今日の臨床サポート

急性骨髄性白血病

著者: 藤澤信 横浜市立大学附属市民総合医療センター 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:2021/02/10
参考ガイドライン:
日本血液学会:造血器腫瘍診療ガイドライン 診療ガイドライン2018年版
患者向け説明資料

概要・推奨   

  1. 標準的寛解導入療法としてIDR(12mg/m2、3日間)またはDNR(50mg/m2、5日間)+Ara-C(100mg/m2、7日間)のセット療法が広く用いられている(推奨度1)。
  1. 60歳以下のCBF白血病の寛解後療法にはシタラビン(Ara-C)大量療法が選択される(推奨度1)。
  1. AMLの予後に最も大きく影響するのが染色体異常で、染色体の核型異常のパターンから予後良好群、予後中間群、予後不良群の3群に分類されている(推奨度1)。
  1. CBF白血病のうち、RUNX1-RUNX1T1陽性AMLではKIT変異、特にexon17変異は予後不良因子である(推奨度1)。
  1. FLT3-ITDは独立した予後不良因子である(推奨度1)。
  1. 正常核型AMLでFLT3-ITD変異を伴わないNPM1変異症例は予後良好である(推奨度1)。
  1. CEBPA遺伝子変異は正常核型AMLにおける独立した予後良好因子である(推奨度1)。
  1. IDH1遺伝子変異は正常核型AMLにおける独立した予後良好因子である(推奨度2)。
  1. WT-1遺伝子変異は正常核型AMLにおける独立した予後良好因子である(推奨度2)。
  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。閲覧にはご契約が
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:
藤澤信 : 未申告[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. 造血細胞移植学会編:造血細胞移植ガイドラインの改訂に基づき、移植適応について改訂を行った。
  1. 急性前骨髄球性白血病について加筆修正を行った。

病態・疫学・診察

疾患情報  
  1. 白血病とは腫瘍化した造血細胞が骨髄のなかで無制限に増殖して末梢血液中に出現する疾患の総称である。白血球系細胞が腫瘍化することが多いため一般に白血病と呼ばれるが、実際には赤血球系や血小板系の細胞が腫瘍化した場合も含めて総称的に白血病と呼ぶ。臨床経過から急性と慢性に分類されるが、一般に急性では分化能を失い、未熟な腫瘍細胞が増加する。一方、慢性では分化能が保持され、主に成熟した腫瘍細胞が増加する。さらに細胞起源から骨髄性とリンパ性に分類される。急性骨髄性白血病(Acute Myeloid Leukemia、AML)はFAB分類でM0からM7の8種類に分類される。
  1. 分子異常としては、1)FLT3やc-KITなどのレセプター型チロシンキナーゼやABLなどの非レセプター型チロシンキナーゼの変異とそれに基づく恒常的活性化、2)t(15;17)、t(8;21)、inv(16)などでみられる転写因子の機能異常による分化成熟障害、3)RASに代表されるGTP結合タンパク質の異常活性化、4)p15、p21などの細胞増殖の停止や分化に必要な遺伝子のエピジェネティックなメカニズムによる発現抑制などが代表的なものである。
  1. 急性骨髄性白血病は、発症頻度の低い疾患であるが、わが国では最も発症頻度の高い成人の白血病である。成人急性白血病の75~80%を占め、急性リンパ性白血病(ALL)の約4倍である。高齢者ほど発症率が高くなる。
問診・診察のポイント  
  1. 骨髄内での白血病細胞の急激な増加によって正常造血が障害されるため、貧血による全身倦怠感、息切れ、動悸、白血球減少による発熱、血小板減少による出血傾向(鼻出血、歯肉出血、血尿、眼底出血など)などの症状がみられる。

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文献 

著者: M L Slovak, K J Kopecky, P A Cassileth, D H Harrington, K S Theil, A Mohamed, E Paietta, C L Willman, D R Head, J M Rowe, S J Forman, F R Appelbaum
雑誌名: Blood. 2000 Dec 15;96(13):4075-83.
Abstract/Text The associations of cytogenetics with complete remission (CR) rates, overall survival (OS), and outcomes after CR were studied in 609 previously untreated AML patients younger than 56 years old in a clinical trial comparing 3 intensive postremission therapies: intensive chemotherapy, autologous transplantation (ABMT), or allogeneic bone marrow transplantation (alloBMT) from matched related donors. Patients were categorized into favorable, intermediate, unfavorable, and unknown cytogenetic risk groups based on pretreatment karyotypes. CR rates varied significantly (P <.0001) among the 4 groups: favorable, 84% (95% confidence interval [CI], 77%-90%); intermediate, 76% (CI, 71%-81%); unfavorable, 55% (CI, 48%-63%); and unknown, 54% (CI, 33%-74%). There was similar significant heterogeneity of OS (P <.0001), with the estimated relative risk of death from any cause being 1.50 (CI, 1.10-2.05), 3. 33 (CI, 2.43-4.55), and 2.66 (CI, 1.59-4.45) for the intermediate, unfavorable, and unknown risk groups, respectively, compared with the favorable group. In multivariate analyses, the effects of cytogenetic risk status on CR rate and OS could not be explained by other patient or disease characteristics. Among postremission patients, survival from CR varied significantly among favorable, intermediate, and unfavorable groups (P =.0003), with significant evidence of interaction (P =.017) between the effects of treatment and cytogenetic risk status on survival. Patients with favorable cytogenetics did significantly better following ABMT and alloBMT than with chemotherapy alone, whereas patients with unfavorable cytogenetics did better with alloBMT. Cytogenetic risk status is a significant factor in predicting response of AML patients to therapy; however, to tighten treatment correlates within genetically defined AML subsets, a significantly larger leukemia cytogenetic database is warranted.

PMID 11110676  Blood. 2000 Dec 15;96(13):4075-83.
著者: D Grimwade, H Walker, F Oliver, K Wheatley, C Harrison, G Harrison, J Rees, I Hann, R Stevens, A Burnett, A Goldstone
雑誌名: Blood. 1998 Oct 1;92(7):2322-33.
Abstract/Text Cytogenetics is considered one of the most valuable prognostic determinants in acute myeloid leukemia (AML). However, many studies on which this assertion is based were limited by relatively small sample sizes or varying treatment approach, leading to conflicting data regarding the prognostic implications of specific cytogenetic abnormalities. The Medical Research Council (MRC) AML 10 trial, which included children and adults up to 55 years of age, not only affords the opportunity to determine the independent prognostic significance of pretreatment cytogenetics in the context of large patient groups receiving comparable therapy, but also to address their impact on the outcome of subsequent transplantation procedures performed in first complete remission (CR). On the basis of response to induction treatment, relapse risk, and overall survival, three prognostic groups could be defined by cytogenetic abnormalities detected at presentation in comparison with the outcome of patients with normal karyotype. AML associated with t(8;21), t(15;17) or inv(16) predicted a relatively favorable outcome. Whereas in patients lacking these favorable changes, the presence of a complex karyotype, -5, del(5q), -7, or abnormalities of 3q defined a group with relatively poor prognosis. The remaining group of patients including those with 11q23 abnormalities, +8, +21, +22, del(9q), del(7q) or other miscellaneous structural or numerical defects not encompassed by the favorable or adverse risk groups were found to have an intermediate prognosis. The presence of additional cytogenetic abnormalities did not modify the outcome of patients with favorable cytogenetics. Subgroup analysis demonstrated that the three cytogenetically defined prognostic groups retained their predictive value in the context of secondary as well as de novo AML, within the pediatric age group and furthermore were found to be a key determinant of outcome from autologous or allogeneic bone marrow transplantation (BMT) in first CR. This study highlights the importance of diagnostic cytogenetics as an independent prognostic factor in AML, providing the framework for a stratified treatment approach of this disease, which has been adopted in the current MRC AML 12 trial.

PMID 9746770  Blood. 1998 Oct 1;92(7):2322-33.
著者: David Grimwade, Robert K Hills, Anthony V Moorman, Helen Walker, Stephen Chatters, Anthony H Goldstone, Keith Wheatley, Christine J Harrison, Alan K Burnett, National Cancer Research Institute Adult Leukaemia Working Group
雑誌名: Blood. 2010 Jul 22;116(3):354-65. doi: 10.1182/blood-2009-11-254441. Epub 2010 Apr 12.
Abstract/Text Diagnostic karyotype provides the framework for risk-stratification schemes in acute myeloid leukemia (AML); however, the prognostic significance of many rare recurring cytogenetic abnormalities remains uncertain. We studied the outcomes of 5876 patients (16-59 years of age) who were classified into 54 cytogenetic subgroups and treated in the Medical Research Council trials. In multivariable analysis, t(15;17)(q22;q21), t(8;21)(q22;q22), and inv(16)(p13q22)/t(16;16)(p13;q22) were the only abnormalities found to predict a relatively favorable prognosis (P < .001). In patients with t(15;17) treated with extended all-trans retinoic acid and anthracycline-based chemotherapy, additional cytogenetic changes did not have an impact on prognosis. Similarly, additional abnormalities did not have a significant adverse effect in t(8;21) AML; whereas in patients with inv(16), the presence of additional changes, particularly +22, predicted a better outcome (P = .004). In multivariable analyses, various abnormalities predicted a significantly poorer outcome, namely abn(3q) (excluding t(3;5)(q25;q34)), inv(3)(q21q26)/t(3;3)(q21;q26), add(5q)/del(5q), -5, -7, add(7q)/del(7q), t(6;11)(q27;q23), t(10;11)(p11 approximately 13;q23), other t(11q23) (excluding t(9;11)(p21 approximately 22;q23) and t(11;19)(q23;p13)), t(9;22)(q34;q11), -17, and abn(17p). Patients lacking the aforementioned favorable or adverse aberrations but with 4 or more unrelated abnormalities also exhibited a significantly poorer prognosis (designated "complex" karyotype group). These data allow more reliable prediction of outcome for patients with rarer abnormalities and may facilitate the development of consensus in reporting of karyotypic information in clinical trials involving younger adults with AML. This study is registered at http://www.isrctn.org as ISRCTN55678797 and ISRCTN17161961.

PMID 20385793  Blood. 2010 Jul 22;116(3):354-65. doi: 10.1182/blood-20・・・
著者:
雑誌名: 2013 May 30;368(22):2059-74.
Abstract/Text
PMID 23634996  2013 May 30;368(22):2059-74.
著者:
雑誌名: 2020 Jan 14;4(1):66-75.
Abstract/Text
PMID 31899799  2020 Jan 14;4(1):66-75.
著者: Susanne Schnittger, Claudia Schoch, Martin Dugas, Wolfgang Kern, Peter Staib, Christian Wuchter, Helmut Löffler, Cristina Maria Sauerland, Hubert Serve, Thomas Büchner, Torsten Haferlach, Wolfgang Hiddemann
雑誌名: Blood. 2002 Jul 1;100(1):59-66.
Abstract/Text FLT3 length mutation (FLT3-LM) is a molecular marker potentially useful for the characterization of acute myeloid leukemia (AML). To evaluate the distribution of FLT3-LM within biologic subgroups, we screened 1003 patients with AML at diagnosis for this mutation. FLT3-LM was found in 234 (23.5%) of all patients and thus is the most frequent mutation in AML described so far. Of all positive patients, 165 (70.5%) revealed a normal karyotype. Of the 69 patients with chromosome aberrations, 24 (34.8%) had a t(15;17). The mutation was rare in AML with t(8;21), inv(16) 11q23 rearrangements, and complex karyotypes. FLT3-LM was not distributed equally within different French-American-British (FAB) subtypes and was correlated with a high peripheral blood count in FAB M1, M2, and M4 (P <.0001). In addition, the median age of patients with the mutation was lower (54.9 vs 57.6 years; P =.043), and, at a ratio of 1.36:1 (P =.023), the mutation was more frequent in females than in males. Within the AMLCG study, FLT3-LM was of intermediate prognostic significance. The complete remission rate of 70.3% in patients with FLT3-LM was similar to that (70.4%) in patients without FLT3-LM. Overall survival was not different between patients with or without FLT3-LM. In contrast, patients with FLT3-LM had a significantly shorter event-free survival (7.4 vs 12.6 months; P =.0072) because of a higher relapse rate. Besides the importance of FLT3-LM for biologic and clinical characterization of AML, we show its value as a marker for disease monitoring based on 120 follow-up samples of 34 patients.

PMID 12070009  Blood. 2002 Jul 1;100(1):59-66.
著者: Rosemary E Gale, Robert Hills, Panagiotis D Kottaridis, Sivatharsini Srirangan, Keith Wheatley, Alan K Burnett, David C Linch
雑誌名: Blood. 2005 Nov 15;106(10):3658-65. doi: 10.1182/blood-2005-03-1323. Epub 2005 Aug 2.
Abstract/Text Fetal liver tyrosine kinase 3 (FLT3) internal tandem duplications (ITDs) are powerful adverse prognostic indicators for relapse in acute myeloid leukemia (AML) but the most efficacious therapy for FLT3/ITD(+) patients is currently unknown. We evaluated outcome according to FLT3/ITD status in 1135 adult patients treated according to United Kingdom Medical Research Council (UK MRC) AML protocols: 141 received an autograft, and 170 received a matched sibling allograft in first complete remission (CR). An FLT3/ITD was detected in 25% of patients and was an independent predictor for relapse (P < .001). It remained prognostic for increased relapse in patients who received a transplant (odds ratio [OR] = 1.91; 95% confidence intervals [CIs] = 1.13-3.21; P = .02), with no evidence of a difference in effect between patients who received an autograft (OR = 2.39; CIs = 1.24-4.62) and patients who received an allograft (OR = 1.31; CIs = 0.56-3.06) (test for interaction, P = .3) or between patients who did or did not receive a transplant (P = .4). These results were confirmed in an analysis of 186 patients randomized to receive or not receive an autograft in first CR and in a donor-versus-no donor analysis of 683 patients to assess the role of allograft (for latter, FLT3/ITD(-) OR = 0.70, CIs = 0.53-0.92; FLT3/ITD(+) OR = 0.59, CIs = 0.40-0.87; test for interaction, P = .5). These results suggest that at present there is no strong evidence that FLT3 status should influence the decision to proceed to transplantation.

PMID 16076872  Blood. 2005 Nov 15;106(10):3658-65. doi: 10.1182/blood-・・・
著者: Richard F Schlenk, Konstanze Döhner, Jürgen Krauter, Stefan Fröhling, Andrea Corbacioglu, Lars Bullinger, Marianne Habdank, Daniela Späth, Michael Morgan, Axel Benner, Brigitte Schlegelberger, Gerhard Heil, Arnold Ganser, Hartmut Döhner, German-Austrian Acute Myeloid Leukemia Study Group
雑誌名: N Engl J Med. 2008 May 1;358(18):1909-18. doi: 10.1056/NEJMoa074306.
Abstract/Text BACKGROUND: Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3), the CCAAT/enhancer binding protein alpha gene (CEPBA), the myeloid-lymphoid or mixed-lineage leukemia gene (MLL), and the neuroblastoma RAS viral oncogene homolog (NRAS). We evaluated the associations of these mutations with clinical outcomes in patients.
METHODS: We compared the mutational status of the NPM1, FLT3, CEBPA, MLL, and NRAS genes in leukemia cells with the clinical outcome in 872 adults younger than 60 years of age with cytogenetically normal AML. Patients had been entered into one of four trials of therapy for AML. In each study, patients with an HLA-matched related donor were assigned to undergo stem-cell transplantation.
RESULTS: A total of 53% of patients had NPM1 mutations, 31% had FLT3 internal tandem duplications (ITDs), 11% had FLT3 tyrosine kinase-domain mutations, 13% had CEBPA mutations, 7% had MLL partial tandem duplications (PTDs), and 13% had NRAS mutations. The overall complete-remission rate was 77%. The genotype of mutant NPM1 without FLT3-ITD, the mutant CEBPA genotype, and younger age were each significantly associated with complete remission. Of the 663 patients who received postremission therapy, 150 underwent hematopoietic stem-cell transplantation from an HLA-matched related donor. Significant associations were found between the risk of relapse or the risk of death during complete remission and the leukemia genotype of mutant NPM1 without FLT3-ITD (hazard ratio, 0.44; 95% confidence interval [CI], 0.32 to 0.61), the mutant CEBPA genotype (hazard ratio, 0.48; 95% CI, 0.30 to 0.75), and the MLL-PTD genotype (hazard ratio, 1.56; 95% CI, 1.00 to 2.43), as well as receipt of a transplant from an HLA-matched related donor (hazard ratio, 0.60; 95% CI, 0.44 to 0.82). The benefit of the transplant was limited to the subgroup of patients with the prognostically adverse genotype FLT3-ITD or the genotype consisting of wild-type NPM1 and CEBPA without FLT3-ITD.
CONCLUSIONS: Genotypes defined by the mutational status of NPM1, FLT3, CEBPA, and MLL are associated with the outcome of treatment for patients with cytogenetically normal AML.

Copyright 2008 Massachusetts Medical Society.
PMID 18450602  N Engl J Med. 2008 May 1;358(18):1909-18. doi: 10.1056/・・・
著者: Martin Bornhäuser, Thomas Illmer, Markus Schaich, Silke Soucek, Gerhard Ehninger, Christian Thiede, AML SHG 96 study group
雑誌名: Blood. 2007 Mar 1;109(5):2264-5; author reply 2265. doi: 10.1182/blood-2006-09-047225.
Abstract/Text
PMID 17312001  Blood. 2007 Mar 1;109(5):2264-5; author reply 2265. doi・・・
著者: Konstanze Döhner, Richard F Schlenk, Marianne Habdank, Claudia Scholl, Frank G Rücker, Andrea Corbacioglu, Lars Bullinger, Stefan Fröhling, Hartmut Döhner
雑誌名: Blood. 2005 Dec 1;106(12):3740-6. doi: 10.1182/blood-2005-05-2164. Epub 2005 Jul 28.
Abstract/Text To assess the prognostic relevance of mutations in the NPM1 gene encoding a nucleocytoplasmic shuttle protein in younger adults with acute myeloid leukemia (AML) and normal cytogenetics, sequencing of NPM1 exon 12 was performed in diagnostic samples from 300 patients entered into 2 consecutive multicenter trials of the AML Study Group (AMLSG). Treatment included intensive double-induction therapy and consolidation therapy with high cumulative doses of high-dose cytarabine. NPM1 mutations were identified in 48% of the patients including 12 novel sequence variants, all leading to a frameshift in the C-terminus of the nucleophosmin 1 (NPM1) protein. Mutant NPM1 was associated with specific clinical, phenotypical, and genetic features. Statistical analysis revealed a significant interaction of NPM1 and FLT3 internal tandem duplications (ITDs). NPM1 mutations predicted for better response to induction therapy and for favorable overall survival (OS) only in the absence of FLT3 ITD. Multivariable analysis for OS revealed combined NPM1-mutated/FLT3 ITD-negative status, CEBPA mutation status, availability of a human leukocyte antigen (HLA)-compatible donor, secondary AML, and lactate dehydrogenase (LDH) as prognostic factors. In conclusion, NPM1 mutations in the absence of FLT3 ITD define a distinct molecular and prognostic subclass of young-adult AML patients with normal cytogenetics.

PMID 16051734  Blood. 2005 Dec 1;106(12):3740-6. doi: 10.1182/blood-20・・・
著者: Veronika Rockova, Saman Abbas, Bas J Wouters, Claudia A J Erpelinck, H Berna Beverloo, Ruud Delwel, Wim L J van Putten, Bob Löwenberg, Peter J M Valk
雑誌名: Blood. 2011 Jul 28;118(4):1069-76. doi: 10.1182/blood-2011-02-334748. Epub 2011 May 19.
Abstract/Text Numerous molecular markers have been recently discovered as potential prognostic factors in acute myeloid leukemia (AML). It has become of critical importance to thoroughly evaluate their interrelationships and relative prognostic importance. Gene expression profiling was conducted in a well-characterized cohort of 439 AML patients (age < 60 years) to determine expression levels of EVI1, WT1, BCL2, ABCB1, BAALC, FLT3, CD34, INDO, ERG and MN1. A variety of AML-specific mutations were evaluated, that is, FLT3, NPM1, N-RAS, K-RAS, IDH1, IDH2, and CEBPA(DM/SM) (double/single). Univariable survival analysis shows that (1) patients with FLT3(ITD) mutations have inferior overall survival (OS) and event-free survival (EFS), whereas CEBPA(DM) and NPM1 mutations indicate favorable OS and EFS in intermediate-risk AML, and (2) high transcript levels of BAALC, CD34, MN1, EVl1, and ERG predict inferior OS and EFS. In multivariable survival analysis, CD34, ERG, and CEBPA(DM) remain significant. Using survival tree and regression methodologies, we show that CEBPA(DM), CD34, and IDH2 mutations are capable of separating the intermediate group into 2 AML subgroups with highly distinctive survival characteristics (OS at 60 months: 51.9% vs 14.9%). The integrated statistical approach demonstrates that from the multitude of biomarkers a greatly condensed subset can be selected for improved stratification of intermediate-risk AML.

PMID 21596848  Blood. 2011 Jul 28;118(4):1069-76. doi: 10.1182/blood-2・・・
著者: Guido Marcucci, Kati Maharry, Michael D Radmacher, Krzysztof Mrózek, Tamara Vukosavljevic, Peter Paschka, Susan P Whitman, Christian Langer, Claudia D Baldus, Chang-Gong Liu, Amy S Ruppert, Bayard L Powell, Andrew J Carroll, Michael A Caligiuri, Jonathan E Kolitz, Richard A Larson, Clara D Bloomfield
雑誌名: J Clin Oncol. 2008 Nov 1;26(31):5078-87. doi: 10.1200/JCO.2008.17.5554. Epub 2008 Sep 22.
Abstract/Text PURPOSE: To evaluate the prognostic significance of CEBPA mutations in the context of established molecular markers in cytogenetically normal (CN) acute myeloid leukemia (AML) and gain biologic insights into leukemogenesis of the CN-AML molecular high-risk subset (FLT3 internal tandem duplication [ITD] positive and/or NPM1 wild type) that has a significantly higher incidence of CEBPA mutations than the molecular low-risk subset (FLT3-ITD negative and NPM1 mutated).
PATIENTS AND METHODS: One hundred seventy-five adults age less than 60 years with untreated primary CN-AML were screened before treatment for CEBPA, FLT3, MLL, WT1, and NPM1 mutations and BAALC and ERG expression levels. Gene and microRNA (miRNA) expression profiles were obtained for the CN-AML molecular high-risk patients.
RESULTS: CEBPA mutations predicted better event-free (P = .007), disease-free (P = .014), and overall survival (P < .001) independently of other molecular and clinical prognosticators. Among patients with CEBPA mutations, 91% were in the CN-AML molecular high-risk group. Within this group, CEBPA mutations predicted better event-free (P < .001), disease-free (P = .004), and overall survival (P = .009) independently of other molecular and clinical characteristics and were associated with unique gene and miRNA expression profiles. The major features of these profiles were upregulation of genes (eg, GATA1, ZFPM1, EPOR, and GFI1B) and miRNAs (ie, the miR-181 family) involved in erythroid differentiation and downregulation of homeobox genes.
CONCLUSION: Pretreatment testing for CEBPA mutations identifies CN-AML patients with different outcomes, particularly in the molecular high-risk group, thus improving molecular risk-based classification of this large cytogenetic subset of AML. The gene and miRNA expression profiling provided insights into leukemogenesis of the CN-AML molecular high-risk group, indicating that CEBPA mutations are associated with partial erythroid differentiation.

PMID 18809607  J Clin Oncol. 2008 Nov 1;26(31):5078-87. doi: 10.1200/J・・・
著者: Stefan Fröhling, Richard F Schlenk, Ina Stolze, Jörg Bihlmayr, Axel Benner, Sylvia Kreitmeier, Karen Tobis, Hartmut Döhner, Konstanze Döhner
雑誌名: J Clin Oncol. 2004 Feb 15;22(4):624-33. doi: 10.1200/JCO.2004.06.060. Epub 2004 Jan 15.
Abstract/Text PURPOSE: To assess the prognostic relevance of mutations in the CEBPA gene encoding CCAAT/enhancer binding protein alpha (C/EBP alpha) in a large prospective series of younger adults with acute myeloid leukemia (AML) and normal cytogenetics.
PATIENTS AND METHODS: The entire CEBPA coding region was sequenced in diagnostic samples from 236 AML patients 16 to 60 years of age with normal cytogenetics who were uniformly treated on two consecutive protocols of the AML Study Group Ulm, and CEBPA mutation status was correlated with clinical outcome.
RESULTS: CEBPA mutations were detected in 36 (15%) of 236 patients. Twenty-one (9%) of 236 patients had mutations predicted to result in loss of C/EBP alpha function. Remission duration and overall survival (OS) were significantly longer for the 36 patients with CEBPA mutations (P =.01 and P =.05, respectively). On multivariate analysis, wild-type CEBPA was an independent prognostic marker affecting remission duration (hazard ratio, 2.85; P =.01) and OS (hazard ratio, 1.87; P =.04). Analysis of cooperating mutations (both types of activating FLT3 mutations and MLL partial tandem duplications) showed that FLT3 mutations had no significant prognostic influence in patients with CEBPA mutations. Furthermore, there was no significant overlap between the subgroup of patients with CEBPA mutation with predicted loss of C/EBP alpha function and patients with FLT3 or MLL mutations, suggesting that CEBPA loss-of-function mutations define a distinct biologic subclass of AML with normal cytogenetics.
CONCLUSION: Mutant CEBPA predicts favorable prognosis and may improve risk stratification in AML patients with normal cytogenetics.

PMID 14726504  J Clin Oncol. 2004 Feb 15;22(4):624-33. doi: 10.1200/JC・・・
著者: Aline Renneville, Nicolas Boissel, Nathalie Gachard, Dina Naguib, Christian Bastard, Stéphane de Botton, Olivier Nibourel, Cécile Pautas, Oumedaly Reman, Xavier Thomas, Claude Gardin, Christine Terré, Sylvie Castaigne, Claude Preudhomme, Hervé Dombret
雑誌名: Blood. 2009 May 21;113(21):5090-3. doi: 10.1182/blood-2008-12-194704. Epub 2009 Mar 16.
Abstract/Text Mutations of the CCAAT/enhancer binding protein alpha (CEBPA) gene have been associated with a favorable outcome in patients with acute myeloid leukemia (AML), but mainly in those with a normal karyotype. Here, we analyzed the impact of associated cytogenetic abnormalities or bad-prognosis fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in 53 patients with CEBPA(+) de novo AML treated in the Acute Leukemia French Association trials. We found that only those with a normal karyotype and no FLT3-ITD displayed the expected favorable outcome. In this context, relapse-free, disease-free, and overall survival were significantly longer than in corresponding patients without the CEBPA mutation (P = .035, .016, and .047, respectively). This was not observed in the context of an abnormal karyotype or associated FLT3-ITD. Furthermore, after adjustment on age, trial, and mutation type, these features were independently predictive of shorter overall survival in the subset of patients with CEBPA(+) AML (multivariate hazard ratio = 2.7; 95% confidence interval, 1.08-6.7; and 2.9; 95% confidence interval, 1.01-8.2; with P = .034 and .05, for abnormal karyotype and FLT3-ITD, respectively).

PMID 19289855  Blood. 2009 May 21;113(21):5090-3. doi: 10.1182/blood-2・・・
著者: K E Yen, M A Bittinger, S M Su, V R Fantin
雑誌名: Oncogene. 2010 Dec 9;29(49):6409-17. doi: 10.1038/onc.2010.444. Epub 2010 Oct 25.
Abstract/Text The discovery of somatic mutations in the isocitrate dehydrogenase (IDH) enzymes through a genome-wide mutational analysis in glioblastoma represents a milestone event in cancer biology. The nature of the heterozygous, point mutations mapping to arginine residues involved in the substrate binding inspired several research teams to investigate their impact on the biochemical activity of these enzymes. Soon, it became clear that the mutations identified impaired the ability of IDH1 and IDH2 to catalyze the conversion of isocitrate to α-ketoglutarate (αKG), whereas conferring a gain of a novel enzymatic activity leading to the reduction of αKG to the metabolite D2-hydroxyglutarate (D-2HG). Across glioma as well as several hematologic malignancies, mutations in IDH1 and IDH2 have shown prognostic value. Several hypotheses implicating the elevated levels of D-2HG and tumorigenesis, and the therapeutic potential of targeting mutant IDH enzymes will be discussed.

PMID 20972461  Oncogene. 2010 Dec 9;29(49):6409-17. doi: 10.1038/onc.2・・・
著者: Guido Marcucci, Kati Maharry, Yue-Zhong Wu, Michael D Radmacher, Krzysztof Mrózek, Dean Margeson, Kelsi B Holland, Susan P Whitman, Heiko Becker, Sebastian Schwind, Klaus H Metzeler, Bayard L Powell, Thomas H Carter, Jonathan E Kolitz, Meir Wetzler, Andrew J Carroll, Maria R Baer, Michael A Caligiuri, Richard A Larson, Clara D Bloomfield
雑誌名: J Clin Oncol. 2010 May 10;28(14):2348-55. doi: 10.1200/JCO.2009.27.3730. Epub 2010 Apr 5.
Abstract/Text PURPOSE To analyze the frequency and associations with prognostic markers and outcome of mutations in IDH genes encoding isocitrate dehydrogenases in adult de novo cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS Diagnostic bone marrow or blood samples from 358 patients were analyzed for IDH1 and IDH2 mutations by DNA polymerase chain reaction amplification/sequencing. FLT3, NPM1, CEBPA, WT1, and MLL mutational analyses and gene- and microRNA-expression profiling were performed centrally. Results IDH mutations were found in 33% of the patients. IDH1 mutations were detected in 49 patients (14%; 47 with R132). IDH2 mutations, previously unreported in AML, were detected in 69 patients (19%; 13 with R172 and 56 with R140). R172 IDH2 mutations were mutually exclusive with all other prognostic mutations analyzed. Younger age (< 60 years), molecular low-risk (NPM1-mutated/FLT3-internal tandem duplication-negative) IDH1-mutated patients had shorter disease-free survival than molecular low-risk IDH1/IDH2-wild-type (wt) patients (P = .046). R172 IDH2-mutated patients had lower complete remission rates than IDH1/IDH2wt patients (P = .007). Distinctive microarray gene- and microRNA-expression profiles accurately predicted R172 IDH2 mutations. The highest expressed gene and microRNAs in R172 IDH2-mutated patients compared with the IDH1/IDH2wt patients were APP (previously associated with complex karyotype AML) and miR-1 and miR-133 (involved in embryonal stem-cell differentiation), respectively. CONCLUSION IDH1 and IDH2 mutations are recurrent in CN-AML and have an unfavorable impact on outcome. The R172 IDH2 mutations, previously unreported in AML, characterize a novel subset of CN-AML patients lacking other prognostic mutations and associate with unique gene- and microRNA-expression profiles that may lead to the discovery of novel, therapeutically targetable leukemogenic mechanisms.

PMID 20368543  J Clin Oncol. 2010 May 10;28(14):2348-55. doi: 10.1200/・・・
著者: Felicitas Thol, Frederik Damm, Katharina Wagner, Gudrun Göhring, Brigitte Schlegelberger, Dieter Hoelzer, Michael Lübbert, Wolfgang Heit, Lothar Kanz, Günter Schlimok, Aruna Raghavachar, Walter Fiedler, Hartmut Kirchner, Gerhard Heil, Michael Heuser, Jürgen Krauter, Arnold Ganser
雑誌名: Blood. 2010 Jul 29;116(4):614-6. doi: 10.1182/blood-2010-03-272146. Epub 2010 Apr 26.
Abstract/Text Mutations in the nicotinamide adenine dinucleotide phosphate(+)-dependent isocitrate dehydrogenase gene 2 (IDH2) have recently been found in patients with acute myeloid leukemia (AML) as well as in patients with leukemic transformation of myeloproliferative neoplasms. We analyzed 272 adult patients with cytogenetically normal AML (CN-AML) for the presence of IDH2 mutations in codons R140 and R172. IDH2 mutations of amino acid 140 or 172 could be identified in 12.1% of CN-AML patients, with the majority of mutations (90%) occurring at position R140. The incidence of IDH2 mutations in AML patients with aberrant karyotypes (n = 130) was significantly lower (3.8%, P = .006). IDH2 mutations were mutually exclusive with mutations in IDH1. IDH2 mutation status alone or in combination with IDH1 mutations had no impact on response to therapy, overall survival, and relapse-free survival in patients with CN-AML. In conclusion, IDH2 mutations are frequently found in CN-AML, but in our analysis these mutations did not influence treatment outcome. This study was registered at www.clinicaltrials.gov as #NCT00209833.

PMID 20421455  Blood. 2010 Jul 29;116(4):614-6. doi: 10.1182/blood-201・・・
著者: Peter Paschka, Guido Marcucci, Amy S Ruppert, Susan P Whitman, Krzysztof Mrózek, Kati Maharry, Christian Langer, Claudia D Baldus, Weiqiang Zhao, Bayard L Powell, Maria R Baer, Andrew J Carroll, Michael A Caligiuri, Jonathan E Kolitz, Richard A Larson, Clara D Bloomfield
雑誌名: J Clin Oncol. 2008 Oct 1;26(28):4595-602. doi: 10.1200/JCO.2007.15.2058. Epub 2008 Jun 16.
Abstract/Text PURPOSE: To analyze the prognostic impact of Wilms' tumor 1 (WT1) gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS We studied 196 adults younger than 60 years with newly diagnosed primary CN-AML, who were treated similarly on Cancer and Leukemia Group B (CALGB) protocols 9621 and 19808, for WT1 mutations in exons 7 and 9. The patients also were assessed for the presence of FLT3 internal tandem duplications (FLT3-ITD), FLT3 tyrosine kinase domain mutations (FLT3-TKD), MLL partial tandem duplications (MLL-PTD), NPM1 and CEBPA mutations, and for the expression levels of ERG and BAALC.
RESULTS: Twenty-one patients (10.7%) harbored WT1 mutations. Complete remission rates were not significantly different between patients with WT1 mutations and those with unmutated WT1 (P = .36; 76% v 84%). Patients with WT1 mutations had worse disease-free survival (DFS; P < .001; 3-year rates, 13% v 50%) and overall survival (OS; P < .001; 3-year rates, 10% v 56%) than patients with unmutated WT1. In multivariable analyses, WT1 mutations independently predicted worse DFS (P = .009; hazard ratio [HR] = 2.7) when controlling for CEBPA mutational status, ERG expression level, and FLT3-ITD/NPM1 molecular-risk group (ie, FLT3-ITD(negative)/NPM1(mutated) as low risk v FLT3-ITD(positive) and/or NPM1(wild-type) as high risk). WT1 mutations also independently predicted worse OS (P < .001; HR = 3.2) when controlling for CEBPA mutational status, FLT3-ITD/NPM1 molecular-risk group, and white blood cell count.
CONCLUSION: We report the first evidence that WT1 mutations independently predict extremely poor outcome in intensively treated, younger patients with CN-AML. Future trials should include testing for WT1 mutations as part of molecularly based risk assessment and risk-adapted treatment stratification of patients with CN-AML.

PMID 18559874  J Clin Oncol. 2008 Oct 1;26(28):4595-602. doi: 10.1200/・・・
著者: Hsin-An Hou, Tai-Chung Huang, Liang-In Lin, Chieh-Yu Liu, Chien-Yuan Chen, Wen-Chien Chou, Jih-Luh Tang, Mei-Hsuan Tseng, Chi-Fei Huang, Ying-Chieh Chiang, Fen-Yu Lee, Ming-Chih Liu, Ming Yao, Shang-Yi Huang, Bor-Sheng Ko, Szu-Chun Hsu, Shang-Ju Wu, Woei Tsay, Yao-Chang Chen, Hwei-Fang Tien
雑誌名: Blood. 2010 Jun 24;115(25):5222-31. doi: 10.1182/blood-2009-12-259390. Epub 2010 Apr 5.
Abstract/Text The impact of WT1 mutations in acute myeloid leukemia (AML) is not completely settled. We aimed to determine the clinical implication of WT1 mutation in 470 de novo non-M3 AML patients and its stability during the clinical course. WT1 mutations were identified in 6.8% of total patients and 8.3% of younger patients with normal karyotype (CN-AML). The WT1 mutation was closely associated with younger age (P < .001), French-American-British M6 subtype (P = .006), and t(7;11)(p15;p15) (P = .003). Multivariate analysis demonstrated that the WT1 mutation was an independent poor prognostic factor for overall survival and relapse-free survival among total patients and the CN-AML group. A scoring system incorporating WT1 mutation, NPM1/FLT3-ITD, CEBPA mutations, and age into survival analysis proved to be very useful to stratify CN-AML patients into different prognostic groups (P < .001). Sequential analyses were performed on 133 patients. WT1 mutations disappeared at complete remission in all WT1-mutated patients studied. At relapse, 3 of the 16 WT1-mutated patients who had paired samples lost the mutation and 2 acquired additional mutations, whereas 3 of 110 WT1-wild patients acquired novel mutations. In conclusion, WT1 mutations are correlated with poor prognosis in AML patients. The mutation status may be changed in some patients during AML progression.

PMID 20368469  Blood. 2010 Jun 24;115(25):5222-31. doi: 10.1182/blood-・・・
著者: Heiko Becker, Guido Marcucci, Kati Maharry, Michael D Radmacher, Krzysztof Mrózek, Dean Margeson, Susan P Whitman, Peter Paschka, Kelsi B Holland, Sebastian Schwind, Yue-Zhong Wu, Bayard L Powell, Thomas H Carter, Jonathan E Kolitz, Meir Wetzler, Andrew J Carroll, Maria R Baer, Joseph O Moore, Michael A Caligiuri, Richard A Larson, Clara D Bloomfield
雑誌名: Blood. 2010 Aug 5;116(5):788-92. doi: 10.1182/blood-2010-01-262543. Epub 2010 May 4.
Abstract/Text We previously reported the adverse prognostic impact of Wilms tumor 1 gene (WT1) mutations in younger adult cytogenetically normal acute myeloid leukemia (CN-AML). Here, we investigated 243 older (> or = 60 years) primary CN-AML patients. WT1 mutated (WT1mut) patients (7%) had FLT3-ITD more frequently (P < .001), lower hemoglobin (P = .01), higher white blood cell count (P = .03) and percentage blood blasts (P = .03), and a shorter overall survival (P = .08) than WT1 wild-type (WT1wt) patients. Comparing older and younger WT1mut patients, they had similar pretreatment characteristics and outcome. By contrast, among WT1wt CN-AML, younger patients had a significantly better outcome. A WT1 mutation-associated gene-expression signature, reported here for the first time, included CD96, a leukemia stem cell-specific marker, and genes involved in gene regulation (eg, MLL, PML, and SNRPN) and in proliferative and metabolic processes (eg, INSR, IRS2, and PRKAA1), supporting the role of mutated WT1 in deregulating multiple homeostatic processes. Our results indicate that WT1mut CN-AML represents a distinct entity with poor treatment response across age groups. This study has been registered at www.clinicaltrials.gov as #NCT00900224.

PMID 20442368  Blood. 2010 Aug 5;116(5):788-92. doi: 10.1182/blood-201・・・
著者: E Berman, G Heller, J Santorsa, S McKenzie, T Gee, S Kempin, S Gulati, M Andreeff, J Kolitz, J Gabrilove
雑誌名: Blood. 1991 Apr 15;77(8):1666-74.
Abstract/Text 4'-Demethoxydaunorubicin (idarubicin [IDR]) is a new anthracycline that differs from its parent compound by the deletion of a methoxy group at position 4 of the chromophore ring. This minor structural modification results in a more lipophilic compound with a unique metabolite that has a prolonged plasma half-life as well as in vitro and in vivo antileukemia activity. To determine its activity in acute myelogenous leukemia (AML), 130 consecutive adult patients between the ages of 16 and 60 with newly diagnosed disease were randomized in a single institution study to receive either IDR in combination with cytosine arabinoside (Ara-C) or standard therapy with daunorubicin (DNR) and Ara-C. The trial was analyzed using the O'Brien-Fleming multiple testing design that allowed for periodic inspection of the data at specific patient accession points. After accrual of 60 patients per arm, analysis showed that patients who received IDR/Ara-C had a superior response compared with those who received standard therapy: 48 of 60 patients (80%) achieved complete remission on the former arm compared with 35 of 60 patients on the latter (58%, P = .005). Logistic regression analysis of factors associated with complete response indicated that treatment with IDR/Ara-C offered a significant advantage to patients who presented with a high initial white blood cell count compared with treatment with DNR/Ara-C. The degree of marrow aplasia was approximately the same on each arm as was nonhematologic toxicity. Overall survival for patients on the IDR/Ara-C arm was 19.5 months compared with 13.5 months on the DNR/Ara-C arm (P = .025) at a median follow-up of 2.5 years. We conclude that IDR/Ara-C can effectively replace standard therapy with DNR/Ara-C in adult patients less than age 60 with newly diagnosed AML.

PMID 2015395  Blood. 1991 Apr 15;77(8):1666-74.
著者: P H Wiernik, P L Banks, D C Case, Z A Arlin, P O Periman, M B Todd, P S Ritch, R E Enck, A B Weitberg
雑誌名: Blood. 1992 Jan 15;79(2):313-9.
Abstract/Text The purpose of this study was to determine the relative merits of idarubicin and daunorubicin in acute myeloid leukemia (AML) therapy. Thirty-two sites provided 214 previously untreated adults with AML aged 15 years or more who were randomized to receive for induction therapy cytarabine 100 mg/m2/d as a continuous 7-day infusion plus either daunorubicin 45 mg/m2/d (A + D) or idarubicin 13 mg/m2/d (A + I), daily on the first three days of treatment. Postremission therapy consisted of two courses of the induction regimen at the same daily doses, with the anthracycline administered for 2 days and cytarabine for 5. The complete response (CR) rates for evaluable patients were 70% (A + I) and 59% (A + D) (P = .08). The difference in CR rates was significant in patients aged 18 to 50 years (88% for A + I, 70% for A + D, P = .035). Resistant disease was a significantly more frequent cause of induction therapy failure with A + D than with A + I. Hyperleukocytosis (white blood cell count greater than 50,000/microL) unfavorably affected the attainment of CR with A + D but not with A + I. CR duration was significantly greater after A + I. CR duration was significantly greater after A + I treatment, and the survival of all randomized patients treated with A + I was significantly better than that observed after A + D treatment (median 12.9 months v 8.7 months, respectively, P = .038). Toxicity of the two treatments was similar, although A + I patients experienced more prolonged myelosuppression during consolidation therapy, and a greater incidence of mild chemical hepatitis was observed in the A + I group. It is concluded that, at the doses and schedule used in this study, A + I is superior to A + D for induction therapy of AML in adults.

PMID 1730080  Blood. 1992 Jan 15;79(2):313-9.
著者: W R Vogler, E Velez-Garcia, R S Weiner, M A Flaum, A A Bartolucci, G A Omura, M C Gerber, P L Banks
雑誌名: J Clin Oncol. 1992 Jul;10(7):1103-11.
Abstract/Text PURPOSE: A randomized clinical trial was undertaken to compare the therapeutic effectiveness of idarubicin (IDR) to daunorubicin (DNR), and both were given in combination with cytarabine (CA) in acute myelogenous leukemic (AML) patients.
PATIENTS AND METHODS: Newly diagnosed patients were given a daily infusion of CA (100 mg/m2) for 7 days and were assigned randomly to receive DNR (45 mg/m2) or IDR (12 mg/m2) daily for the first 3 days. Those patients who achieved a complete remission (CR) were given three consolidation courses that consisted of CA (100 mg/m2 intravenously [IV]) and thioguanine (TG; 100 mg/m2 orally) every 12 hours for 5 days and either DNR (50 mg/m2) or IDR (15 mg/m2) on the first day of each cycle. After consolidation, patients received late intensification, which consisted of the same drugs used for induction except that the CA was given for 5 days and the anthracycline for 2 days. Four courses were planned at 13-week intervals.
RESULTS: The CR rates were 75 of 105 (71%) on the IDR arm and 65 of 113 (58%) on the DNR arm (P = .03). The median survival and median remission durations were 297 and 433 days, respectively, on the IDR arm. The median survival and median remission durations were 277 and 328 days, respectively, on the DNR arm. Six deaths occurred during late intensification, five on IDR and one on DNR; this approach was abandoned after 47 patients were entered. The median survival was significantly longer for patients who received late intensification.
CONCLUSION: This trial demonstrated that IDR was more effective than DNR in remission induction in AML.

PMID 1607916  J Clin Oncol. 1992 Jul;10(7):1103-11.
著者:
雑誌名: Br J Haematol. 1998 Oct;103(1):100-9.
Abstract/Text A collaborative overview, using individual patient data, has been performed to compare idarubicin versus daunorubicin or other anthracyclines, when used with cytosine arabinoside as induction chemotherapy for newly diagnosed acute myeloid leukaemia. There were 1052 patients in five trials versus daunorubicin, 100 in one trial versus doxorubicin, and 745 in one trial versus zorubicin. In the trials of idarubicin versus daunorubicin, early induction failures were similar with the two treatments (20% idarubicin v 18% daunorubicin: P = 0.4), but after day 40 the later induction failures were fewer with idarubicin (17% v 29%: P < 0.0001). Therefore complete remission rates were higher with idarubicin (62% v 53%; P = 0.002). Among remitters, fewer of the patients allocated to idarubicin relapsed (P = 0.008) but slightly more died in remission, leading to a non-significant benefit (P = 0.07) in disease-free survival. Overall survival in these five trials was significantly better with idarubicin than with daunorubicin (13% v 9% alive at 5 years; P = 0.03). There was a trend (P = 0.006 for remission rate) for the benefit of idarubicin over daunorubicin to decrease with increasing age. There were no significant differences in outcome in the small trial comparing idarubicin versus doxorubicin, or in the large trial comparing idarubicin versus zorubicin. The induction regimens based on idarubicin achieved, in the particular circumstances of the trials reviewed here, better remission rates and better overall survival than those based on daunorubicin.

PMID 9792296  Br J Haematol. 1998 Oct;103(1):100-9.
著者: Shigeki Ohtake, Shuichi Miyawaki, Hitoshi Kiyoi, Yasushi Miyazaki, Hirokazu Okumura, Shin Matsuda, Tadashi Nagai, Yuji Kishimoto, Masaya Okada, Masatomo Takahashi, Hiroshi Handa, Jin Takeuchi, Shinichi Kageyama, Norio Asou, Fumiharu Yagasaki, Yasuhiro Maeda, Kazunori Ohnishi, Tomoki Naoe, Ryuzo Ohno
雑誌名: Int J Hematol. 2010 Mar;91(2):276-83. doi: 10.1007/s12185-009-0480-5.
Abstract/Text A multicenter, prospective, randomized study was conducted to compare a response-oriented individualized remission induction therapy with a standard fixed-schedule induction therapy, using idarubicin (IDR) and cytarabine (Ara-C), in adult patients with acute myeloid leukemia (AML). Newly diagnosed patients with AML of age less than 65 were randomly assigned to receive either of the two schedules. Both groups received IDR (12 mg/m2) for 3 days and Ara-C (100 mg/m2) for 7 days. In the individualized group, if the bone marrow on day 8 did not become hypocellular with less than 15% blasts, patients received additional IDR for one more day and Ara-C for 2 or 3 more days. Patients achieving complete remission (CR) received the same post-remission therapy. The CR rate was 79.4% for the individualized group (n = 209) and 81.9% for the fixed group (n = 221) (p = 0.598). At a median follow-up of 81 months, 7-year predicted overall survival was 37% for the individualized group and 39% for the fixed group (p = 0.496), and 7-year predicted event-free survival was 22% for the individualized group and 23% for the fixed group (p = 0.546). Thus, the present study could not demonstrate any advantage of a response-oriented individualized induction therapy over a fixed-schedule induction therapy in this protocol setting.

PMID 20054669  Int J Hematol. 2010 Mar;91(2):276-83. doi: 10.1007/s121・・・
著者: Shuichi Miyawaki, Hisashi Sakamaki, Shigeki Ohtake, Nobuhiko Emi, Fumiharu Yagasaki, Kinuko Mitani, Shin Matsuda, Yuji Kishimoto, Yasushi Miyazaki, Norio Asou, Takafumi Matsushima, Masatomo Takahashi, Yoshiaki Ogawa, Sumihisa Honda, Ryuzo Ohno, Japan Adult Leukemia Study Group AML 97 Study
雑誌名: Cancer. 2005 Dec 15;104(12):2726-34. doi: 10.1002/cncr.21493.
Abstract/Text BACKGROUND: A major concern in the treatment of patients with acute myeloid leukemia (AML) is how to prevent disease recurrences. Although intensive consolidation therapy has proven useful, the effectiveness of maintenance therapy remains controversial.
METHODS: Seven hundred eighty-nine patients ages 15-64 (median: 45 yrs) with de novo AML received induction therapy, which consisted of cytosine arabinoside (at a dose of 100 mg/m(2) on Days 1-7) and idarubicin (at a dose of 12 mg/m(2) on Days 1-3). The patients who achieved complete remission (CR) were then randomized into groups that received either four courses of standard-dose consolidation therapy without maintenance (Arm A) or three courses of standard-dose consolidation and six courses of maintenance therapy (Arm B).
RESULTS: In total, 78.7% of patients achieved CR. The 5-year overall survival (OS) rate for the 789 eligible patients was 46.9%, and the disease-free survival (DFS) rate for the 621 patients who achieved CR was 32.9%. The 5-year OS rate for Arm A was 52.4%, and 58.4% for Arm B (P = 0.599). The 5-year DFS rate for the patients who achieved CR was 35.8% in Arm A and 30.4% in Arm B (P = 0.543). In analyzing the data according to the risk groups, no statistical difference was observed either in the 5-year OS rate or in the 5-year DFS rate between the 2 arms.
CONCLUSIONS: In the current study, the Japan Adult Leukemia Study Group's conventional postremission therapy (three courses of standard-dose consolidation and six courses of maintenance therapy) was replaced successfully by a shorter duration of four courses of standard-dose consolidation therapy without the need for additional maintenance therapy.

Copyright 2005 American Cancer Society.
PMID 16284985  Cancer. 2005 Dec 15;104(12):2726-34. doi: 10.1002/cncr.・・・
著者: Shigeki Ohtake, Shuichi Miyawaki, Hiroyuki Fujita, Hitoshi Kiyoi, Katsuji Shinagawa, Noriko Usui, Hirokazu Okumura, Koichi Miyamura, Chiaki Nakaseko, Yasushi Miyazaki, Atsushi Fujieda, Tadashi Nagai, Takahisa Yamane, Masafumi Taniwaki, Masatomo Takahashi, Fumiharu Yagasaki, Yukihiko Kimura, Norio Asou, Hisashi Sakamaki, Hiroshi Handa, Sumihisa Honda, Kazunori Ohnishi, Tomoki Naoe, Ryuzo Ohno
雑誌名: Blood. 2011 Feb 24;117(8):2358-65. doi: 10.1182/blood-2010-03-273243. Epub 2010 Aug 6.
Abstract/Text We conducted a multi-institutional randomized study to determine whether high-dose daunorubicin would be as effective as standard-dose idarubicin in remission-induction therapy for newly diagnosed adult patients younger than 65 years of age with acute myeloid leukemia. Of 1064 patients registered, 1057 were evaluable. They were randomly assigned to receive either daunorubicin (50 mg/m(2) daily for 5 days) or idarubicin (12 mg/m(2) daily for 3 days) in combination with 100 mg/m(2) of cytarabine by continuous infusion daily for 7 days as induction therapy. Complete remission was achieved in 407 (77.5%) of 525 patients in the daunorubicin group and 416 (78.2%) of 532 in the idarubicin group (P = .79). Patients achieving complete remission received intensive postremission therapy that consisted of either 3 courses of high-dose cytarabine or 4 courses of standard-dose therapy. Overall survival rates at 5 years were 48% for the daunorubicin group and 48% for the idarubicin group (P = .54), and relapse-free survival rates at 5 years were 41% and 41% (P = .97), respectively. Thus, high-dose daunorubicin and standard-dose idarubicin were equally effective for the treatment of adult acute myeloid leukemia, achieving a high rate of complete remission and good long-term efficacy. This study is registered at http://www.umin.ac.jp/ctrj/ as C000000157.

PMID 20693429  Blood. 2011 Feb 24;117(8):2358-65. doi: 10.1182/blood-2・・・
著者: Hugo F Fernandez, Zhuoxin Sun, Xiaopan Yao, Mark R Litzow, Selina M Luger, Elisabeth M Paietta, Janis Racevskis, Gordon W Dewald, Rhett P Ketterling, John M Bennett, Jacob M Rowe, Hillard M Lazarus, Martin S Tallman
雑誌名: N Engl J Med. 2009 Sep 24;361(13):1249-59. doi: 10.1056/NEJMoa0904544.
Abstract/Text BACKGROUND: In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival.
METHODS: In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Patients who had a complete remission were offered either allogeneic hematopoietic stem-cell transplantation or high-dose cytarabine, with or without a single dose of the monoclonal antibody gemtuzumab ozogamicin, followed by autologous stem-cell transplantation. The primary end point was overall survival.
RESULTS: In the intention-to-treat analysis, high-dose daunorubicin, as compared with a standard dose of the drug, resulted in a higher rate of complete remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P=0.003). The rates of serious adverse events were similar in the two groups. Median follow-up was 25.2 months.
CONCLUSIONS: In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose. (ClinicalTrials.gov number, NCT00049517.)

2009 Massachusetts Medical Society
PMID 19776406  N Engl J Med. 2009 Sep 24;361(13):1249-59. doi: 10.1056・・・
著者: Alan K Burnett, Nigel H Russell, Robert K Hills, Jonathan Kell, Jamie Cavenagh, Lars Kjeldsen, Mary-Frances McMullin, Paul Cahalin, Mike Dennis, Lone Friis, Ian F Thomas, Don Milligan, Richard E Clark, UK NCRI AML Study Group
雑誌名: Blood. 2015 Jun 18;125(25):3878-85. doi: 10.1182/blood-2015-01-623447. Epub 2015 Apr 1.
Abstract/Text Modifying induction therapy in acute myeloid leukemia (AML) may improve the remission rate and reduce the risk of relapse, thereby improving survival. Escalation of the daunorubicin dose to 90 mg/m(2) has shown benefit for some patient subgroups when compared with a dose of 45 mg/m(2), and has been recommended as a standard of care. However, 60 mg/m(2) is widely used and has never been directly compared with 90 mg/m(2). As part of the UK National Cancer Research Institute (NCRI) AML17 trial, 1206 adults with untreated AML or high-risk myelodysplastic syndrome, mostly younger than 60 years of age, were randomized to a first-induction course of chemotherapy, which delivered either 90 mg/m(2) or 60 mg/m(2) on days 1, 3, and 5 combined with cytosine arabinoside. All patients then received a second course that included daunorubicin 50 mg/m(2) on days 1, 3, and 5. There was no overall difference in complete remission rate (73% vs 75%; odds ratio, 1.07 [0.83-1.39]; P = .6) or in any recognized subgroup. The 60-day mortality was increased in the 90 mg/m(2) arm (10% vs 5% (hazard ratio [HR] 1.98 [1.30-3.02]; P = .001), which resulted in no difference in overall 2-year survival (59% vs 60%; HR, 1.16 [0.95-1.43]; P = .15). In an exploratory subgroup analysis, there was no subgroup that showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. This trial is registered at http://www.isrctn.com as #ISRCTN55675535.

© 2015 by The American Society of Hematology.
PMID 25833957  Blood. 2015 Jun 18;125(25):3878-85. doi: 10.1182/blood-・・・
著者: B Löwenberg, R Zittoun, H Kerkhofs, U Jehn, J Abels, L Debusscher, C Cauchie, M Peetermans, G Solbu, S Suciu
雑誌名: J Clin Oncol. 1989 Sep;7(9):1268-74.
Abstract/Text We report the results of a prospective study in patients more than 65 years of age in whom two different therapeutic strategies were compared: immediate intensive-induction chemotherapy (arm A) versus "wait and see" and supportive care and mild cytoreductive chemotherapy only for relief of progressive acute myeloid leukemia (AML)-related symptoms (arm B). The major objective of the study was to compare survival outcome of both regimens. Thirty-one patients on arm A received one or two courses of daunorubicin, vincristine, and cytarabine for remission induction followed by one additional cycle for consolidation in case of complete remission (CR). Among 29 patients on arm B, cytoreductive chemotherapy (hydroxyurea, cytarabine) had to be initiated for palliation of leukemia-associated complications in 21 patients at a median of 9 days after diagnosis. Overall survival duration for patients treated on arm A was significantly (P = .015) longer than the survival in arm B (median survival, 21 weeks v 11 weeks; projected survival at 2.5 years, 13% v 0%). Eighteen (58%) of arm A patients and none (0%) of arm B patients entered CR. Of the first group, projected disease-free survival at 2 years is 17%. The median percentages of days spent in the hospital by arm A and B patients were 55% and 50%, respectively. This study shows that a strategy based on modern supportive care and a wait and see approach yields extremely poor results. It is not superior in regard to the frequency of hospital admission and is inferior regarding survival outcome.

PMID 2475589  J Clin Oncol. 1989 Sep;7(9):1268-74.
著者: Atsushi Wakita, Shigeki Ohtake, Satoru Takada, Fumiharu Yagasaki, Hirokazu Komatsu, Yasushi Miyazaki, Kohmei Kubo, Yukihiko Kimura, Akihiro Takeshita, Yoko Adachi, Hitoshi Kiyoi, Takuhiro Yamaguchi, Minoru Yoshida, Kazunori Ohnishi, Shuichi Miyawaki, Tomoki Naoe, Ryuzo Ueda, Ryuzo Ohno
雑誌名: Int J Hematol. 2012 Jul;96(1):84-93. doi: 10.1007/s12185-012-1105-y. Epub 2012 May 26.
Abstract/Text We conducted a multicenter prospective randomized study to compare a fixed-scheduled induction therapy with a response-oriented individualized induction therapy for elderly patients with acute myeloid leukemia (AML). Newly diagnosed AML patients, aged between 65 and 80, were randomly assigned to receive fixed or individualized induction. Both groups received daunorubicin (DNR) 40 mg/m(2) for 3 days and behenoyl cytarabine (BHAC) 200 mg/m(2) for 8 days. In the individualized group, bone marrow biopsy was done on days 8 and 10, and according to the cellularity and blast ratio, the patients received additional DNR and BHAC for two to four more days. All patients achieving complete remission (CR) were randomized a second time to determine whether they would receive ubenimex. CR was obtained in 60.1 % of the fixed group and 63.6 % of the individualized group. Predicted 4-year relapse-free survival (RFS) was 9 % for the fixed group and 18 % for the individualized group. There were no statistically significant differences in CR and RFS between the fixed and individualized groups. In the ubenimex group, prolonged RFS was observed. Notably, gender was a prognostic factor in this study, as 102 female patients had a significantly higher CR rate (72.5 vs. 54.3 %, p = 0.0048) and better OS (24 vs. 14 % at 4 years, p = 0.018), compared with 140 male patients.

PMID 22639053  Int J Hematol. 2012 Jul;96(1):84-93. doi: 10.1007/s1218・・・
著者: R J Mayer, R B Davis, C A Schiffer, D T Berg, B L Powell, P Schulman, G A Omura, J O Moore, O R McIntyre, E Frei
雑誌名: N Engl J Med. 1994 Oct 6;331(14):896-903. doi: 10.1056/NEJM199410063311402.
Abstract/Text BACKGROUND: About 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline. However, such responses are rarely durable when conventional postremission therapy is administered. Uncontrolled trials have suggested that intensive postremission therapy may prolong these complete remissions.
METHODS: We treated 1088 adults with newly diagnosed AML with three days of daunorubicin and seven days of cytarabine and randomly assigned patients who had a complete remission to receive four courses of cytarabine at one of three doses: 100 mg per square meter of body-surface area per day for five days by continuous infusion, 400 mg per square meter per day for five days by continuous infusion, or 3 g per square meter in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5. All patients then received four courses of monthly maintenance treatment.
RESULTS: Of the 693 patients who had a complete remission, 596 were randomly assigned to receive postremission cytarabine. After a median follow-up of 52 months, the disease-free survival rates in the three treatment groups were significantly different (P = 0.003). Relative to the 100-mg group, the hazard ratios were 0.67 for the 3-g group (95 percent confidence interval, 0.53 to 0.86) and 0.75 for the 400-mg group (95 percent confidence interval, 0.60 to 0.94). The probability of remaining in continuous complete remission after four years for patients 60 years of age or younger was 24 percent in the 100-mg group, 29 percent in the 400-mg group, and 44 percent in the 3-g group (P = 0.002). In contrast, for patients older than 60, the probability of remaining disease-free after four years was 16 percent or less in each of the three postremission cytarabine groups.
CONCLUSIONS: These data support the concept of a dose-response effect for cytarabine in patients with AML who are 60 years of age or younger. The results with the high-dose schedule in this age group are comparable to those reported in similar patients who have undergone allogeneic bone marrow transplantation during a first remission.

PMID 8078551  N Engl J Med. 1994 Oct 6;331(14):896-903. doi: 10.1056/・・・
著者: C D Bloomfield, D Lawrence, J C Byrd, A Carroll, M J Pettenati, R Tantravahi, S R Patil, F R Davey, D T Berg, C A Schiffer, D C Arthur, R J Mayer
雑誌名: Cancer Res. 1998 Sep 15;58(18):4173-9.
Abstract/Text Advances in the treatment of acute myeloid leukemia (AML) have occurred with the introduction of new therapies including high-dose cytarabine and the identification of powerful prognostic factors such as cytogenetics that predict for long-term outcome. To date, the prognostic impact of cytarabine dose escalation within various cytogenetic groups of AML has not been assessed. We describe 285 newly diagnosed patients with primary AML who had adequate karyotypes and were enrolled on a prospective Cancer and Leukemia Group B cytogenetic study. All patients were randomly assigned to postremission treatment with standard-, intermediate-, or high-dose cytarabine intensification. Patients were categorized to one of three cytogenetic groups: (a) core binding factor type [(CBF); ie., t(8;21) inv(16), t(16;16), and del(16)]; (b) normal; and (c) other abnormality karyotype. An evaluation of these patients after a median follow-up time of over 7 years was performed to determine the relationship of intensification to outcome by cytogenetic group. Patients included 57 patients with CBF AML, 140 patients with normal karyotype AML, and 88 patients with other cytogenetic abnormalities. The treatment outcome of CBF AML patients was superior, with an estimated 50% still in complete remission (CR) after 5 years as compared with 32 and 15% for patients with normal karyotype AML and other abnormality AML, respectively (P < 0.001). Univariate analysis showed the following nonkaryotype factors to predict a prolonged CR duration: (a) younger age (P < 0.008); (b) lower leukocyte count (P=0.01); (c) the presence of Auer rods (P=0.004); (d) a lower percentage of bone marrow blasts (P=0.001) at the time of diagnosis, (e) and a higher postremission cytarabine dose (P < 0.001). The impact of cytarabine dose on long-term remission was most marked (P < 0.001) in the CBF AML group (after 5 years, 78% of those with a dose of 3 g/m2 were still in CR, 57% of those with a dose of 400 mg/m2 were still in CR, and 16% of those with a dose of 100 mg/m2 were still in CR) followed by normal karyotype AML (P=0.01; after 5 years, 40% of those with a dose of 3 g/m2 were still in CR, 37% of those with a dose of 400 mg/m2 were still in CR, and 20% of those with a dose of 100 mg/m2 were still in CR). In contrast, cytarabine at all doses produced only a 21% or less chance of long-term continuous CR for patients with other cytogenetic abnormalities. A multivariate analysis of CR duration assessed the independent impact of each of these variables on cure. Significant factors entering this model in descending order of importance were cytogenetic group (CBF > normal > other abnormality; P=0.00001), cytarabine dose (3 g/m2 > 400 mg/m2 > 100 mg/m2; P=0.00001), logarithm of leukocyte count at the time of diagnosis (P=0.0005), and histological subtype of AML (P=0.005). This study demonstrates that the curative impact of cytarabine intensification varies significantly among cytogenetic groups and results in a substantial prolongation of CR among patients with CBF and normal karyotypes, but not in those with other karyotypic abnormalities. These findings support the use of pretreatment cytogenetics in risk stratification of postremission AML therapy.

PMID 9751631  Cancer Res. 1998 Sep 15;58(18):4173-9.
著者: J C Byrd, R K Dodge, A Carroll, M R Baer, C Edwards, J Stamberg, M Qumsiyeh, J O Moore, R J Mayer, F Davey, C A Schiffer, C D Bloomfield
雑誌名: J Clin Oncol. 1999 Dec;17(12):3767-75.
Abstract/Text PURPOSE: To examine the effect of single compared with repetitive (at least three) cycles of high-dose cytarabine after induction therapy for patients with acute myeloid leukemia (AML) who have the t(8;21)(q22;q22) karyotype.
PATIENTS AND METHODS: Patients entered onto the study had AML and t(8;21) and attained a complete remission on four successive Cancer and Leukemia Group B studies. In these studies, either > or = three cycles of high-dose cytarabine or one cycle of high-dose cytarabine was administered, followed by sequential cyclophosphamide/etoposide and mitoxantrone/diaziquone with or without filgrastim support. Outcomes of these two groups of t(8;21) patients were compared.
RESULTS: A total of 50 patients with centrally reviewed AML and t(8;21) were assigned to receive one (n = 29) or > or = three cycles (n = 21) of high-dose cytarabine as postinduction therapy. The clinical features of these two groups of patients were similar. Initial remission duration for t(8;21) patients assigned to one cycle of high-dose cytarabine was significantly inferior (P =.03), with 62% of patients experiencing relapse with a median failure-free survival of 10.5 months, compared with the group of patients who received > or = three cycles, in which only 19% experienced relapse and failure-free survival is estimated to be greater than 35 months. Furthermore, overall survival was also significantly compromised (P =.04) in patients assigned to one cycle of high-dose cytarabine, with 59% having died as a consequence of AML, compared with 24% of those who received > or = three cycles of high-dose cytarabine.
CONCLUSION: These data demonstrate that failure-free survival and overall survival of patients with t(8;21)(q22;q22) may be compromised by treatment approaches that do not include sequential high-dose cytarabine therapy.

PMID 10577848  J Clin Oncol. 1999 Dec;17(12):3767-75.
著者: Shuichi Miyawaki, Shigeki Ohtake, Shin Fujisawa, Hitoshi Kiyoi, Katsuji Shinagawa, Noriko Usui, Toru Sakura, Koichi Miyamura, Chiaki Nakaseko, Yasushi Miyazaki, Atsushi Fujieda, Tadashi Nagai, Takahisa Yamane, Masafumi Taniwaki, Masatomo Takahashi, Fumiharu Yagasaki, Yukihiko Kimura, Norio Asou, Hisashi Sakamaki, Hiroshi Handa, Sumihisa Honda, Kazunori Ohnishi, Tomoki Naoe, Ryuzo Ohno
雑誌名: Blood. 2011 Feb 24;117(8):2366-72. doi: 10.1182/blood-2010-07-295279. Epub 2010 Dec 29.
Abstract/Text We conducted a prospective randomized study to assess the optimal postremission therapy for adult acute myeloid leukemia in patients younger than 65 years in the first complete remission. A total of 781 patients in complete remission were randomly assigned to receive consolidation chemotherapy of either 3 courses of high-dose cytarabine (HiDAC, 2 g/m(2) twice daily for 5 days) alone or 4 courses of conventional standard-dose multiagent chemotherapy (CT) established in the previous JALSG AML97 study. Five-year disease-free survival was 43% for the HiDAC group and 39% for the multiagent CT group (P = .724), and 5-year overall survival was 58% and 56%, respectively (P = .954). Among the favorable cytogenetic risk group (n = 218), 5-year disease-free survival was 57% for HiDAC and 39% for multiagent CT (P = .050), and 5-year overall survival was 75% and 66%, respectively (P = .174). In the HiDAC group, the nadir of leukocyte counts was lower, and the duration of leukocyte less than 1.0 × 10(9)/L longer, and the frequency of documented infections higher. The present study demonstrated that the multiagent CT regimen is as effective as our HiDAC regimen for consolidation. Our HiDAC regimen resulted in a beneficial effect on disease-free survival only in the favorable cytogenetic leukemia group. This trial was registered at www.umin.ac.jp/ctr/ as #C000000157.

PMID 21190996  Blood. 2011 Feb 24;117(8):2366-72. doi: 10.1182/blood-2・・・
著者: Shuichi Miyawaki, Nahoko Hatsumi, Toshiharu Tamaki, Tomoki Naoe, Keiya Ozawa, Kunio Kitamura, Takahiro Karasuno, Kinuko Mitani, Yoshihisa Kodera, Tamotsu Yamagami, Daisuke Koga
雑誌名: Leuk Lymphoma. 2010 Oct;51(10):1855-61. doi: 10.3109/10428194.2010.507829.
Abstract/Text We retrospectively analyzed the potential of Wilms' tumor gene 1 (WT1) mRNA levels in peripheral blood for predicting the prognosis of 50 patients with AML. After achieving complete remission (CR), 34 patients (69.4%) were determined to be positive and 15 (30.6%) were negative for WT1. The relapse rate of the positive and negative patients was 73.5% and 40.0% (p = 0.02), respectively. After consolidation therapy, only 15 patients (32.6%) were positive and 31 (67.4%) were negative for WT1. Although the relapse rate of the positive and negative patients was 80.0% and 54.8% (p = 0.10), respectively, the rate of relapse within 1 year was 73.3% in positive patients and only 33.3% in negative patients (p = 0.01), respectively. The disease-free survival (DFS) rate at 3 years was 20.0% for positive patients and 50.0% for negative patients (p = 0.01). The overall survival (OS) rate at 3 years was 42.8% in positive patients and 69.8% in negative patients (p = 0.04), respectively. WT1 mRNA levels in the peripheral blood can predict relapse after CR, and its levels after consolidation therapy are closely correlated with DFS, OS, and early relapse.

PMID 20849384  Leuk Lymphoma. 2010 Oct;51(10):1855-61. doi: 10.3109/10・・・
著者: P Fenaux, C Chastang, S Chevret, M Sanz, H Dombret, E Archimbaud, M Fey, C Rayon, F Huguet, J J Sotto, C Gardin, P C Makhoul, P Travade, E Solary, N Fegueux, D Bordessoule, J S Miguel, H Link, B Desablens, A Stamatoullas, E Deconinck, F Maloisel, S Castaigne, C Preudhomme, L Degos
雑誌名: Blood. 1999 Aug 15;94(4):1192-200.
Abstract/Text All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA-->CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment]) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/microL (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA -->CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P =.0002) and close to significance in the elderly group (P =.086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA-->CT group (P =.04, relative risk [RR] =.41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA-->CT group (P =.1, RR =.62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P =.0002) and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P =.02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had relapsed. Overall survival was improved in patients who received maintenance CT (P =.01), and there was a trend for better survival in patients who received maintenance ATRA (P =.22). Our findings strongly suggest that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT and intermittent ATRA can reduce the incidence of relapse in APL. This effect already translates into significantly better survival for maintenance treatment with continuous CT.

PMID 10438706  Blood. 1999 Aug 15;94(4):1192-200.
著者: M S Tallman, J W Andersen, C A Schiffer, F R Appelbaum, J H Feusner, A Ogden, L Shepherd, C Willman, C D Bloomfield, J M Rowe, P H Wiernik
雑誌名: N Engl J Med. 1997 Oct 9;337(15):1021-8. doi: 10.1056/NEJM199710093371501.
Abstract/Text BACKGROUND: All-trans-retinoic acid induces complete remission in acute promyelocytic leukemia. However, it is not clear whether induction therapy with all-trans-retinoic acid is superior to chemotherapy alone or whether maintenance treatment with all-trans-retinoic acid improves outcome.
METHODS: Three hundred forty-six patients with previously untreated acute promyelocytic leukemia were randomly assigned to receive all-trans-retinoic acid or daunorubicin plus cytarabine as induction treatment. Patients who had a complete remission received consolidation therapy consisting of one cycle of treatment identical to the induction chemotherapy, then high-dose cytarabine plus daunorubicin. Patients still in complete remission after two cycles of consolidation therapy were then randomly assigned to maintenance treatment with all-trans-retinoic acid or to observation.
RESULTS: Of the 174 patients treated with chemotherapy, 120 (69 percent) had a complete remission, as did 124 of the 172 (72 percent) given all-trans-retinoic acid (P=0.56). When both induction and maintenance treatments were taken into account, the estimated rates of disease-free survival at one, two, and three years were 77, 61, and 55 percent, respectively, for patients assigned to chemotherapy then all-trans-retinoic acid; 86, 75, and 75 percent for all-trans-retinoic acid then all-trans-retinoic acid; 75, 60, and 60 percent for all-trans-retinoic acid then observation; and 29, 18, and 18 percent for chemotherapy then observation. By intention-to-treat analysis, the rates of overall survival at one, two, and three years after entry into the study were 75, 57, and 50 percent, respectively, among patients assigned to chemotherapy, and 82, 72, and 67 percent among those assigned to all-trans-retinoic acid (P= 0.003).
CONCLUSIONS: All-trans-retinoic acid as induction or maintenance treatment improves disease-free and overall survival as compared with chemotherapy alone and should be included in the treatment of acute promyelocytic leukemia.

PMID 9321529  N Engl J Med. 1997 Oct 9;337(15):1021-8. doi: 10.1056/N・・・
著者: Z X Shen, G Q Chen, J H Ni, X S Li, S M Xiong, Q Y Qiu, J Zhu, W Tang, G L Sun, K Q Yang, Y Chen, L Zhou, Z W Fang, Y T Wang, J Ma, P Zhang, T D Zhang, S J Chen, Z Chen, Z Y Wang
雑誌名: Blood. 1997 May 1;89(9):3354-60.
Abstract/Text The therapeutic effect of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL) was evaluated among 15 APL patients at relapse after all-trans retinoic acid (ATRA) induced and chemotherapy maintained complete remission (CR). As2O3 was administered intravenously at the dose of 10 mg/d. Clinical CR was achieved in nine of 10 (90%) patients treated with As2O3 alone and in the remaining five patients treated by the combination of As2O3 and low-dose chemotherapeutic drugs or ATRA. During the treatment with As2O3, there was no bone marrow depression and only limited side effects were encountered. Pharmacokinetic studies, which were performed in eight patients, showed that after a peak level of 5.54 micromol/L to 7.30 micromol/L, plasma arsenic was rapidly eliminated, and the continuous administration of As2O3 did not alter its pharmacokinetic behaviors. In addition, increased amounts of arsenic appeared in the urine, with a daily excretion accounting for approximately 1% to 8% of the total daily dose administered. Arsenic contents in hair and nail were increased, and the peak content of arsenic could reach 2.5 to 2.7 microg/g tissue at CR. On the other hand, a decline of the arsenic content in hair and nail was observed after withdrawal of the drug. We conclude that As2O3 treatment is an effective and relatively safe drug in APL patients refractory to ATRA and conventional chemotherapy.

PMID 9129042  Blood. 1997 May 1;89(9):3354-60.

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