) in MDS patients and to determine their influence on the progression of the disease. We detected major alterations of the immune microenvironment in MDS patients, with a reduced count of CD4 T cells, a more frequent presence of markers related to T cell exhaustion, a more frequent presence of myeloid-derived suppressor cells (MDSCs), and changes in the functional phenotype of NK cells. HLA Class I (HLA-I) expression was normally expressed in CD34 blasts and during myeloid differentiation. Only two out of thirty-six patients with homozygosity for HLA-C groups acquired complete copy-neutral loss of heterozygosity in the HLA region. PD-L1 expression on the leukemic clone was also increased in MDS patients. Finally, no interplay was observed between the anti-tumor immune microenvironment and mutational genomic features. In summary, extrinsic and intrinsic immunological factors might severely impair immune surveillance and contribute to clonal immune escape. Genomic alterations appear to make an independent contribution to the clonal evolution and progression of MDS.
Secondary myelodysplastic syndrome and leukemia in acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria.
Sun Lova,Babushok Daria V
Acquired aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are pathogenically related nonmalignant bone marrow failure disorders linked to T-cell-mediated autoimmunity; they are associated with an increased risk of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Approximately 15% to 20% of AA patients and 2% to 6% of PNH patients go on to develop secondary MDS/AML by 10 years of follow-up. Factors determining an individual patient's risk of malignant transformation remain poorly defined. Recent studies identified nearly ubiquitous clonal hematopoiesis (CH) in AA patients. Similarly, CH with additional, non-PIGA, somatic alterations occurs in the majority of patients with PNH. Factors associated with progression to secondary MDS/AML include longer duration of disease, increased telomere attrition, presence of adverse prognostic mutations, and multiple mutations, particularly when occurring early in the disease course and at a high allelic burden. Here, we will review the prevalence and characteristics of somatic alterations in AA and PNH and will explore their prognostic significance and mechanisms of clonal selection. We will then discuss the available data on post-AA and post-PNH progression to secondary MDS/AML and provide practical guidance for approaching patients with PNH and AA who have CH.
c.9253-6T>c REV3L: A novel marker of poor prognosis in Myelodysplastic syndrome.
Oliveira Roberta Taiane G de,França Ivo Gabriel F,Junior Howard L R,Riello Giovanna B C,Borges Daniela de Paula,Cavalcante Gabrielle Melo,Magalhães Silvia M M,Pinheiro Ronald F
Hematology, transfusion and cell therapy
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by dysplasias, ineffective hematopoiesis and risk of acute myeloid leukemia transformation. Approximately 90% of MDS patients present mutations in genes involved in various cell signaling pathways. Specialized DNA polymerases, such as POLN, POLI, POLK, POLQ, POLH, POLL and REV3L, insert a nucleotide opposite replication-blocking DNA lesions in an error-prone manner and, in this way, sometimes can actively promote the generation of mutation. For the best of our knowledge, has not been described the mutations of these genes in MDS. DNA target sequencing CDS regions of the REV3L gene was performed in a 58-year-old man diagnosed as High Risk Myelodysplastic Syndrome. The patient presented very low hemoglobin, increased number of blasts, karyotype:47,XY,+8/47,XY,del(7)(q32),+8, no response to hypomethylating therapy (decitabine), all markers of poor prognosis. Target sequencing identified a mutation c.9253-6T>C REV3L (Substitution - intronic) with VAF (variant allele frequency)=16% considered pathogenic according to Functional Analysis through. Hidden Markov Models (FATHMM). This is the first evidence of REV3L mutation in MDS and, of utmost importance, associated with poor prognosis.
FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome.
Schieber Michael,Marinaccio Christian,Bolanos Lyndsey C,Haffey Wendy D,Greis Kenneth D,Starczynowski Daniel T,Crispino John D
Blood cancer journal
Myelodysplastic syndrome (MDS) is a heterogeneous myeloid malignancy characterized by blood cell morphological dysplasia, ineffective clonal hematopoiesis, and risk of transformation to secondary acute myeloid leukemia (sAML). A number of genetic abnormalities have been identified in MDS and sAML, but sensitive sequencing methods can detect these mutations in nearly all healthy individuals by 60 years of age. To discover novel cellular pathways that accelerate MDS and sAML, we performed a CRISPR/Cas9 screen in the human MDS-L cell line. We report here that loss of the F-Box protein FBXO11, a component of the SCF ubiquitin ligase complex, confers cytokine independent growth to MDS-L cells, suggesting a tumor suppressor role for FBXO11 in myeloid malignancies. Putative FBXO11 substrates are enriched for proteins with functions in RNA metabolism and, of note, spliceosome mutations that are commonly found in MDS/sAML are rare in patients with low FBXO11 expression. We also reveal that loss of FBXO11 leads to significant changes in transcriptional pathways influencing leukocyte proliferation, differentiation, and apoptosis. Last, we find that FBXO11 expression is reduced in patients with secondary AML. We conclude that loss of FBXO11 is a mechanism for disease transformation of MDS into AML, and may represent a future therapeutic target.
Clinical outcome of patients diagnosed with myelodysplastic syndrome-unclassifiable (MDS-U): single center experience.
Baidoun Firas,Chen Dong,Patnaik Mrinal,Gangat Naseema,Begna Kebede,Elliott Michelle,Hogan William,Litzow Mark,Al-Kali Aref
Leukemia & lymphoma
Myelodysplastic syndrome unclassifiable (MDS-U) is a small subtype of myelodysplastic syndromes (MDS). However, rare literature exists in terms of natural progression and clinical outcome of patients with MDS-U. In the present study, we investigated the characteristics and the clinical outcomes of patients categorized as MDS-U based on 2008 World Health Organization criteria (WHO) in a single center comparing to other MDS groups. Out of eight hundred and two patients who met WHO criteria for MDS at our institution, ninety patients (11%) were initially classified as MDS-U. Upon pathological review, only half of the cases were confirmed to be MDS-U. With follow up, half of the MDS-U cases were reclassified to another subtype. We found neither significant difference in median overall survival nor in risk of transformation to acute myeloid leukemia when comparing MDS-U to other MDS groups. Additional larger studies are needed to confirm our results.
Disease characteristics and prognosis of myelodysplastic syndrome presenting with isolated thrombocytopenia.
Waisbren Julie,Dinner Shira,Altman Jessica,Frankfurt Olga,Helenowski Irena,Gao Juehua,McMahon Brandon J,Stein Brady L
International journal of hematology
Patients with myelodysplastic syndrome (MDS) who present with isolated thrombocytopenia (TCP) constitute a poorly described subgroup. The aim of the present study was to retrospectively evaluate disease characteristics and prognosis in patients with MDS and isolated TCP at a tertiary care center. Fifty patients (12 %) had isolated thrombocytopenia as the first presentation of MDS. Patients had varying MDS sub-classifications and cytogenetic profiles. The most common IPSS-R risk score was low (n = 24), although half of the patients had either IPSS-R intermediate (n = 18), high or very high risk disease (n = 7). Leukemic transformation occurred in 10 patients and there were 14 deaths (28 %) amongst all IPSS-R risk scores. Therapeutic agents used in this patient subgroup included hypomethylating agents and thrombopoietin receptor agonists. Overall, MDS with isolated TCP did not appear to have an inherently indolent course, as has been suggested previously. Future studies are needed to improve risk stratification, identify relevant contributors to disease pathogenesis, and better define treatment modalities.
Does the platelet‑to‑lymphocyte ratio have a prognostic effect in patients with myelodysplastic syndrome?
Yikilmaz A S,Akinci S,Bakanay S M,Dilek I
Bratislavske lekarske listy
INTRODUCTION:Myelodysplastic syndromes (MDS) include various hematologic abnormalities characterized by chronic cytopenia due to disruption in cellular differentiation. This study aims to evaluate the prognostic value of PLR in patients with MDS. MATERIAL AND METHODS:Clinical-laboratory findings and the results of bone marrow biopsies of MDS patients before treatment were recorded. p value of <0.05 was considered statistically significant. SPSS version 20.0 was used for statistical analysis. RESULTS:The study included 62 patients with median follow-up time of 62.8±4.5 months and median age of 68.5 years. In 13 patients, acute leukemia was transformed. In these subjects, a PLR cut-off level of 46 was established for mortality (p=0.015). We found a significant relationship between PLR and multilineage series with the presence of dysplasia (p=0.017). The survival analysis showed a decreased survival in cases with dysplasia in two and/or more series, transformation into acute leukemia, and thrombocytopenia. CONCLUSION:Our study demonstrated that there was a relationship between PLR and MDS with multilineage dysplasia (mld-MDS). PLR is investigated as an inflammatory finding in various hematologic malignancies. Further studies investigating the value of PLR in MDS are needed to determine whether PLR may be a marker of bone marrow dysplasia grading (Tab. 2, Fig. 4, Ref. 32).
Immunosuppressive Therapy: Exploring an Underutilized Treatment Option for Myelodysplastic Syndrome.
Haider Mintallah,Al Ali Najla,Padron Eric,Epling-Burnette Pearlie,Lancet Jeffrey,List Alan,Komrokji Rami
Clinical lymphoma, myeloma & leukemia
BACKGROUND:Immunosuppressive therapy (IST) in low risk myelodysplastic syndrome (MDS) is known to achieve hematologic improvement but remains an underutilized treatment option. We report our experience using antithymocyte globulin (ATG) and cyclosporine A (CSA) to explore clinical predictive response factors. PATIENTS AND METHODS:Patients treated with IST identified in the Moffitt Cancer Center MDS database were analyzed using baseline data, IST details, and response rates. RESULTS:Sixty-six patients treated with IST were identified. The median age was 61 years; the majority were at low risk and had a good karyotype. The median time to start IST was 1 year. All patients received ATG, 60% rabbit (r-ATG), 32% equine ATG (e-ATG), and 60% received CSA. Overall hematologic improvement was 42% with a trend favoring e-ATG over r-ATG (52% vs. 39%; P = .09). Erythroid improvement was evaluated in 30 patients, and 60% responded; neutrophil improvement was evaluated in 15, and 39% responded; platelet improvement was evaluated in 18, and 57% responded. Six of 18 pancytopenic patients experienced trilineage response. Mean time from ATG to next therapy was 12 months. None of the patients with very high risk or high risk revised International Prognostic Scoring System (IPSS-R) responded. Poor karyotype had a lower response rate, 25%, compared to 41% for intermediate and 44% for good karyotype. No difference in predicting response was found based on the National Institutes of Health Response Model; 38% with low and 45% with high probability responded. A trend favored treatment within 2 years from diagnosis, with 46% responding compared to 33% treated after 2 years. First-line ATG or after lenalidomide responded better than after azacitidine or third-line therapy. CSA provided an advantage: the disease of 51% responded compared to 27% with ATG alone (P = .05). Ten patients experienced transformation to acute myeloid leukemia, 7% with disease that responded to therapy and 24% with disease that did not respond to therapy (P = .08). Overall survival was 67.2 months without difference between those with and without response. Adverse events were reported in 55 patients. Infusion reactions occurred in 85% but was similar between ATG types. Infection rate was 25% and higher with e-ATG. Serum sickness was reported in 18% and significantly higher with r-ATG. CONCLUSION:IST has a hematologic improvement response rate in the range of other therapies approved for lower risk MDS. High risk IPSS-R, poor karyotype, and treatment after 2 years from diagnosis have unfavorable response trend. ATG with CSA has higher response than ATG alone. First-line ATG or after lenalidomide had better response trend compared to third-line therapy or azacitidine therapy.
Myelodysplastic Syndromes in Adolescent Young Adults: One Institution's Experience.
Grabska Joanna,Shah Bijal,Reed Damon,Al Ali Najla,Padron Eric,Ramadan Hanadi,Lancet Jeffrey,List Alan,Komrokji Rami
Clinical lymphoma, myeloma & leukemia
INTRODUCTION:There has been little improvement in cancer survival of adolescent and young adult (AYA) patients, aged 18 to 39 years, possibly reflecting different disease biology. Myelodysplastic syndrome (MDS) is mainly a disease of the elderly. The characteristics, outcomes, and response to treatment are not well described in the AYA population. PATIENTS AND METHODS:This was a retrospective review of patients from the Moffitt Cancer Center MDS database. We compared baseline characteristics and outcomes of the AYA population to older patients. We identified 51 AYA and 1897 older MDS patients. More female subjects and Hispanics were noted in AYA group. RESULTS:The AYA patients had higher risk disease, more circulating myeloblasts, and more hypoplastic MDS. Autoimmune disorders were more prevalent in older patients. The median overall survival (OS) was 47 months in the AYA group versus 40 months in the older group (P = .26). The median OS was 47 versus 56 months in lower risk AYA group and older group, respectively (P = .46). In the higher risk group, median OS was 82 months in the AYA group compared to 17 months in the older group (P = .001). Thirty individuals (59%) underwent allogeneic stem-cell transplantation in the AYA group versus 241 (13%) in the older group. The median OS for transplanted patients was 55 months in the AYA group and 46 months in the older group (P = .4). In the nontransplanted patients, median survival was 31 months for the AYA group and 39 months for the older group (P = .9). The rate of acute myeloid leukemia transformation was 37% versus 28% in the AYA and older groups, respectively (P = .17). No differences in use or response to hypomethylating agents were observed. Lenalidomide therapy was seldom used in AYA, as none presented with del5q. In AYA, poor karyotype was the only variable strongly associated with worse outcome. Fifteen patients had poor risk karyotypes (29%). The median OS was 47 months, not reached, and 29 months among patients with good, intermediate, and poor risk cytogenetics, respectively (P = .035). CONCLUSION:MDS is rare and tends to be more aggressive in the AYA population. Karyotype was the most important prognostic factor. Allogeneic stem-cell transplantation offered younger patients the best outcomes.
Acute Myeloid Leukemia with Basophilic Differentiation Transformed from Myelodysplastic Syndrome.
Tanaka Yasuhiro,Tanaka Atsushi,Hashimoto Akiko,Hayashi Kumiko,Shinzato Isaku
Case reports in hematology
Myelodysplastic syndrome (MDS) terminally transforms to acute myeloid leukemia (AML) or bone marrow failure syndrome, but acute myeloid leukemia with basophilic differentiation has been rarely reported. An 81-year-old man was referred to our department for further examination of intermittent fever and normocytic anemia during immunosuppressive treatment. Chromosomal analysis showed additional abnormalities involving chromosome 7. He was diagnosed as having MDS. At the time of diagnosis, basophils had not proliferated in the bone marrow. However, his anemia and thrombocytopenia rapidly worsened with the appearance of peripheral basophilia three months later. He was diagnosed as having AML with basophilic differentiation transformed from MDS. At that time, monosomy 7 was detected by chromosomal analysis. We found that basophils can be confirmed on the basis of the positivity for CD203c and CD294 by flow cytometric analysis. We also found by cytogenetic analysis that basophils were derived from myeloblasts. He refused any chemotherapy and became transfusion-dependent. He died nine months after the transformation. We should keep in mind that MDS could transform to AML with basophilic differentiation when peripheral basophilia in addition to myeloblasts develops in patients with MDS.
GPX3 methylation in bone marrow predicts adverse prognosis and leukemia transformation in myelodysplastic syndrome.
Zhou Jing-Dong,Lin Jiang,Zhang Ting-Juan,Ma Ji-Chun,Yang Lei,Wen Xiang-Mei,Guo Hong,Yang Jing,Deng Zhao-Qun,Qian Jun
Epigenetic inactivation of GPX3 has been identified in various cancers including leukemia. Moreover, aberrant DNA methylation was also found as a dominant mechanism of disease progression in myelodysplastic syndrome (MDS). This study intended to explore GPX3 promoter methylation and its clinical relevance in 110 patients with MDS. GPX3 methylation was examined by real-time quantitative methylation-specific PCR (RQ-MSP) and bisulfite sequencing PCR (BSP). GPX3 methylation was identified in 15% (17/110) MDS patients, and significantly higher than controls, and lower than acute myeloid leukemia (AML) patients (P = 0.024 and 0.041). GPX3 methylated patients had older age and higher frequency of DNMT3A mutation (P = 0.015 and 0.066). Cases with GPX3 methylation showed significantly shorter overall survival (OS) time than those with GPX3 unmethylation analyzed with Kaplan-Meier analysis (P = 0.012). Moreover, Cox regression analysis revealed that GPX3 methylation might act as an independent prognostic indicator in MDS (HR = 1.847, P = 0.072). GPX3 methylation density was significantly increased during the progression from MDS to secondary acute myeloid leukemia (sAML) in three follow-up paired patients. Our study concludes that GPX3 methylation in bone marrow is associated with adverse prognosis and leukemia transformation in MDS.
ASXL1 mutations in myeloid neoplasms: pathogenetic considerations, impact on clinical outcomes and survival.
Alvarez Argote Juliana,Dasanu Constantin A
Current medical research and opinion
BACKGROUND:ASXL1 gene mutations include nonsense, missense, and frameshift mutations. Although their clinical significance is still debated, they may play an important role in the pathogenesis of several hematologic malignancies. METHODS:Herein, we offer a comprehensive review on ASXL1 mutations, and link them with survival and clinical outcomes in patients with various myeloid neoplasms. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to February 2016. FINDINGS:In acute myeloid leukemia (AML), ASXL1 mutations tend to correlate with older age and male gender, and affect predominantly patients with secondary AML. De novo AML patients with ASXL1 mutations had significantly lower complete remission rates after standard high-dose chemotherapy and shorter survival. In chronic myelomonocytic leukemia and low- or intermediate-risk myelodysplastic syndromes, frameshift and nonsense mutations correlated with shorter survival and a higher risk of leukemic transformation. Overall survival was also shorter in primary myelofibrosis in the presence of ASXL1 mutations. CONCLUSIONS:Further research on the role of ASXL1 mutations and therapeutic implications in neoplastic myeloid disorders is stringently needed. Given the relatively high prevalence of ASXL1 mutations, larger studies involving patients affected by these mutations will be feasible in the near future.
Monosomy 7/del (7q) in inherited bone marrow failure syndromes: A systematic review.
Pezeshki Alex,Podder Shreya,Kamel Ralph,Corey Seth J
Pediatric blood & cancer
Inherited bone marrow failure syndromes (IBMFS) are rare cancer predisposition syndromes with an especially high risk of transformation to myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). We performed a retrospective systematic review of reported MDS/AML arising in the eight most common IBMFS to determine the frequency and outcome of chromosome 7 abnormalities. We identified 738 MDS/AML cases of 4,293 individuals. Monosomy 7 or del (7q) occurred in ∼17%. Greater understanding of the roles played by sequential acquisition of genetic and cytogenetic changes will provide insights into myeloid leukemogenesis and improve the surveillance and hopefully outcomes for individuals with IBMFS.
The prognostic value of circulating myeloblasts in patients with myelodysplastic syndromes.
Duong Vu H,Padron Eric,Al Ali Najla H,Lancet Jeffrey E,Hall Jeff,Kwok Brian,Zhang Ling,Epling-Burnette Pearlie K,List Alan F,Komrokji Rami S
Annals of hematology
The prognostic value of peripheral blasts (PB) is not well-studied in patients with myelodysplastic syndromes (MDS). We evaluated the impact of PB on overall survival (OS) and transformation to acute myeloid leukemia (AML) in a large cohort. The MDS database at the Moffitt Cancer Center was retrospectively reviewed to identify patients with ≥ 1% PB (PB-MDS) and those without PB (BM-MDS). We also assessed the correlation between PB and gene mutations. One thousand seven hundred fifty-eight patients were identified, among whom 13% had PB near the time of diagnosis. PB-MDS patients were more likely to be younger with trilineage cytopenia, complex karyotype, higher-risk disease, transfusion dependence, and therapy-related MDS. The rate of AML transformation was 49 vs. 26% (p < 0.005) and median OS was 16.5 vs. 45.8 months (p < 0.005) in the PB-MDS and BM-MDS groups, respectively. In Cox regression analysis, the presence of PB was an independent prognostic covariate for OS, HR 1.57 (95% CI 1.2-2). Among 51 patients with an available gene panel, the rate of ≥ 1 gene mutation in the PB-MDS group (n = 4) was 100% compared to 81% in the BM-MDS group (n = 47). The presence of PB in MDS is an adverse independent prognostic variable that refines prognostic discrimination.
[Myelodysplastic syndrome, acute leukemia and stem cell transplantation].
Schmalzing M,Aringer M,Bornhäuser M,Atta J
Zeitschrift fur Rheumatologie
Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders. They are characterized by inefficient hematopoiesis leading to peripheral cytopenia of one or more lineages and a variable risk of transformation into acute myeloid leukemia. They may either arise de novo as well as following exposition to environmental toxins, previous radiotherapy or chemotherapy or in the context of autoinflammatory diseases and related therapy. Characteristic cytogenetic abnormalities, along with the numbers of hematopoietic lineages affected and bone marrow blasts, enable an assessment of the risk of leukemic transformation. Acute leukemias are characterized by an accumulation of immature myeloid or lymphatic progenitor cells with limited differentiation capacity in the bone marrow. Proliferation of blast cells leads to suppression of normal hematopoiesis resulting in peripheral pancytopenia or leukocytosis associated with anemia and thrombocytopenia. Acute leukemias following MDS are defined as high-risk diseases. Intensive induction therapy followed by allogeneic stem cell transplantation is currently regarded as the only potentially curative treatment strategy. In this article the basic aspects of current diagnostics and treatment strategies for MDS and acute leukemia are outlined. Because of similarities with rheumatic inflammatory diseases, manifestations and treatment of graft versus host disease (GvHD) are also included.
Atypical chronic myeloid leukaemia: A case of an orphan disease-A multicenter report by the Polish Adult Leukemia Group.
Drozd-Sokołowska Joanna,Mądry Krzysztof,Waszczuk-Gajda Anna,Biecek Przemysław,Szwedyk Paweł,Budziszewska Katarzyna,Raźny Magdalena,Dutka Magdalena,Obara Agata,Wasilewska Ewa,Lewandowski Krzysztof,Piekarska Agnieszka,Bober Grażyna,Krzemień Helena,Stella-Hołowiecka Beata,Kapelko-Słowik Katarzyna,Sawicki Waldemar,Paszkowska-Kowalewska Małgorzata,Machowicz Rafał,Dwilewicz-Trojaczek Jadwiga
Atypical chronic myeloid leukaemia (aCML) belongs to myelodysplastic/myeloproliferative neoplasms. Because of its rarity and changing diagnostic criteria throughout subsequent classifications, data on aCML are very scarce. Therefore, we at the Polish Adult Leukemia Group performed a nationwide survey on aCML. Eleven biggest Polish centres participated in the study. Altogether, 45 patients were reported, among whom only 18 patients (40%) fulfilled diagnostic criteria. Among misdiagnosed patients, myelodysplastic/myeloproliferative syndrome unclassifiable and chronic myelomonocytic leukaemia were the most frequent diagnoses. Thirteen patients were male, median age 64.6 years (range 40.4-80.9). The median parameters at diagnosis were as follows: white blood cell count 97 × 10 /L (23.8-342) with immature progenitors amounting at 27.5% (12-72), haemoglobin 8.6 g/dL (3.9-14.9), and platelet count 66 × 10 /L (34-833). Cytoreductive treatment was used in all patients, and 2 patients underwent allogeneic hematopoietic stem cell transplantation. The median overall survival was 14.1 months (95% CI, 7.2), with median acute myeloid leukaemia-free survival of 13.3 months (95% CI, 3.6-22.6). Cumulative incidence of acute myeloid leukaemia transformation after 1 year in aCML group was 12.5% (95% CI, 0%-29.6%). To conclude, aCML harbours a poor prognosis. Treatment options are limited, with allogeneic hematopoietic stem cell transplantation being the only curative method at present, although only a minority of patients are transplant eligible. Educational measures are needed to improve the quality of diagnoses.