今日の臨床サポート

骨髄異形成症候群

著者: 宮﨑泰司 長崎大学病院血液内科

監修: 木崎昌弘 埼玉医科大学総合医療センター

著者校正/監修レビュー済:2021/03/03
参考ガイドライン:
  1. 日本血液学会:造血器腫瘍診療ガイドライン2018版追補版 第2版追補版(2020年)
  1. 厚生労働科学研究費補助金(難治性疾患政策研究事業)特発性造血障害に関する調査研究班:特発性造血障害疾患の診療の参照ガイド(令和元年度改訂版)
患者向け説明資料

概要・推奨   

  1. MDSの予後予測にはIPSSあるいはIPSS-Rを用いる(推奨度1)
  1. 同種造血幹細胞移植は高リスク例に対して実施する(推奨度2)
  1. 5番染色体長腕の欠失を伴う低リスクMDS(5q-症候群を含む)に対してはレナリドミドが赤血球造血回復作用を示す。特に赤血球輸血依存からも高率に脱却でき、一部の例では細胞遺伝学的反応性が得られる(推奨度1)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要とな
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
宮﨑泰司 : 講演料(アッヴィ合同会社,ノバルティスファーマ,大塚製薬,中外製薬,セルジーン,日本新薬,協和キリン,大日本住友,アステラス,シンバイオ),研究費・助成金など(大日本住友,中外製薬),奨学(奨励)寄付など(中外製薬)[2021年]
監修:木崎昌弘 : 講演料(ブリストル・マイヤーズスクイブ,ヤンセンファーマ,ノバルティスファーマ,セルジーン,MSD,小野薬品,武田薬品,大日本住友製薬),研究費・助成金など(武田薬品),奨学(奨励)寄付など(協和キリン,中外製薬,武田薬品,小野薬品,第一三共)[2021年]

改訂のポイント
  1. 造血器腫瘍診療ガイドライン2018版追補版 第2版追補版 に基づき確認を行った。

病態・疫学・診察

疾患情報  
  1. 骨髄異形成症候群の発症は年間10万人あたり3~6人程度とされているが、高齢者に多く、社会の高齢化とともに増加していると考えられる[1]
  1. 骨髄は過形成だが末梢では血球減少を呈する、いわゆる無効造血と血球の異形成、芽球の増加を特徴としている。
  1. 予後は症例によってさまざまであり、予後予測システムによって治療を選択することが多い。
  1. 輸血や感染対策といった支持療法を中心に、脱メチル化薬、レナリドミド、同種造血幹細胞移植によって治療されることが多い。必要に応じて、化学療法も実施される。確実に治癒をもたらすのは、同種移植のみである。
  1. 現在の診断、病型分類はWHO分類2017年改訂による[2]
問診・診察のポイント  
  1. 骨髄異形成症候群では、血球減少に関連した臨床症状を呈することがほとんどである。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: Guillermo Garcia-Manero
雑誌名: Am J Hematol. 2011 Jun;86(6):490-8. doi: 10.1002/ajh.22047.
Abstract/Text DISEASE OVERVIEW: The myelodysplastic (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older male and in individuals with prior exposure to cytotoxic therapy.
DIAGNOSIS: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry, or molecular genetics is complementary but not diagnostic. RISK-STRATIFICATION: Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow, and cytogenetic characteristics. The most commonly used system is the International Prognostic Scoring System. This score divides patients into a lower risk subset (low and intermediate-1) and a higher risk subset (int-2 and high). Other more modern systems have been developed that allow more precise risk calculation.
RISK-ADAPTED THERAPY: Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts and more recently cytogenetic profile. Goals of therapy are different in lower risk patients than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML. In higher risk, the goal is to prolong survival. Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy, and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia, and a chromosome 5 alteration. 5-azacitidine and decitabine have activity in higher risk MDS. 5-azacitidine has been shown to improve survival in higher risk MDS. Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation.
MANAGEMENT OF PROGRESSIVE OR REFRACTORY DISEASE: At the present time, there are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include cytarabine-based therapy, transplantation, and participation on a clinical trial.

Copyright © 2011 Wiley-Liss, Inc.
PMID 21594886  Am J Hematol. 2011 Jun;86(6):490-8. doi: 10.1002/ajh.22・・・
著者: Daniel A Arber, Attilio Orazi, Robert Hasserjian, Jürgen Thiele, Michael J Borowitz, Michelle M Le Beau, Clara D Bloomfield, Mario Cazzola, James W Vardiman
雑誌名: Blood. 2016 May 19;127(20):2391-405. doi: 10.1182/blood-2016-03-643544. Epub 2016 Apr 11.
Abstract/Text The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists, and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition. The major changes in the classification and their rationale are presented here.

© 2016 by The American Society of Hematology.
PMID 27069254  Blood. 2016 May 19;127(20):2391-405. doi: 10.1182/blood・・・
著者: Peter Valent, Hans-Peter Horny, John M Bennett, Christa Fonatsch, Ulrich Germing, Peter Greenberg, Torsten Haferlach, Detlef Haase, Hans-Jochen Kolb, Otto Krieger, Michael Loken, Arjan van de Loosdrecht, Kiyoyuki Ogata, Alberto Orfao, Michael Pfeilstöcker, Björn Rüter, Wolfgang R Sperr, Reinhard Stauder, Denise A Wells
雑誌名: Leuk Res. 2007 Jun;31(6):727-36. doi: 10.1016/j.leukres.2006.11.009. Epub 2007 Jan 25.
Abstract/Text The classification, scoring systems, and response criteria for myelodysplastic syndromes (MDS) have recently been updated and have become widely accepted. In addition, several new effective targeted drugs for patients with MDS have been developed. The current article provides a summary of updated and newly proposed markers, criteria, and standards in MDS, with special reference to the diagnostic interface and refinements in evaluations and scoring. Concerning the diagnostic interface, minimal diagnostic criteria for MDS are proposed, and for patients with unexplained cytopenia who do not fulfill these criteria, the term 'idiopathic cytopenia of uncertain significance' (ICUS) is suggested. In addition, new diagnostic and prognostic parameters, histopathologic and immunologic determinants, proposed refinements in scoring systems, and new therapeutic approaches are discussed. Respective algorithms and recommendations should facilitate diagnostic and prognostic evaluations in MDS, selection of patients for therapies, and the conduct of clinical trials.

PMID 17257673  Leuk Res. 2007 Jun;31(6):727-36. doi: 10.1016/j.leukres・・・
著者: Pierre Fenaux, Ghulam J Mufti, Eva Hellstrom-Lindberg, Valeria Santini, Carlo Finelli, Aristoteles Giagounidis, Robert Schoch, Norbert Gattermann, Guillermo Sanz, Alan List, Steven D Gore, John F Seymour, John M Bennett, John Byrd, Jay Backstrom, Linda Zimmerman, David McKenzie, Cl Beach, Lewis R Silverman, International Vidaza High-Risk MDS Survival Study Group
雑誌名: Lancet Oncol. 2009 Mar;10(3):223-32. doi: 10.1016/S1470-2045(09)70003-8. Epub 2009 Feb 21.
Abstract/Text BACKGROUND: Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens.
METHODS: In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799.
FINDINGS: Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments.
INTERPRETATION: Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.

PMID 19230772  Lancet Oncol. 2009 Mar;10(3):223-32. doi: 10.1016/S1470・・・
著者: Luca Malcovati, Ulrich Germing, Andrea Kuendgen, Matteo G Della Porta, Cristiana Pascutto, Rosangela Invernizzi, Aristoteles Giagounidis, Barbara Hildebrandt, Paolo Bernasconi, Sabine Knipp, Corinna Strupp, Mario Lazzarino, Carlo Aul, Mario Cazzola
雑誌名: J Clin Oncol. 2007 Aug 10;25(23):3503-10. doi: 10.1200/JCO.2006.08.5696.
Abstract/Text PURPOSE: The aims of this study were to identify the most significant prognostic factors in myelodysplastic syndromes (MDS) taking into account both their values at clinical onset and their changes in time and to develop a dynamic model for predicting survival and leukemic evolution that can be applied at any time during the course of the disease.
PATIENTS AND METHODS: We studied a learning cohort of 426 MDS patients diagnosed at the Department of Hematology, San Matteo Hospital, Pavia, Italy, between 1992 and 2004, and a validation cohort of 739 patients diagnosed at the Heinrich-Heine-University Hospital, Düsseldorf, Germany, between 1982 and 2003. All patients were reclassified according to WHO criteria. Univariable and multivariable analyses were performed using Cox models with time-dependent covariates.
RESULTS: The most important variables for the prognostic model were WHO subgroups, karyotype, and transfusion requirement. We defined a WHO classification-based prognostic scoring system (WPSS) that was able to classify patients into five risk groups showing different survivals (median survival from 12 to 103 months) and probabilities of leukemic evolution (P < .001). WPSS was shown to predict survival and leukemia progression at any time during follow-up (P < .001), and its prognostic value was confirmed in the validation cohort.
CONCLUSION: WPSS is a dynamic prognostic scoring system that provides an accurate prediction of survival and risk of leukemic evolution in MDS patients at any time during the course of their disease. This time-dependent system seems particularly useful in lower risk patients and may be used for implementing risk-adapted treatment strategies.

PMID 17687155  J Clin Oncol. 2007 Aug 10;25(23):3503-10. doi: 10.1200/・・・
著者: Peter L Greenberg, Heinz Tuechler, Julie Schanz, Guillermo Sanz, Guillermo Garcia-Manero, Francesc Solé, John M Bennett, David Bowen, Pierre Fenaux, Francois Dreyfus, Hagop Kantarjian, Andrea Kuendgen, Alessandro Levis, Luca Malcovati, Mario Cazzola, Jaroslav Cermak, Christa Fonatsch, Michelle M Le Beau, Marilyn L Slovak, Otto Krieger, Michael Luebbert, Jaroslaw Maciejewski, Silvia M M Magalhaes, Yasushi Miyazaki, Michael Pfeilstöcker, Mikkael Sekeres, Wolfgang R Sperr, Reinhard Stauder, Sudhir Tauro, Peter Valent, Teresa Vallespi, Arjan A van de Loosdrecht, Ulrich Germing, Detlef Haase
雑誌名: Blood. 2012 Sep 20;120(12):2454-65. doi: 10.1182/blood-2012-03-420489. Epub 2012 Jun 27.
Abstract/Text The International Prognostic Scoring System (IPSS) is an important standard for assessing prognosis of primary untreated adult patients with myelodysplastic syndromes (MDS). To refine the IPSS, MDS patient databases from international institutions were coalesced to assemble a much larger combined database (Revised-IPSS [IPSS-R], n = 7012, IPSS, n = 816) for analysis. Multiple statistically weighted clinical features were used to generate a prognostic categorization model. Bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation. This system comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS. As such, this IPSS-R should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease.

PMID 22740453  Blood. 2012 Sep 20;120(12):2454-65. doi: 10.1182/blood-・・・
著者: P Greenberg, C Cox, M M LeBeau, P Fenaux, P Morel, G Sanz, M Sanz, T Vallespi, T Hamblin, D Oscier, K Ohyashiki, K Toyama, C Aul, G Mufti, J Bennett
雑誌名: Blood. 1997 Mar 15;89(6):2079-88.
Abstract/Text Despite multiple disparate prognostic risk analysis systems for evaluating clinical outcome for patients with myelodysplastic syndrome (MDS), imprecision persists with such analyses. To attempt to improve on these systems, an International MDS Risk Analysis Workshop combined cytogenetic, morphological, and clinical data from seven large previously reported risk-based studies that had generated prognostic systems. A global analysis was performed on these patients, and critical prognostic variables were re-evaluated to generate a consensus prognostic system, particularly using a more refined bone marrow (BM) cytogenetic classification. Univariate analysis indicated that the major variables having an impact on disease outcome for evolution to acute myeloid leukemia were cytogenetic abnormalities, percentage of BM myeloblasts, and number of cytopenias; for survival, in addition to the above, variables also included age and gender. Cytogenetic subgroups of outcome were as follows: "good" outcomes were normal, -Y alone, del(5q) alone, del(20q) alone; "poor" outcomes were complex (ie, > or = 3 abnormalities) or chromosome 7 anomalies; and "intermediate" outcomes were other abnormalities. Multivariate analysis combined these cytogenetic subgroups with percentage of BM blasts and number of cytopenias to generate a prognostic model. Weighting these variables by their statistical power separated patients into distinctive subgroups of risk for 25% of patients to undergo evolution to acute myeloid leukemia, with: low (31% of patients), 9.4 years; intermediate-1 (INT-1; 39%), 3.3 years; INT-2 (22%), 1.1 years; and high (8%), 0.2 year. These features also separated patients into similar distinctive risk groups for median survival: low, 5.7 years; INT-1, 3.5 years; INT-2, 1.2 years; and high, 0.4 year. Stratification for age further improved analysis of survival. Compared with prior risk-based classifications, this International Prognostic Scoring System provides an improved method for evaluating prognosis in MDS. This classification system should prove useful for more precise design and analysis of therapeutic trials in this disease.

PMID 9058730  Blood. 1997 Mar 15;89(6):2079-88.
著者: Pierre Fenaux, Aristoteles Giagounidis, Dominik Selleslag, Odile Beyne-Rauzy, Ghulam Mufti, Moshe Mittelman, Petra Muus, Peter Te Boekhorst, Guillermo Sanz, Consuelo Del Cañizo, Agnes Guerci-Bresler, Lars Nilsson, Uwe Platzbecker, Michael Lübbert, Bruno Quesnel, Mario Cazzola, Arnold Ganser, David Bowen, Brigitte Schlegelberger, Carlo Aul, Robert Knight, John Francis, Tommy Fu, Eva Hellström-Lindberg, MDS-004 Lenalidomide del5q Study Group
雑誌名: Blood. 2011 Oct 6;118(14):3765-76. doi: 10.1182/blood-2011-01-330126. Epub 2011 Jul 13.
Abstract/Text This phase 3, randomized, double-blind study assessed the efficacy and safety of lenalidomide in 205 red blood cell (RBC) transfusion-dependent patients with International Prognostic Scoring System Low-/Intermediate-1-risk del5q31 myelodysplastic syndromes. Patients received lenalidomide 10 mg/day on days 1-21 (n = 69) or 5 mg/day on days 1-28 (n = 69) of 28-day cycles; or placebo (n = 67). Crossover to lenalidomide or higher dose was allowed after 16 weeks. More patients in the lenalidomide 10- and 5-mg groups achieved RBC-transfusion independence (TI) for ≥ 26 weeks (primary endpoint) versus placebo (56.1% and 42.6% vs 5.9%; both P < .001). Median duration of RBC-TI was not reached (median follow-up, 1.55 years), with 60% to 67% of responses ongoing in patients without progression to acute myeloid leukemia (AML). Cytogenetic response rates were 50.0% (10 mg) versus 25.0% (5 mg; P = .066). For the lenalidomide groups combined, 3-year overall survival and AML risk were 56.5% and 25.1%, respectively. RBC-TI for ≥ 8 weeks was associated with 47% and 42% reductions in the relative risks of death and AML progression or death, respectively (P = .021 and .048). The safety profile was consistent with previous reports. Lenalidomide is beneficial and has an acceptable safety profile in transfusion-dependent patients with Low-/Intermediate-1-risk del5q myelodysplastic syndrome. This trial was registered at www.clinicaltrials.gov as #NCT00179621.

PMID 21753188  Blood. 2011 Oct 6;118(14):3765-76. doi: 10.1182/blood-2・・・
著者: E Hellström-Lindberg
雑誌名: Br J Haematol. 1995 Jan;89(1):67-71.
Abstract/Text Erythropoietin (epo) can be used to improve the anaemia of patients with myelodysplastic syndromes (MDS), but the efficacy is relatively low and the treatment is expensive. So far, no individual clinical trial has been sufficiently extensive to provide a basis for a decision model for the use of epo in MDS. This meta-analysis included 17 original articles with a total of 205 patients with MDS who had been treated with epo. 33 patients (16%) showed a significant response to treatment. Patients with refractory anaemia with ring sideroblasts (RAS) showed a lower response rate than all other patients (7.5% v 21%, P = 0.010). The difference in response rate between patients with and without transfusion need was also highly significant (10% v 44%, P < 0.001). The serum level of epo was significantly lower in the responding patients, but this parameter on its own could not be used to identify patients with a favourable response. FAB group (RAS versus others), transfusion need and s-epo (>/< 200 U/l) were combined in a model to provide information about the probability of response in different groups of patients. Patients with no transfusion requirement and MDS other than RAS showed a response rate of > or = 50%, irrespective of their serum level of epo. In patients with RAS and s-epo > 200 U/l, no response was observed. In the remaining groups the response rates varied between 9% and 33%. This meta-analysis shows that the efficacy of epo in MDS in general was low, but that groups of patients with an acceptable response rate could be identified.

PMID 7833279  Br J Haematol. 1995 Jan;89(1):67-71.
著者: Peter L Greenberg, Eyal Attar, John M Bennett, Clara D Bloomfield, Carlos M De Castro, H Joachim Deeg, James M Foran, Karin Gaensler, Guillermo Garcia-Manero, Steven D Gore, David Head, Rami Komrokji, Lori J Maness, Michael Millenson, Stephen D Nimer, Margaret R O'Donnell, Mark A Schroeder, Paul J Shami, Richard M Stone, James E Thompson, Peter Westervelt, National Comprehensive Cancer Network
雑誌名: J Natl Compr Canc Netw. 2011 Jan;9(1):30-56.
Abstract/Text These suggested practice guidelines are based on extensive evaluation of the reviewed risk-based data and indicate useful current approaches for managing patients with MDS. Four drugs have recently been approved by the FDA for treating specific subtypes of MDS: lenalidomide for MDS patients with del(5q) cytogenetic abnormalities; azacytidine and decitabine for treating patients with higher-risk or nonresponsive MDS; and deferasirox for iron chelation of iron overloaded patients with MDS. However, because a substantial proportion of patient subsets with MDS lack effective treatment for their cytopenias or for altering disease natural history, clinical trials with these and other novel therapeutic agents along with supportive care remain the hallmark of management for this disease. The role of thrombopoietic cytokines for management of thrombocytopenia in MDS needs further evaluation. In addition, further determination of the effects of these therapeutic interventions on the patient's quality of life is important.(116,119,120,128,129) Progress toward improving management of MDS has occurred over the past few years, and more advances are anticipated using these guidelines as a framework for coordination of comparative clinical trials.

PMID 21233243  J Natl Compr Canc Netw. 2011 Jan;9(1):30-56.
著者: Elaine M Sloand, Colin O Wu, Peter Greenberg, Neal Young, John Barrett
雑誌名: J Clin Oncol. 2008 May 20;26(15):2505-11. doi: 10.1200/JCO.2007.11.9214. Epub 2008 Apr 14.
Abstract/Text PURPOSE: Marrow failure in some patients with myelodysplastic syndrome (MDS) responds to immunosuppressive treatment (IST), but long-term outcome after IST has not been described. We evaluated patients with MDS treated with IST at our institution to determine their clinical course compared with a comparable supportive care only group.
PATIENTS AND METHODS: One hundred twenty-nine patients with MDS received IST with a median follow-up of 3.0 years (range, 0.03 to 11.3 years), using antithymocyte globulin (ATG) or cyclosporine (CsA) in combination or singly. Variables affecting response and survival were studied and outcomes were compared with those of 816 patients with MDS reported to the International Myelodysplasia Risk Analysis Workshop (IMRAW) who received only supportive care.
RESULTS: Thirty-nine (30%) of 129 patients receiving IST responded either completely or partially: 18 (24%) of 74 patients responded to ATG, 20 (48%) of 42 patients responded to ATG plus CsA, and one (8%) of 13 patients responded to CsA. Thirty-one percent (12 of 39) of the responses were complete, resulting in transfusion independence and near-normal blood counts. In multivariate analysis, younger age was the most significant factor favoring response to therapy. Other favorable factors affecting response were HLA-DR15 positivity and combination ATG plus CsA treatment (P = .001 and P = .048, respectively). In multivariate analysis of the combined IMRAW and IST cohorts, younger age, treatment with IST, and intermediate or low International Prognostic Scoring System score significantly favored survival.
CONCLUSION: IST produced significant improvement in the pancytopenia of a substantial proportion of patients with MDS and was associated with improved overall and progression-free survival, especially in younger individuals with lower-risk disease.

PMID 18413642  J Clin Oncol. 2008 May 20;26(15):2505-11. doi: 10.1200/・・・
著者: Takayuki Ishikawa, Kaoru Tohyama, Shinji Nakao, Yataro Yoshida, Masanao Teramura, Toshiko Motoji, Masaaki Takatoku, Mineo Kurokawa, Kinuko Mitani, Takashi Uchiyama, Mitsuhiro Omine
雑誌名: Int J Hematol. 2007 Aug;86(2):150-7. doi: 10.1532/IJH97.07052.
Abstract/Text Although immunosuppressive therapy using antithymocyte globulin or cyclosporine A (CSA) is effective in selected patients with low-risk myelodysplastic syndrome, the response rates reported so far are inconsistent, and the indication of immunosuppressive therapy for myelodysplastic syndrome has not been clearly defined. We treated 20 myelodysplastic syndrome patients (17 refractory anemia cases [RA], 2 RA with excess blasts, and one RA with ringed sideroblasts) with 4 mg/kg per day of CSA for 24 weeks. Among the 19 patients evaluated, 10 showed hematologic improvement; 8 patients showed an erythroid response, 6 showed a platelet response, and one showed a neutrophil response. Most patients with hematologic improvement continued CSA thereafter, and the progressive response was observed until the latest follow-up (median, 30 months). Most toxicities associated with CSA usage were manageable, and no patient had developed acute leukemia up to this point. Short duration of illness, refractory anemia with minimal dysplasia determined by bone marrow morphology, and the presence of paroxysmal nocturnal hemoglobinuria-type cells were significantly associated with the platelet response. A minority of RA patients who did not possess such predictive variables achieved an isolated erythroid response. In conclusion, CSA may be a therapeutic option for patients with RA who do not have adverse prognostic factors.

PMID 17875530  Int J Hematol. 2007 Aug;86(2):150-7. doi: 10.1532/IJH97・・・
著者: Jeffrey J Molldrem, Eric Leifer, Erkut Bahceci, Yogen Saunthararajah, Mary Rivera, Cynthia Dunbar, Johnson Liu, Riotoro Nakamura, Neal S Young, A John Barrett
雑誌名: Ann Intern Med. 2002 Aug 6;137(3):156-63.
Abstract/Text BACKGROUND: Almost half of the deaths that result from myelodysplastic syndromes are due to cytopenia associated with bone marrow failure. Treatment is mostly supportive care.
OBJECTIVE: To determine whether treatment with antithymocyte globulin improves cytopenia and reverses dependence on red blood cell transfusions in patients with myelodysplastic syndromes.
DESIGN: Single-treatment, prospective study.
SETTING: Tertiary referral center.
PATIENTS: 61 patients with myelodysplastic syndromes.
INTERVENTION: Antithymocyte globulin, 40 mg/kg of body weight, given daily for 4 days.
MEASUREMENTS: Evaluation of bone marrow, blood counts, transfusions, progression, and survival for a median of 30 months (range, 1 to 88 months).
RESULTS: Within 8 months of treatment, 21 of 61 patients (34%) no longer required red blood cell transfusions. This independence from transfusions was maintained in 17 responders (81%) for a median of 36 months (range, 3 to 72 months). Ten of 21 patients (47.5%) with severe thrombocytopenia had sustained platelet count increases, and 6 of 11 patients (55%) with severe neutropenia had sustained neutrophil counts of greater than 1 x 10(9) cells/L. Characteristics favorable for response were younger patient age (P = 0.005) and lower platelet counts (P = 0.038). One of the 21 responders (5%) and 22 of the 40 nonresponders (55%) died before the end of the study (P = 0.008). One of the 21 responders (5%) and 13 of the 40 nonresponders (33%) had disease progression (P = 0.086).
CONCLUSIONS: Although this study was a nonrandomized, single-treatment study, 34% of patients treated with antithymocyte globulin became transfusion independent. Response was associated with a statistically significant longer survival and an almost significant decreased time to disease progression. Treatment with antithymocyte globulin did not seem to be detrimental because historical overall median survival times were similar to those of nonresponders.

PMID 12160363  Ann Intern Med. 2002 Aug 6;137(3):156-63.
著者: Lewis R Silverman, Erin P Demakos, Bercedis L Peterson, Alice B Kornblith, Jimmie C Holland, Rosalie Odchimar-Reissig, Richard M Stone, Douglas Nelson, Bayard L Powell, Carlos M DeCastro, John Ellerton, Richard A Larson, Charles A Schiffer, James F Holland
雑誌名: J Clin Oncol. 2002 May 15;20(10):2429-40.
Abstract/Text PURPOSE: Patients with high-risk myelodysplastic syndrome (MDS) have high mortality from bone marrow failure or transformation to acute leukemia. Supportive care is standard therapy. We previously reported that azacitidine (Aza C) was active in patients with high-risk MDS.
PATIENTS AND METHODS: A randomized controlled trial was undertaken in 191 patients with MDS to compare Aza C (75 mg/m(2)/d subcutaneously for 7 days every 28 days) with supportive care. MDS was defined by French-American-British criteria. New rigorous response criteria were applied. Both arms received transfusions and antibiotics as required. Patients in the supportive care arm whose disease worsened were permitted to cross over to Aza C.
RESULTS: Responses occurred in 60% of patients on the Aza C arm (7% complete response, 16% partial response, 37% improved) compared with 5% (improved) receiving supportive care (P <.001). Median time to leukemic transformation or death was 21 months for Aza C versus 13 months for supportive care (P =.007). Transformation to acute myelogenous leukemia occurred as the first event in 15% of patients on the Aza C arm and in 38% receiving supportive care (P =.001). Eliminating the confounding effect of early cross-over to Aza C, a landmark analysis after 6 months showed median survival of an additional 18 months for Aza C and 11 months for supportive care (P =.03). Quality-of-life assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially randomized to Aza C.
CONCLUSION: Aza C treatment results in significantly higher response rates, improved quality of life, reduced risk of leukemic transformation, and improved survival compared with supportive care. Aza C provides a new treatment option that is superior to supportive care for patients with the MDS subtypes and specific entry criteria treated in this study.

PMID 12011120  J Clin Oncol. 2002 May 15;20(10):2429-40.
著者: Alan List, Gordon Dewald, John Bennett, Aristotle Giagounidis, Azra Raza, Eric Feldman, Bayard Powell, Peter Greenberg, Deborah Thomas, Richard Stone, Craig Reeder, Kenton Wride, John Patin, Michele Schmidt, Jerome Zeldis, Robert Knight, Myelodysplastic Syndrome-003 Study Investigators
雑誌名: N Engl J Med. 2006 Oct 5;355(14):1456-65. doi: 10.1056/NEJMoa061292.
Abstract/Text BACKGROUND: Severe, often refractory anemia is characteristic of the myelodysplastic syndrome associated with chromosome 5q31 deletion. We investigated whether lenalidomide (CC5013) could reduce the transfusion requirement and suppress the abnormal 5q31- clone in patients with this disorder.
METHODS: One hundred forty-eight patients received 10 mg of lenalidomide for 21 days every 4 weeks or daily. Hematologic, bone marrow, and cytogenetic changes were assessed after 24 weeks of treatment by an intention-to-treat analysis.
RESULTS: Among the 148 patients, 112 had a reduced need for transfusions (76%; 95% confidence interval [CI], 68 to 82) and 99 patients (67%; 95% CI, 59 to 74) no longer required transfusions, regardless of the karyotype complexity. The response to lenalidomide was rapid (median time to response, 4.6 weeks; range, 1 to 49) and sustained; the median duration of transfusion independence had not been reached after a median of 104 weeks of follow-up. The maximum hemoglobin concentration reached a median of 13.4 g per deciliter (range, 9.2 to 18.6), with a corresponding median rise of 5.4 g per deciliter (range, 1.1 to 11.4), as compared with the baseline nadir value before transfusion. Among 85 patients who could be evaluated, 62 had cytogenetic improvement, and 38 of the 62 had a complete cytogenetic remission. There was complete resolution of cytologic abnormalities in 38 of 106 patients whose serial bone marrow samples could be evaluated. Moderate-to-severe neutropenia (in 55% of patients) and thrombocytopenia (in 44%) were the most common reasons for interrupting treatment or adjusting the dose of lenalidomide.
CONCLUSIONS: Lenalidomide can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients who have the myelodysplastic syndrome with the 5q31 deletion. (ClinicalTrials.gov number, NCT00065156 [ClinicalTrials.gov].).

Copyright 2006 Massachusetts Medical Society.
PMID 17021321  N Engl J Med. 2006 Oct 5;355(14):1456-65. doi: 10.1056/・・・
著者: Hagop Kantarjian, Miloslav Beran, Jorge Cortes, Susan O'Brien, Francis Giles, Sherry Pierce, Jianqin Shan, William Plunkett, Michael Keating, Elihu Estey
雑誌名: Cancer. 2006 Mar 1;106(5):1099-109. doi: 10.1002/cncr.21699.
Abstract/Text BACKGROUND: Progressive or higher-risk myelodysplastic syndrome (MDS) is often treated with intensive chemotherapy regimens used for acute myelogenous leukemia (AML). Patients with MDS are often older and may have contraindications to anthracycline-based regimens. Topotecan-cytarabine regimens have shown encouraging results in higher-risk MDS. The aim of this study was to analyze the long-term results with topotecan-cytarabine versus other intensive chemotherapy regimens in higher-risk MDS.
METHODS: Five hundred ten patients with higher-risk MDS treated with intensive chemotherapy were reviewed. Their median age was 63 years; 82% had intermediate 2 or high-risk MDS; 32% had secondary MDS; 40% had chromosome 5 or 7 abnormalities. Therapy was: topotecan-cytarabine in 77; idarubicin-cytarabine regimens in 270; topotecan-cytarabine and cyclophosphamide in 67; fludarabine-cytarabine in 96. Univariate and multivariate analyses were conducted to evaluate the independent associations of different variables, and most important, the treatment regimen, with complete response, induction mortality, and survival.
RESULTS: The overall complete response (CR) rate was 55%, induction mortality 17%, and 5-year survival rate 8%. The 5-year survival rate was 11% for patients younger than 65 years old and 17% for patients with a normal karyotype. Among 82 patients younger than 65 years with a normal karyotype, the CR rate was 67%, 5-year survival rate 27%, and 5-year CR duration rate 33%. Topotecan-cytarabine regimens were equivalent to idarubicin-cytarabine regimens in relation to CR rates and survival rates, but were associated with a lower induction mortality. Multivariate analysis confirmed that treatment regimens were not associated with independent significant differences in CR rates or survival. However, topotecan-cytarabine regimens were still selected to be associated with lower induction mortality rates.
CONCLUSIONS: This analysis suggests that topotecan-cytarabine regimens are equally effective to other AML regimens in higher-risk MDS and may be less toxic. Topotecan-cytarabine may be considered a reasonable alternative to idarubicin-cytarabine in higher-risk MDS, particularly in older patients with contraindications to anthracyclines.

PMID 16435387  Cancer. 2006 Mar 1;106(5):1099-109. doi: 10.1002/cncr.2・・・
著者: Katharina Götze, Uwe Platzbecker, Aristoteles Giagounidis, Detlef Haase, Michael Lübbert, Carlo Aul, Arnold Ganser, Ulrich Germing, Wolf-Karsten Hofmann
雑誌名: Ann Hematol. 2010 Sep;89(9):841-50. doi: 10.1007/s00277-010-1015-0. Epub 2010 Jun 22.
Abstract/Text Myelodysplastic syndromes (MDS) are a group of common bone marrow disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and a substantial risk of progression to acute myeloid leukemia (AML). For many years, the main treatment option for MDS was best supportive care which alleviates symptoms, but has no effect on the natural course of the disease. Recently, demethylating agents have become available as a promising new treatment for patients with MDS. In two randomized clinical trials, the demethylating agent azacitidine has demonstrated a reduced risk of transformation to AML, improvement of peripheral blood values, an improved quality of life, and a definite survival advantage compared to conventional care regimens for patients with International Prognostic Scoring System score of intermediate-2 or high-risk MDS. This review aims to provide practical recommendations for the use of azacitidine and the management of its side effects in patients with MDS, assuring safe administration and best efficacy of treatment.

PMID 20567826  Ann Hematol. 2010 Sep;89(9):841-50. doi: 10.1007/s00277・・・
著者: Corey S Cutler, Stephanie J Lee, Peter Greenberg, H Joachim Deeg, Waleska S Pérez, Claudio Anasetti, Brian J Bolwell, Mitchell S Cairo, Robert Peter Gale, John P Klein, Hillard M Lazarus, Jane L Liesveld, Philip L McCarthy, Gustavo A Milone, J Douglas Rizzo, Kirk R Schultz, Michael E Trigg, Armand Keating, Daniel J Weisdorf, Joseph H Antin, Mary M Horowitz
雑誌名: Blood. 2004 Jul 15;104(2):579-85. doi: 10.1182/blood-2004-01-0338. Epub 2004 Mar 23.
Abstract/Text Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.

PMID 15039286  Blood. 2004 Jul 15;104(2):579-85. doi: 10.1182/blood-20・・・

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