今日の臨床サポート

急性リンパ芽球性白血病(ALL)

著者: 薄井紀子 東京慈恵会医科大学

監修: 木崎昌弘 埼玉医科大学総合医療センター

著者校正済:2020/09/03
現在監修レビュー中
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年補訂版(2020年5月25日 第2版補訂版) I.白血病、3.急性リンパ芽球性白血病/リンパ芽球性リンパ腫(ALL/LBL)
  1. National Comprehensive Cancer Network (NCCN) Acute lymphoblastic leukemia (ALL) ver. 2.2019
患者向け説明資料

概要・推奨   

  1. ALLの治療前には、診断のための骨髄検査と合併症の評価のための各種検査を行う(推奨度1)
  1. ALLの初回寛解導入治療法には、リンパ系腫瘍に有効性の高い抗がん薬の多剤併用療法が用いられる(推奨度1)
  1. ALL治療においては、標準的とされるベストな治療法は確立されていない。したがってALL患者はすべて治療成績の向上のために施行される臨床試験に可能な限り参加すべきである(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。閲覧にはご契約が必要となります。閲覧に
  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
  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
  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
  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
  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。閲覧にはご契約が必要となります。閲覧にはご
  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。閲覧にはご契約が必要となりま
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:
薄井紀子 : 原稿料(シミック株式会社,日本新薬,アッヴィ合同会社,第一三共株式会社)[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. 日本血液学会 造血器腫瘍診療ガイドラインのALL/LBL部分を踏まえて、アルゴリズムを改訂を行った。
  1. ALL治療図はJALSGALL202-Oプロトコールを基本として改訂を行った。

病態・疫学・診察

疾患情報  
  1. 年間の新規急性リンパ芽球性白血病(ALL)の発症は2,300人で、成人急性白血病の20~25%、小児の75~80%を占めていると推定される。
  1. 発症年齢は、乳幼児期と50歳以降の2つのピークを認めている。
  1. 前駆B細胞(Precursor B cell、Pre-B)ALL、成熟B細胞ALL(Burkitt-ALL/リンパ腫)、前駆T細胞(Precursor T cell、Pre-T)ALLのサブタイプがある。(表<図表>,表<図表>
  1. 自覚症状は、全身倦怠感、易出血性、動悸息切れ、眩暈、易感染性、発熱、盗汗や体重減少を認め、他覚的に皮下出血、貧血、全身リンパ節腫脹(リンパ節腫張)、肝脾腫を認める。初診時より約6%に白血病細胞の中枢神経(CNS)浸潤を認める。
  1. 無治療では、ALLは週単位の急激な致死的転帰を取るため、診断後速やかに治療が施行される。
  1. 治療方針は、多剤併用療法による寛解導入療法と寛解到達後の地固め療法、維持療法からなり、CNS浸潤の予防目的の髄腔内化学療法(髄注)を適宜加える。予後不良では、同種造血幹細胞移植療法を寛解後療法として考慮する。(図アルゴリズム
  1. 重要な予後因子は、年齢、染色体異常である。(表<図表>,表<図表>
問診・診察のポイント  
  1. ALLは、軽度の血液検査異常を指摘され、自覚的・他覚的症状が皆無の比較的早期のものから、高熱、全身倦怠感、リンパ節腫張出血傾向、白血球数の増加、貧血、血小板減少や肺炎を呈するものまでさまざまである。

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文献 

著者: S B Murphy
雑誌名: N Engl J Med. 1978 Dec 28;299(26):1446-8. doi: 10.1056/NEJM197812282992606.
Abstract/Text
PMID 362210  N Engl J Med. 1978 Dec 28;299(26):1446-8. doi: 10.1056/・・・
著者: S K Williford, P L Salisbury, J E Peacock, J M Cruz, B L Powell, E S Lyerly, R L Capizzi
雑誌名: J Clin Oncol. 1989 Jun;7(6):798-802.
Abstract/Text Dental disorders have been recognized as major sources of infection in patients with hematologic malignancies (HM). Management of severe dental infections usually includes dental extractions (DE), but the safety of extractions in patients with HM who are at risk for bleeding, sepsis, and poor wound healing has not been well established. In conjunction with an aggressive program of dental care, 142 DE were performed in 26 patients with acute leukemia, myelodysplastic syndromes, and myeloproliferative disorders. Granulocytopenia (less than 1,000 granulocytes/microL) was present during or within ten days following surgery in 14 patients. In these 14 patients (101 DE), the mean granulocyte count was less than 450/microL, with a median duration of granulocytopenia following surgery of 32 days (range, four to 169 days). Thrombocytopenia (less than 100,000 platelets/microL) occurred during or within two days following surgery in 13 patients (80 DE), with a mean platelet count of 63,500/microL. Transfusions were given for platelet counts less than 50,000/microL. All DE were performed without significant complications. Bleeding was minor to moderate and easily controlled with local measures; no patient required transfusion due to hemorrhage. Average maximum temperature 24 hours after DE was 37.7 degrees C. No episodes of bacteremia were documented within ten days of DE. Minor delay in wound healing was observed in two patients. We conclude that DE can be safely performed in patients with HM in combination with aggressive supportive care.

PMID 2523958  J Clin Oncol. 1989 Jun;7(6):798-802.
著者: Jacob M Rowe, Georgina Buck, Alan K Burnett, Raj Chopra, Peter H Wiernik, Susan M Richards, Hillard M Lazarus, Ian M Franklin, Mark R Litzow, Niculae Ciobanu, H Grant Prentice, Jill Durrant, Martin S Tallman, Anthony H Goldstone, ECOG, MRC/NCRI Adult Leukemia Working Party
雑誌名: Blood. 2005 Dec 1;106(12):3760-7. doi: 10.1182/blood-2005-04-1623. Epub 2005 Aug 16.
Abstract/Text The international acute lymphoblastic leukemia (ALL) study was designed to prospectively define the optimal therapy for adults 60 years of age or younger with newly diagnosed ALL. All patients received identical induction therapy, and 91% achieved complete remission (CR). Patients 50 years of age or younger with a compatible sibling were assigned to undergo allogeneic transplantation; the others were randomly assigned to autologous transplantation or to consolidation/maintenance therapy for 2.5 years. Patients who did not achieve CR after induction had an overall survival rate of 5% compared with 45% for patients who achieved CR. Factors at diagnosis predictive of overall survival and disease-free survival were age (P = .001), white blood cell count less than 30 x 10(9)/L for B lineage or less than 100 x 10(9)/L for T lineage (P = .001) and immunophenotype, T lineage versus B lineage (P = .001). The data demonstrate that achieving CR with induction therapy is indispensable for long-term survival in adult patients with ALL. Furthermore, with a response rate greater than 90%, the induction regimen was highly efficacious as remission-inducing therapy. This large database has validated several previously identified independent prognostic factors in ALL, such as age, white blood cell count at presentation, cytogenetics, and immunophenotype. However, the achievement of CR within 4 weeks does not appear to be an independent prognostic factor.

PMID 16105981  Blood. 2005 Dec 1;106(12):3760-7. doi: 10.1182/blood-20・・・
著者: Anthony V Moorman, Christine J Harrison, Georgina A N Buck, Sue M Richards, Lorna M Secker-Walker, Mary Martineau, Gail H Vance, Athena M Cherry, Rodney R Higgins, Adele K Fielding, Letizia Foroni, Elisabeth Paietta, Martin S Tallman, Mark R Litzow, Peter H Wiernik, Jacob M Rowe, Anthony H Goldstone, Gordon W Dewald, Adult Leukaemia Working Party, Medical Research Council/National Cancer Research Institute
雑誌名: Blood. 2007 Apr 15;109(8):3189-97. doi: 10.1182/blood-2006-10-051912. Epub 2006 Dec 14.
Abstract/Text Pretreatment cytogenetics is a known predictor of outcome in hematologic malignancies. However, its usefulness in adult acute lymphoblastic leukemia (ALL) is generally limited to the presence of the Philadelphia (Ph) chromosome because of the low incidence of other recurrent abnormalities. We present centrally reviewed cytogenetic data from 1522 adult patients enrolled on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. The incidence and clinical associations for more than 20 specific chromosomal abnormalities are presented. Patients with a Ph chromosome, t(4;11)(q21;q23), t(8;14)(q24.1;q32), complex karyotype (5 or more chromosomal abnormalities), or low hypodiploidy/near triploidy (Ho-Tr) all had inferior rates of event-free and overall survival when compared with other patients. In contrast, patients with high hyperdiploidy or a del(9p) had a significantly improved outcome. Multivariate analysis demonstrated that the prognostic relevance of t(8;14), complex karyotype, and Ho-Tr was independent of sex, age, white cell count, and T-cell status among Ph-negative patients. The observation that Ho-Tr and, for the first time, karyotype complexity confer an increased risk of treatment failure demonstrates that cytogenetic subgroups other than the Ph chromosome can and should be used to risk stratify adults with ALL in future trials.

PMID 17170120  Blood. 2007 Apr 15;109(8):3189-97. doi: 10.1182/blood-2・・・
著者: Ching-Hon Pui, William E Evans
雑誌名: N Engl J Med. 2006 Jan 12;354(2):166-78. doi: 10.1056/NEJMra052603.
Abstract/Text
PMID 16407512  N Engl J Med. 2006 Jan 12;354(2):166-78. doi: 10.1056/N・・・
著者: J Takeuchi, T Kyo, K Naito, H Sao, M Takahashi, S Miyawaki, K Kuriyama, S Ohtake, F Yagasaki, H Murakami, N Asou, T Ino, T Okamoto, N Usui, M Nishimura, K Shinagawa, T Fukushima, H Taguchi, T Morii, S Mizuta, H Akiyama, Y Nakamura, T Ohshima, R Ohno
雑誌名: Leukemia. 2002 Jul;16(7):1259-66. doi: 10.1038/sj.leu.2402526.
Abstract/Text In order to improve the disappointing prognosis of adult patients with acute lymphoblastic leukemia (ALL), we applied similar induction therapy as that used for acute myeloid leukemia (AML), ie frequent administration of doxorubicin (DOX). DOX 30 mg/m(2) was administered from days 1 to 3 and from days 8 to 10 together with vincristine, prednisolone, cyclophosphamide and L-asparaginase, followed by three courses of consolidation and four courses of intensification. From December 1993 to February 1997, 285 untreated adult patients with de novo ALL were entered. Of 263 evaluable patients (age 15 to 59; median 31), 205 (78%) obtained complete remission (CR). At a median follow-up period of 63 months, the predicted 6-year overall survival (OS) rate of all patients was 33%, and disease-free survival (DFS) rate of CR patients was 30%, respectively. By multivariate analysis, favorable prognostic factors for the achievement of CR were age <40 and WBC <50 000/microl; for longer OS were age <30 and WBC <30 000/microl; and for longer DFS of CR patients were FAB L1 and ALT <50 IU/l. Among 229 patients who had adequate cytogenetic data, 51 (22%) had Philadelphia (Ph) chromosome. Ph-negative chromosome was a common favorable prognostic factor for CR, longer OS and DFS. DFS was not different between early sequential intensification (n = 48) and intermittent intensification (n = 43) during the maintenance phase. Among CR patients under 40 years old, the 6-year survival was not different between the allocated related allo-BMT group (34 patients) and the allocated chemotherapy group (108 patients). However, among patients with Ph-positive ALL, the survival of patients who actually received allo-BMT was superior to that of patients who received chemotherapy (P = 0.046).

PMID 12094249  Leukemia. 2002 Jul;16(7):1259-66. doi: 10.1038/sj.leu.2・・・
著者: Itsuro Jinnai, Tohru Sakura, Motohiro Tsuzuki, Yasuhiro Maeda, Noriko Usui, Masayuki Kato, Hirokazu Okumura, Taiichi Kyo, Yasunori Ueda, Yuji Kishimoto, Fumiharu Yagasaki, Kosuke Tsuboi, Shigeo Horiike, Jin Takeuchi, Masako Iwanaga, Yasushi Miyazaki, Shuichi Miyawaki, Kazunori Ohnishi, Tomoki Naoe, Ryuzo Ohno
雑誌名: Int J Hematol. 2010 Oct;92(3):490-502. doi: 10.1007/s12185-010-0672-z. Epub 2010 Sep 10.
Abstract/Text We designed a treatment protocol for newly diagnosed adult acute lymphoblastic leukemia (ALL) in the pre-imatinib era, employing intensified consolidation therapy with a total of 330 mg/m² doxorubicin and adopting slightly modified induction and maintenance regimen of the CALGB 8811 study. Of 404 eligible patients (median age 38 years, range 15-64 years), 298 (74%) achieved complete remission (CR). The 5-year overall survival (OS) rate was 32%, and the 5-year disease-free survival (DFS) rate was 33%. Of 256 Philadelphia chromosome (Ph)-negative patients, 208 (81%) achieved CR and the 5-year OS rate was 39%, and 60 of them underwent allogeneic-hematopoietic stem cell transplantation (allo-HSCT) from related or unrelated donors during the first CR, resulting in 63% 5-year OS. Of 116 Ph-positive patients, 65 (56%) achieved CR and the 5-year OS rate was 15%, and 22 of them underwent allo-HSCT from related or unrelated donors during the first CR, resulting in 47% 5-year OS. In Ph-negative patients, multivariate analysis showed that older age, advanced performance status and unfavorable karyotypes were significant poor prognostic factors for OS and higher WBC counts for DFS. The present treatment regimen could not show a better outcome than that of our previous JALSG-ALL93 study for adult ALL.

PMID 20830614  Int J Hematol. 2010 Oct;92(3):490-502. doi: 10.1007/s12・・・
著者: Oliver G Ottmann, Barbara Wassmann
雑誌名: Hematology Am Soc Hematol Educ Program. 2005;:118-22. doi: 10.1182/asheducation-2005.1.118.
Abstract/Text Philadelphia chromosome positive (Ph(+)) acute lymphoblastic leukemia (ALL) includes at least one-quarter of all adults with ALL. Until recently, conventional chemotherapy programs that have been effective in other precursor B-cell ALL cases have been unable to cure patients with this diagnosis. Allogeneic stem cell transplantation early in first remission has been the recommended therapy. The availability of imatinib mesylate and other tyrosine kinase inhibitors and small molecules that affect the BCR/ABL signaling pathways may be changing the treatment paradigm and the prognosis for these patients. The results from clinical trials using imatinib in the frontline setting and in relapsed patients as well as preliminary experience treating imatinib-resistant Ph(+) ALL will be described.

PMID 16304368  Hematology Am Soc Hematol Educ Program. 2005;:118-22. d・・・
著者: T Sakura, F Hayakawa, I Sugiura, T Murayama, K Imai, N Usui, S Fujisawa, T Yamauchi, T Yujiri, K Kakihana, Y Ito, H Kanamori, Y Ueda, Y Miyata, M Kurokawa, N Asou, K Ohnishi, S Ohtake, Y Kobayashi, K Matsuo, H Kiyoi, Y Miyazaki, T Naoe
雑誌名: Leukemia. 2018 Mar;32(3):626-632. doi: 10.1038/leu.2017.283. Epub 2017 Sep 15.
Abstract/Text High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2) or Id-MTX (0.5 g/m2). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.

PMID 28914260  Leukemia. 2018 Mar;32(3):626-632. doi: 10.1038/leu.2017・・・
著者: Masamitsu Yanada, Jin Takeuchi, Isamu Sugiura, Hideki Akiyama, Noriko Usui, Fumiharu Yagasaki, Tohru Kobayashi, Yasunori Ueda, Makoto Takeuchi, Shuichi Miyawaki, Atsuo Maruta, Nobuhiko Emi, Yasushi Miyazaki, Shigeki Ohtake, Itsuro Jinnai, Keitaro Matsuo, Tomoki Naoe, Ryuzo Ohno, Japan Adult Leukemia Study Group
雑誌名: J Clin Oncol. 2006 Jan 20;24(3):460-6. doi: 10.1200/JCO.2005.03.2177. Epub 2005 Dec 12.
Abstract/Text PURPOSE: A novel therapeutic approach is urgently needed for BCR-ABL-positive acute lymphoblastic leukemia (ALL). In this study, we assessed the efficacy and feasibility of chemotherapy combined with imatinib.
PATIENTS AND METHODS: A phase II study of imatinib-combined chemotherapy was conducted for newly diagnosed BCR-ABL-positive ALL in adults. Eighty patients were entered into the trial between September 2002 and January 2005.
RESULTS: Remission induction therapy resulted in complete remission (CR) in 77 patients (96.2%), resistant disease in one patient, and early death in two patients, as well as polymerase chain reaction negativity of bone marrow in 71.3%. The profile and incidence of severe toxicity were not different from those associated with our historic chemotherapy-alone regimen. Relapse occurred in 20 patients after median CR duration of 5.2 months. Allogeneic hematopoietic stem-cell transplantation (HSCT) was performed for 49 patients, 39 of whom underwent transplantation during their first CR. The 1-year event-free and overall survival (OS) rates were estimated to be 60.0%, and 76.1%, respectively, which were significantly better than those for our historic controls treated with chemotherapy alone (P < .0001 for both). Among the current trial patients, the probability for OS at 1 year was 73.3% for those who underwent allogeneic HSCT, and 84.8% for those who did not.
CONCLUSION: Our results demonstrated that imatinib-combined regimen is effective and feasible for newly diagnosed BCR-ABL-positive ALL. Despite a relatively short period of observation, a major potential of this treatment is recognized. Longer follow-up is required to determine its overall effect on survival.

PMID 16344315  J Clin Oncol. 2006 Jan 20;24(3):460-6. doi: 10.1200/JCO・・・
著者: Deborah A Thomas, Stefan Faderl, Jorge Cortes, Susan O'Brien, Francis J Giles, Steven M Kornblau, Guillermo Garcia-Manero, Michael J Keating, Michael Andreeff, Sima Jeha, Miloslav Beran, Srdan Verstovsek, Sherry Pierce, Laurie Letvak, August Salvado, Richard Champlin, Moshe Talpaz, Hagop Kantarjian
雑誌名: Blood. 2004 Jun 15;103(12):4396-407. doi: 10.1182/blood-2003-08-2958. Epub 2003 Oct 9.
Abstract/Text Imatinib mesylate, an inhibitor of the Bcr-Abl tyrosine kinase, has modest activity in refractory/relapsed Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL). Use of concurrent chemotherapy and imatinib mesylate in newly diagnosed Ph-positive ALL was explored. There were 20 patients who received hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) and imatinib mesylate followed by imatinib mesylate-based consolidation/maintenance therapy. Of these patients, 11 had de novo disease, 4 were primary failures after induction (without imatinib mesylate), and 5 were in complete remission (CR) after induction (without imatinib mesylate). All 15 patients treated for active disease achieved CR. Within a median of 3.5 months in first CR, 10 patients underwent allogeneic stem cell transplantation (SCT). One patient relapsed after matched related SCT. The other 9 patients remained alive in CR with median follow-up of 12 months after SCT (range, 1+ to 17+ months). Among 10 patients ineligible for (no donor or older age) or refusing allogeneic SCT, 1 patient relapsed after one year. There were 5 patients who remained alive in continuous CR for a median of 20 months (range, 4+ to 24+ months), with 2 older patients dying in CR at 15 and 16 months of comorbid conditions. Molecular CRs were achieved in both groups (SCT or no SCT). Outcome with hyper-CVAD and imatinib mesylate appears better than with prior regimens; continued accrual and longer follow-up of the current cohort is needed.

PMID 14551133  Blood. 2004 Jun 15;103(12):4396-407. doi: 10.1182/blood・・・
著者: Juan-Manuel Sancho, Josep-Maria Ribera, Albert Oriol, Jesus-Maria Hernandez-Rivas, Concepcion Rivas, Concepcion Bethencourt, Ricardo Parody, Guillermo Deben, Jose-Luis Bello, Evarist Feliu, Programa para el Estudio y Tratamiento de Hemopatias Malignas Group
雑誌名: Cancer. 2006 Jun 15;106(12):2540-6. doi: 10.1002/cncr.21948.
Abstract/Text Recurrence of acute lymphoblastic leukemia (ALL) in the central nervous system (CNS) confers a poor prognosis, although to the authors' knowledge, only a few studies have analyzed this issue in adults. For the current study, the authors analyzed the frequency, predictive factors, and prognosis of CNS involvement and recurrence in adult patients with ALL who did not receive cranial irradiation for CNS prophylaxis. Four hundred sixty-seven adult patients (age > or = 15 years) with ALL were treated on 4 protocols: ALL-89 (standard-risk and high-risk ALL; n = 108 patients), ALL-93 (high-risk ALL; n = 222 patients), ALL-96 (standard-risk ALL; n = 84 patients), and ALL3-97 (Burkitt leukemia; n = 53 patients). CNS prophylaxis consisted of intrathecal methotrexate, cytarabine, and hydrocortisone together with high-dose systemic methotrexate and cytarabine. The mean age (+/- standard deviation) was 33 years (+/- 16 years), and 272 patients were males. ALL subtypes included an early pre-B phenotype (15%), a common phenotype (45%), a pre-B phenotype (5%), a mature B phenotype (11%), and a T phenotype (24%). CNS involvement at diagnosis was observed in 18 patients (3.9%). Of 159 recurrences, 22 occurred (5.8%) in the CNS (14 isolated and 8 combined). A lactate dehydrogenase level > 1000 U/L was the only factor associated with the risk of CNS recurrence. A complete remission was attained in 7 of 22 patients (32%). The median overall survival after recurrence was 0.7 years for patients with isolated CNS recurrence, 0.13 years for patients with combined recurrence, and 0.41 years for patients with bone marrow recurrence (P = .11). The only 2 survivors underwent stem cell transplantation. The frequency of CNS recurrence in adult patients with ALL who do not receive radiotherapy for CNS prophylaxis was similar to the frequency observed in protocols that included cranial irradiation. A lactate dehydrogenase value >1000 U/L was the only factor found to be associated with CNS recurrence. The prognosis for patients who develop CNS recurrence is poor, identical to that for patients who develop bone marrow recurrence.

Copyright 2006 American Cancer Society.
PMID 16700036  Cancer. 2006 Jun 15;106(12):2540-6. doi: 10.1002/cncr.2・・・
著者: Xavier Thomas, Jean-Michel Boiron, Françoise Huguet, Hervé Dombret, Ken Bradstock, Norbert Vey, Tibor Kovacsovics, André Delannoy, Nathalie Fegueux, Pierre Fenaux, Aspasia Stamatoullas, Jean-Paul Vernant, Olivier Tournilhac, Agnès Buzyn, Oumedaly Reman, Christiane Charrin, Claude Boucheix, Jean Gabert, Véronique Lhéritier, Denis Fiere
雑誌名: J Clin Oncol. 2004 Oct 15;22(20):4075-86. doi: 10.1200/JCO.2004.10.050. Epub 2004 Sep 7.
Abstract/Text PURPOSE: We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL.
PATIENTS AND METHODS: A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT.
RESULTS: Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3.
CONCLUSION: Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.

PMID 15353542  J Clin Oncol. 2004 Oct 15;22(20):4075-86. doi: 10.1200/・・・
著者: Hillard M Lazarus, Susan M Richards, Raj Chopra, Mark R Litzow, Alan K Burnett, Peter H Wiernik, Ian M Franklin, Martin S Tallman, Lucy Cook, Georgina Buck, I Jill Durrant, Jacob M Rowe, Anthony H Goldstone, Medical Research Council (MRC)/National Cancer Research Institute (NCRI) Adult Leukaemia Working Party of the United Kingdom and the Eastern Cooperative Oncology Group
雑誌名: Blood. 2006 Jul 15;108(2):465-72. doi: 10.1182/blood-2005-11-4666. Epub 2006 Mar 23.
Abstract/Text Outcome of acute lymphoblastic leukemia (ALL) in adults with central nervous system (CNS) disease at diagnosis is unclear. We treated 1508 de novo ALL patients with 2-phase induction and then high-dose methotrexate with l-asparaginase. Patients up to 50 years old in first remission (CR1) with a matched related donor (MRD) underwent an allogeneic stem cell transplantation (SCT); the remainder in CR1 were randomized to an autologous SCT or intensive consolidation followed by maintenance chemotherapy. Philadelphia chromosome (Ph)-positive patients were offered a matched unrelated donor (MUD) allogeneic SCT. Seventy-seven of 1508 (5%) patients a median age of 29 years had CNS leukemia at presentation; 13 of the 77 (17%) had Ph-positive ALL. Sixty-nine of 77 (90%) patients attained CR1. Thirty-six patients underwent transplantation in CR1 (25 MRD, 5 MUD, and 6 autografts). Eleven of 25 patients with MRD transplantation remain alive at 21 to 102 months, 2 of 5 with MUD at 42 and 71 months, and 1 of 6 with autologous SCT at 35 months. Seven of 27 treated with consolidation/maintenance remain in CR1 56 to 137 months after diagnosis. Overall survival at 5 years was 29% in those with CNS involvement at diagnosis versus 38% (P = .03) for those without. CNS leukemia in adult ALL is uncommon at diagnosis. Adult Ph-negative ALL patients, however, can attain long-term disease-free survival using SCT as well as conventional chemotherapy.

PMID 16556888  Blood. 2006 Jul 15;108(2):465-72. doi: 10.1182/blood-20・・・
著者: Hervé Dombret, Jean Gabert, Jean-Michel Boiron, Françoise Rigal-Huguet, Didier Blaise, Xavier Thomas, André Delannoy, Agnès Buzyn, Chrystèle Bilhou-Nabera, Jean-Michel Cayuela, Pierre Fenaux, Jean-Henri Bourhis, Nathalie Fegueux, Christiane Charrin, Claude Boucheix, Véronique Lhéritier, Hélène Espérou, Elizabeth MacIntyre, Jean-Paul Vernant, Denis Fière, Groupe d'Etude et de Traitement de la Leucémie Aiguë Lymphoblastique de l'Adulte (GET-LALA Group)
雑誌名: Blood. 2002 Oct 1;100(7):2357-66. doi: 10.1182/blood-2002-03-0704.
Abstract/Text From 1994 to 2000, 154 adults with Philadelphia chromosome-positive (Ph(+)) and/or BCR-ABL(+) acute lymphoblastic leukemia (ALL) were treated according to a prospective trial (median follow-up, 4.5 years) with the aim to study the prognostic value of early response to therapy and the role of stem cell transplantation (SCT) in first complete remission (CR). All patients received a standard induction course followed by a course of mitoxantrone and intermediate-dose cytarabine (HAM). After each course, minimal residual disease was tested by specific reverse transcriptase-polymerase chain reaction (RT-PCR) (median sensitivity, 10(-5)). Allogeneic SCT (if a donor) or autologous SCT (if not) was planned at 3 months in all patients in CR after HAM. CR rates after induction, after HAM, and at 3 months were 53%, 67%, and 62%, respectively. High leukocyte count and m-bcr subtype were the 2 identified bad-prognosis factors for CR at 3 months, both superseded by a poor early response assessed at day 8 of the induction course. HAM-associated salvage rate was higher in patients with M-bcr than in those with m-bcr ALL (55% vs 30%; P =.05). In the 103 patients eligible for SCT, the existence of a donor and the negative BCR-ABL status after HAM were independently predictive of remission duration (P <.001 and.01, respectively) and survival (P =.02 and.01, respectively). Relapse was the most common cause of treatment failure in all patient groups. Allogeneic SCT in first CR is the current best treatment option in adults with the disease. New strategies must be tested during early phases of therapy to increase the rate of BCR-ABL(-) remissions.

PMID 12239143  Blood. 2002 Oct 1;100(7):2357-66. doi: 10.1182/blood-20・・・
著者: K Miyamura, M Tanimoto, Y Morishima, K Horibe, K Yamamoto, M Akatsuka, Y Kodera, S Kojima, K Matsuyama, N Hirabayashi
雑誌名: Blood. 1992 Mar 1;79(5):1366-70.
Abstract/Text Minimal residual disease (MRD) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1 ALL) who received allogeneic (n = 9) or autologous (n = 6) bone marrow transplantation (BMT) was evaluated by the polymerase chain reaction (PCR) for the bcr-abl transcript. Twelve patients received BMT at the time of hematologic and cytogenetic remission. However, MRD was detected in 8 of 10 patients evaluated. Seven patients, including three who had MRD before BMT, continue to have a disease-free survival 5 to 64 months after BMT. Twenty-one specimens obtained from these patients at various times after BMT did not show MRD. In three patients, MRD detected just before BMT seems to be eradicated by BMT protocol. The other eight patients developed cytogenetic or hematologic relapses 2 to 8 months after BMT. Seven of 14 samples from these patients demonstrated MRD, which preceded clinical relapse by 3 to 9 weeks. Thus, this technique for the detection of MRD appears to be useful for the more precise assessment of various antileukemia therapies and for early detection of leukemia recurrence.

PMID 1371420  Blood. 1992 Mar 1;79(5):1366-70.
著者: Masamitsu Yanada, Isamu Sugiura, Jin Takeuchi, Hideki Akiyama, Atsuo Maruta, Yasunori Ueda, Noriko Usui, Fumiharu Yagasaki, Toshiaki Yujiri, Makoto Takeuchi, Kazuhiro Nishii, Yukihiko Kimura, Shuichi Miyawaki, Hiroto Narimatsu, Yasushi Miyazaki, Shigeki Ohtake, Itsuro Jinnai, Keitaro Matsuo, Tomoki Naoe, Ryuzo Ohno, Japan Adult Leukemia Study Group
雑誌名: Br J Haematol. 2008 Nov;143(4):503-10. doi: 10.1111/j.1365-2141.2008.07377.x.
Abstract/Text The clinical significance of minimal residual disease (MRD) is uncertain in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) treated with imatinib-combined chemotherapy. Here we report the results of prospective MRD monitoring in 100 adult patients. Three hundred and sixty-seven follow-up bone marrow samples, collected at predefined time points during a uniform treatment protocol, were analysed for BCR-ABL1 transcripts by quantitative reverse transcription polymerase chain reaction. Ninety-seven patients (97%) achieved complete remission (CR), and the relapse-free survival (RFS) rate was 46% at 3 years. Negative MRD at the end of induction therapy was not associated with longer RFS or a lower relapse rate (P = 0.800 and P = 0.964 respectively). Twenty-nine patients showed MRD elevation during haematological CR. Of these, 10 of the 16 who had undergone allogeneic haematopoietic stem cell transplantation (HSCT) in first CR were alive without relapse at a median of 2.9 years after transplantation, whereas 12 of the 13 who had not undergone allogeneic HSCT experienced a relapse. These results demonstrate that, in Ph+ ALL patients treated with imatinib-combined chemotherapy, rapid molecular response is not associated with a favourable prognosis, and that a single observation of elevated MRD is predictive of subsequent relapse, but allogeneic HSCT can override its adverse effect.

PMID 18986386  Br J Haematol. 2008 Nov;143(4):503-10. doi: 10.1111/j.1・・・
著者: Dieter Hoelzer, Nicola Gökbuget, Werner Digel, Thomas Faak, Michael Kneba, Regina Reutzel, Joanna Romejko-Jarosinska, Jacek Zwolinski, Jan Walewski
雑誌名: Blood. 2002 Jun 15;99(12):4379-85. doi: 10.1182/blood-2002-01-0110.
Abstract/Text We treated 45 adult patients with T-lymphoblastic lymphoma (T-LBL) (age range 15-61 years) with 2 protocols designed for adult acute lymphoblastic leukemia (ALL). An encouraging cure rate of 90% was recently reported for T-LBL in children treated with a similar approach. In our study, an 8-drug standard induction was administered over 8 weeks including prophylactic cranial (24 Gy) and mediastinal irradiation (24 Gy) followed by consolidation and reinduction therapy. At diagnosis, 91% of the 45 patients showed a mediastinal tumor and 40% had pleural/pericardial effusions; 73% of the patients had stage III/IV disease. Overall, 42 patients (93%) achieved a complete remission (CR), 2 patients (4%) achieved a partial remission, and 1 patient (2%) died during induction. In patients with stage I-III disease (n = 18) the CR rate was 100% compared with 89% in stage IV (n = 27). There were 15 patients who relapsed (36%) within 12 months. The majority of relapses (47%) occurred in the mediastinum (n = 7) despite mediastinal irradiation with 24 Gy in 6 out of 7 patients. The estimates for overall survival, continuous CR, and disease-free survival at 7 years are 51%, 65%, and 62%, respectively. Stage, age, lactate dehydrogenase, and all other parameters had no influence on achievement of CR or outcome. This study demonstrates in a large cohort of patients with adult T-LBL that a high CR rate and a favorable outcome can be achieved with an ALL-type regimen. Mediastinal recurrence was the major obstacle and further improvement by intensification of chemotherapy, increased dose of mediastinal irradiation (36 Gy), and extended indications for stem cell transplantation seem to be required.

PMID 12036865  Blood. 2002 Jun 15;99(12):4379-85. doi: 10.1182/blood-2・・・
著者: Luciana Annino, Maria Luce Vegna, Andrea Camera, Giorgina Specchia, Giuseppe Visani, Giuseppe Fioritoni, Felicetto Ferrara, Antonio Peta, Stefania Ciolli, Wilma Deplano, Francesco Fabbiano, Simona Sica, Francesco Di Raimondo, Nicola Cascavilla, Antonio Tabilio, Pietro Leoni, Rosangela Invernizzi, Michele Baccarani, Bruno Rotoli, Sergio Amadori, Franco Mandelli, GIMEMA Group
雑誌名: Blood. 2002 Feb 1;99(3):863-71.
Abstract/Text The GIMEMA ALL 0288 trial was designed to evaluate the impact of a 7-day prednisone (PDN) pretreatment on complete remission (CR) achievement and length, the influence of the addition of cyclophosphamide (random I) to a conventional 4-drug induction on CR rate and duration, and whether an early post-CR intensification (random II) by an 8-drug consolidation could improve CR duration. Median follow-up of this study was 7.3 years. From January 1988 to April 1994, among 794 adult (> 12 but < 60 years) patients registered, 778 were eligible. Their median age was 27.5 years; 73% had B-lineage acute lymphoblastic leukemia (ALL) and 22% had T-lineage disease; 18% showed associated myeloid markers; 47 of 216 analyzed patients (22%) had Philadelphia chromosome-positive ALL. Response to PDN pretreatment was observed in 65% of cases. CR was achieved in 627 patients (82%). Resistant patients and induction death rates were 11% and 7%, respectively. Random II was applied to 388 patients with CR; 201 had maintenance alone and 187 had consolidation followed by maintenance. The relapse rate was 60%; isolated central nervous system relapses were 8% of all CRs and 13% of all relapses. Median survival (overall survival [OS]), continuous complete remission (CCR), and disease-free survival (DFS) were 2.2, 2.4, and 2 years, respectively. PDN pretreatment response resulted the main independent factor influencing CR achievement, OS, CCR, and DFS; the addition of cyclophosphamide in induction significantly influenced CR achievement in a multivariate analysis. Neither induction intensification nor early consolidation appeared to influence CCR and DFS duration. For the first time PDN pretreatment response proved to be a powerful factor predicting disease outcome in adult ALL patients.

PMID 11806988  Blood. 2002 Feb 1;99(3):863-71.
著者: Elly Barry, Daniel J DeAngelo, Donna Neuberg, Kristen Stevenson, Mignon L Loh, Barbara L Asselin, Ronald D Barr, Luis A Clavell, Craig A Hurwitz, Albert Moghrabi, Yvan Samson, Marshall Schorin, Harvey J Cohen, Stephen E Sallan, Lewis B Silverman
雑誌名: J Clin Oncol. 2007 Mar 1;25(7):813-9. doi: 10.1200/JCO.2006.08.6397.
Abstract/Text PURPOSE: Historically, adolescents with acute lymphoblastic leukemia (ALL) have had inferior outcomes when compared with younger children. We report the outcome of adolescents treated on Dana-Farber Cancer Institute (DFCI; Boston, MA) ALL Consortium Protocols conducted between 1991 and 2000.
PATIENTS AND METHODS: A total of 844 patients aged 1 to 18 years, with newly diagnosed ALL were enrolled onto two consecutive DFCI-ALL Consortium Protocols. We compared outcomes in three age groups: children aged 1 to 10 years (n = 685), young adolescents aged 10 to 15 years (n = 108), and older adolescents aged 15 to 18 years (n = 51).
RESULTS: With a median follow-up of 6.5 years, the 5-year event-free survival (EFS) for those aged 1 to 10 years was 85% (SE, 1%), compared with 77% (SE, 4%) for those aged 10 to 15 years, and 78% (SE, 6%) for those aged 15 to 18 years (P = .09). Adolescents were more likely to present with T-cell phenotype (P < .001) and less likely to have the TEL-AML1 fusion (P = .05). The incidence of pancreatitis and thromboembolic complications, but not asparaginase allergy, was higher in patients 10 years of age compared with those younger than 10 years. However, there was no difference in the rate of treatment-related complications between the 10- to 15-year and 15- to 18-year age groups.
CONCLUSION: Adolescents were more likely to present at diagnosis with biologically higher risk disease (T-cell phenotype and absence of the TEL-AML1 fusion) and more likely to experience treatment-related complications than younger children. However, the 5-year EFS for older adolescents was 78% +/- 6%, which is superior to published outcomes for similarly aged patients treated with other pediatric and adult ALL regimens. Based on this experience, we currently are piloting our regimen in patients aged 18 to 50 years.

PMID 17327603  J Clin Oncol. 2007 Mar 1;25(7):813-9. doi: 10.1200/JCO.・・・
著者: James B Nachman, Mei K La, Stephen P Hunger, Nyla A Heerema, Paul S Gaynon, Caroline Hastings, Leonard A Mattano, Harland Sather, Meenakshi Devidas, David R Freyer, Peter G Steinherz, Nita L Seibel
雑誌名: J Clin Oncol. 2009 Nov 1;27(31):5189-94. doi: 10.1200/JCO.2008.20.8959. Epub 2009 Oct 5.
Abstract/Text PURPOSE: Patients 16 to 21 years of age with acute lymphoblastic leukemia (ALL) have an inferior outcome compared with younger children, leading some medical oncologists to advocate allogeneic stem-cell transplantation in first remission for these patients. We examined outcome for young adults with ALL enrolled onto the Children's Cancer Group (CCG) 1961 study between 1996 and 2002.
PATIENTS AND METHODS: CCG 1961 entered patients with ALL 1 to 21 years of age with initial WBC count > or = 50,000/microL and/or age > or = 10 years. Randomly assigned therapies evaluated the impact of postinduction treatment intensification on outcome. We examined outcome and prognostic factors for 262 young adults with ALL.
RESULTS: Five-year event-free and overall survival rates for young adult patients are 71.5% (SE, 3.6%) and 77.5% (SE, 3.3%), respectively. Rapid responder patients (< 25% bone marrow blasts on day 7) randomly assigned to augmented therapy had 5-year event-free survival of 81.8% (SE, 7%), as compared with 66.8% (SE, 6.7%) for patients receiving standard therapy (P = .07). One versus two interim maintenance and delayed intensification courses had no significant impact on event-free survival. WBC count more than 50,000/microL was an adverse prognostic factor.
CONCLUSION: Young adult patients with ALL showing a rapid response to induction chemotherapy benefit from early intensive postinduction therapy but do not benefit from a second interim maintenance and delayed intensification phase. Given the excellent outcome with this chemotherapy, there seems to be no role for the routine use of allogeneic stem-cell transplantation in first remission for young adults with ALL.

PMID 19805689  J Clin Oncol. 2009 Nov 1;27(31):5189-94. doi: 10.1200/J・・・
著者: Wendy Stock, Mei La, Ben Sanford, Clara D Bloomfield, James W Vardiman, Paul Gaynon, Richard A Larson, James Nachman, Children's Cancer Group, Cancer and Leukemia Group B studies
雑誌名: Blood. 2008 Sep 1;112(5):1646-54. doi: 10.1182/blood-2008-01-130237. Epub 2008 May 23.
Abstract/Text We performed a retrospective comparison of presenting features, planned treatment, complete remission (CR) rate, and outcome of 321 adolescents and young adults (AYAs) ages 16 to 20 years with newly diagnosed acute lymphoblastic leukemia (ALL) who were treated on consecutive trials in either the Children's Cancer Group (CCG) or the Cancer and Leukemia Group B (CALGB) from 1988 to 2001. CR rates were identical, 90% for both CALGB and CCG AYAs. CCG AYAs had a 63% event-free survival (EFS) and 67% overall survival (OS) at 7 years in contrast to the CALGB AYAs, in which 7-year EFS was only 34% (P < .001; relative hazard rate [RHR] = 2.2) and OS was 46% (P < .001; RHR = 1.9). While CALGB AYAs aged 16 to 17 years achieved similar outcomes to all CCG AYAs with a 7-year EFS of 55%, the EFS for 18- to 20-year-old CALGB patients was only 29%. Comparison of the regimens showed that CCG AYAs received earlier and more intensive central nervous system prophylaxis and higher cumulative doses of nonmyelosuppressive agents. There were no differences in outcomes of those who reached maintenance therapy on time compared with those who were delayed. Based on these observations, a prospective study for AYAs with ALL using the more successful approach of the CCG has been initiated.

PMID 18502832  Blood. 2008 Sep 1;112(5):1646-54. doi: 10.1182/blood-20・・・
著者: F Hayakawa, T Sakura, T Yujiri, E Kondo, K Fujimaki, O Sasaki, J Miyatake, H Handa, Y Ueda, Y Aoyama, S Takada, Y Tanaka, N Usui, S Miyawaki, S Suenobu, K Horibe, H Kiyoi, K Ohnishi, Y Miyazaki, S Ohtake, Y Kobayashi, K Matsuo, T Naoe, Japan Adult Leukemia Study Group (JALSG)
雑誌名: Blood Cancer J. 2014 Oct 17;4:e252. doi: 10.1038/bcj.2014.72. Epub 2014 Oct 17.
Abstract/Text The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR-ABL-negative ALL. Patients aged 15-24 years (n=139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58-75%) and 73% (95% CI 64-80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, P<0.001). These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR-ABL-negative ALL.

PMID 25325302  Blood Cancer J. 2014 Oct 17;4:e252. doi: 10.1038/bcj.20・・・
著者: G M Mead, M R Sydes, J Walewski, A Grigg, C S Hatton, N Pescosta, C Guarnaccia, M S Lewis, J McKendrick, S P Stenning, D Wright, P Norbert, UKLG LY06 collaborators
雑誌名: Ann Oncol. 2002 Aug;13(8):1264-74.
Abstract/Text BACKGROUND: Burkitt's lymphoma (BL) is a rare and rapidly progressive form of B-cell non-Hodgkin's lymphoma. Cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate (CODOX-M)/ifosfamide, etoposide and high-dose cytarabine (IVAC) is a highly effective alternating non-cross-resistant regimen developed by Magrath et al. (Magrath I., Adde M., Shad A. et al. J Clin Oncol 1996; 14: 925-934) at the US National Cancer Institute. The aim was to confirm these results in a larger, international, multi-centre study using International Prognostic Index-based criteria to assign prognostic groups, whilst slightly simplifying the protocol.
PATIENTS AND METHODS: A phase II study where: (i) low risk (LR) patients were treated with three cycles of modified CODOX-M; and (ii) high risk (HR) patients received treatment with four cycles of alternating modified CODOX-M and IVAC chemotherapy. Target of 60 patients, fit for protocol treatment, from 16 to 60 years of age with locally diagnosed, non-HIV-related, non-organ-transplant-related BL.
RESULTS: Results are given for 52 of 72 registered patients whose pathological eligibility was confirmed by central pathology review: 12 LR plus 40 HR. The majority of patients (n = 41) completed protocol treatment, but toxicity was severe, especially myelosuppression and mucositis. Overall, 2-year event-free survival (EFS) was 64.6% (95% CI 50.4% to 78.9%) and 2-year overall survival (OS) was 72.8% (95% CI 59.4% to 86.3%). For LR, 2-year EFS was 83.3% and OS was 81.5%. For HR, 2-year EFS was 59.5% and OS was 69.9%.
CONCLUSIONS: This study confirms high cure rates with this CODOX-M/IVAC approach.

PMID 12181251  Ann Oncol. 2002 Aug;13(8):1264-74.
著者: David A Rizzieri, Jeffrey L Johnson, Donna Niedzwiecki, Edward J Lee, James W Vardiman, Bayard L Powell, Maurice Barcos, Clara D Bloomfield, Charles A Schiffer, Bruce A Peterson, George P Canellos, Richard A Larson
雑誌名: Cancer. 2004 Apr 1;100(7):1438-48. doi: 10.1002/cncr.20143.
Abstract/Text BACKGROUND: The objective of the current study was to evaluate the efficacy of intensive chemotherapy with and without cranial radiation for central nervous system (CNS) prophylaxis in adults with Burkitt leukemia or lymphoma.
METHODS: Patients received 18 weeks of therapy. Prophylactic cranial radiation (2400 centigrays) and 12 doses of triple intrathecal chemotherapy were administered to the first cohort of patients. A subsequent cohort received the same therapy, with the exceptions that intrathecal therapy was reduced to six doses and radiotherapy was administered only to high-risk individuals.
RESULTS: The median follow-up durations were 6.8 years in Cohort 1 and 4.1 years in Cohort 2. Three occurrences of transverse myelitis, 2 severe neuropathies, 3 cases of aphasia, and 1 case of blindness were documented in the first cohort of 52 patients (Cohort 1). In the subsequent cohort of 40 patients (Cohort 2), none of these occurrences were observed, and patients experienced less neurologic toxicity overall (61% vs. 26%; P=0.001). Responses were similar, and the 3-year event-free survival rate was 0.52 (95% confidence interval, 0.38-0.65) for Cohort 1 and 0.45 (0.29-0.60) for Cohort 2.
CONCLUSIONS: Intensive, short-duration chemotherapy with less intensive CNS prophylaxis led to control at this sanctuary site with little neurotoxicity and may be curative for adults with Burkitt leukemia or lymphoma.

Copyright 2004 by the American Cancer Society.
PMID 15042678  Cancer. 2004 Apr 1;100(7):1438-48. doi: 10.1002/cncr.20・・・
著者: D A Thomas, J Cortes, S O'Brien, S Pierce, S Faderl, M Albitar, F B Hagemeister, F F Cabanillas, S Murphy, M J Keating, H Kantarjian
雑誌名: J Clin Oncol. 1999 Aug;17(8):2461-70.
Abstract/Text PURPOSE: To evaluate response and outcome with a front-line intensive multiagent chemotherapy regimen in adults with Burkitt's-type acute lymphoblastic leukemia (B-ALL).
PATIENTS AND METHODS: From September 1992 to June 1997, 26 consecutive adults with newly diagnosed untreated B-ALL received hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD). Their median age was 58 years (range, 17 to 79 years), and 46% were > or = 60 years. Patients received Hyper-CVAD alternated with courses of high-dose methotrexate and cytarabine. Granulocyte colony-stimulating factor and prophylactic antibiotics were administered for all eight planned courses. CNS prophylaxis alternated intrathecal methotrexate and cytarabine on days 2 and 7 of each course.
RESULTS: Complete remission (CR) was obtained in 21 patients (81%). There were five induction deaths (19%). The median time to CR was 22 days (range, 15 to 89 days); 70% achieved CR within 4 weeks. The 3-year survival rate was 49% (+/- 11%); the 3-year continuous CR rate was 61% (+/- 11%). Twelve CR patients (57%) were in continuous CR at a median follow-up of 3+ years (range, 13+ months to 6.5+ years). Characteristics predicting for worse survival were age > or = 60 years, poor performance status, anemia, thrombocytopenia, peripheral blasts, and increased lactate dehydrogenase level. The 3-year survival rate was 77% for 14 patients younger than 60 years and 17% for 12 patients > or = 60 years (P <.01). Regression analysis identified older age, anemia, and presence of peripheral blasts as independent factors associated with shorter survival. Patients could be stratified according to (1) no or one adverse feature, (2) two adverse features, and (3) all adverse features. The 3-year survival rates were 89%, 47%, and 0%, respectively (P <.01).
CONCLUSION: Hyper-CVAD is effective in adult B-ALL. Identification of patients with high risk for relapse and improved methods to detect residual disease may result in risk-oriented approaches.

PMID 10561310  J Clin Oncol. 1999 Aug;17(8):2461-70.
著者: Anthony H Goldstone, Susan M Richards, Hillard M Lazarus, Martin S Tallman, Georgina Buck, Adele K Fielding, Alan K Burnett, Raj Chopra, Peter H Wiernik, Letizia Foroni, Elisabeth Paietta, Mark R Litzow, David I Marks, Jill Durrant, Andrew McMillan, Ian M Franklin, Selina Luger, Niculae Ciobanu, Jacob M Rowe
雑誌名: Blood. 2008 Feb 15;111(4):1827-33. doi: 10.1182/blood-2007-10-116582. Epub 2007 Nov 29.
Abstract/Text An international collaboration was set up to prospectively evaluate the role of allogeneic transplantation for adults with acute lymphoblastic leukemia (ALL) and compare autologous transplantation with standard chemotherapy. Patients received 2 phases of induction and, if in remission, were assigned to allogeneic transplantation if they had a compatible sibling donor. Other patients were randomized to chemotherapy for 2.5 years versus an autologous transplantation. A donor versus no-donor analysis showed that Philadelphia chromosome-negative patients with a donor had a 5-year improved overall survival (OS), 53% versus 45% (P = .01), and the relapse rate was significantly lower (P < or = .001). The survival difference was significant in standard-risk patients, but not in high-risk patients with a high nonrelapse mortality rate in the high-risk donor group. Patients randomized to chemotherapy had a higher 5-year OS (46%) than those randomized to autologous transplantation (37%; P = .03). Matched related allogeneic transplantations for ALL in first complete remission provide the most potent antileukemic therapy and considerable survival benefit for standard-risk patients. However, the transplantation-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk. There is no evidence that a single autologous transplantation can replace consolidation/maintenance in any risk group. This study is registered at http://clinicaltrials.gov as NCT00002514.

PMID 18048644  Blood. 2008 Feb 15;111(4):1827-33. doi: 10.1182/blood-2・・・
著者: C Sebban, E Lepage, J P Vernant, E Gluckman, M Attal, J Reiffers, L Sutton, E Racadot, M Michallet, D Maraninchi
雑誌名: J Clin Oncol. 1994 Dec;12(12):2580-7.
Abstract/Text PURPOSE: Optimal postremission therapy remains controversial in adult patients with acute lymphoblastic leukemia (ALL). In a large multicentric trial (LALA87), we compared allogeneic bone marrow transplantation (BMT) with other postremission therapies (chemotherapy or autologous transplantation) using the result of the human leukocyte antigen (HLA) typing as a random allocation.
PATIENTS AND METHODS: Patient eligibility requirements were as follows: (1) inclusion in LALA87 trial, (2) complete response to induction or salvage therapy, (3) age 15 to 40 years, and (4) at least one potential sibling donor. Patients with an HLA-identical sibling were assigned to the BMT group, while patients without a sibling donor constituted the control group. Allogeneic transplantation was scheduled for patients in the BMT group; in the control group, patients were randomly allocated to receive chemotherapy or autologous transplantation.
RESULTS: Of 284 eligible points, 257 entered the study: 116 were allocated to the BMT group and 141 to the control group. The 5-year survival rates were not statistically significantly different between the two groups. When only patients with high-risk ALL were considered (those with [1] Philadelphia chromosome [Ph1] ALL, [2] null or undifferentiated ALL, or [3] c-ALL with either age greater than 35 years or WBC count > 30 x 10(9)/L or time to achieve complete remission > 4 weeks), overall survival (P = .03) and disease-free-survival (P = .01) were better for the BMT group compared with the control group (5-year overall survival rates, 44% v 20%; 5-year disease-free survival rates, 39% v 14%).
CONCLUSION: Allogeneic transplantation does not improve survival in patients with standard-risk ALL and should be recommended only for patients with adverse prognostic factors.

PMID 7989932  J Clin Oncol. 1994 Dec;12(12):2580-7.
著者: R A Larson, R K Dodge, C P Burns, E J Lee, R M Stone, P Schulman, D Duggan, F R Davey, R E Sobol, S R Frankel
雑誌名: Blood. 1995 Apr 15;85(8):2025-37.
Abstract/Text The goal of this phase II multicenter clinical trial was to evaluate a new intensive chemotherapy program for adults with untreated acute lymphoblastic leukemia (ALL) and to examine prospectively the impact of clinical and biologic characteristics on the outcome. One hundred ninety-seven eligible and evaluable patients (16 to 80 years of age; median, 32 years of age) received cyclophosphamide, daunorubicin, vincristine, prednisone, and L-asparaginase; 167 patients (85%) achieved a complete remission (CR), 13 (7%) had refractory disease, and 17 (9%) died during induction. A higher CR rate was observed in younger patients (94% for those < 30 years old, 85% for those 30 to 59 years old, and 39% for those > or = 60 years old, P < .001) and in those who had a mediastinal mass (100%) or blasts with a T-cell immunophenotype. Eighty percent of B-lineage and 97% of T-cell ALL patients achieved a CR (P = .01). The coexpression of myeloid antigens did not affect the response rate or duration. Seventy percent of those with cytogenetic or molecular evidence of the Philadelphia (Ph) chromosome and 84% of those without such evidence achieved a CR (P = .11). Patients in remission received multiagent consolidation treatment, central nervous system prophylaxis, late intensification, and maintenance chemotherapy for a total of 24 months. After a median follow-up time of 43 months, the median survival for all 197 patients is 36 months; the median remission duration for the 167 CR patients is 29 months. Favorable pretreatment characteristics relative to remission duration or survival are younger age, the presence of a mediastinal mass or lymphadenopathy, a white blood cell count (WBC) less than 30,000/microL, L1 morphology, T or TMy immunophenotype, and the absence of the Ph chromosome. The estimates of the proportion surviving at 3 years are 69% for patients less than 30 years old, 39% for those 30 to 59 years old, 89% for those who had a mediastinal mass, 59% with WBC less than 30,000/microL, 63% with L1 morphology, 69% for T or TMy antigen expression, and 62% for those who lack the Ph chromosome. Fifteen patients (8%) had no unfavorable prognostic factors and have an estimated probability of survival at 5 years of 100% (95% confidence interval, 77% to 100%). This intensive chemotherapy regimen produces a high remission rate and a high proportion of durable remissions in adults with ALL.

PMID 7718875  Blood. 1995 Apr 15;85(8):2025-37.
著者: H M Kantarjian, S O'Brien, T L Smith, J Cortes, F J Giles, M Beran, S Pierce, Y Huh, M Andreeff, C Koller, C S Ha, M J Keating, S Murphy, E J Freireich
雑誌名: J Clin Oncol. 2000 Feb;18(3):547-61.
Abstract/Text PURPOSE: To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL).
PATIENTS AND METHODS: Adults with newly diagnosed ALL referred since 1992 were entered onto the study; treatment was initiated in 204 patients between 1992 and January 1998. No exclusions were made because of older age, poor performance status, organ dysfunction, or active infection. Median age was 39.5 years; 37% were at least 50 years old. Mature B-cell disease (Burkitt type) was present in 9%, T-cell disease in 17%. Leukocytosis of more than 30 x 10(9)/L was found in 26%, Philadelphia chromosome-positive disease in 16% (20% of patients with assessable metaphases), CNS leukemia at the time of diagnosis in 7%, and a mediastinal mass in 7%. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP).
RESULTS: Overall, 185 patients (91%) achieved complete remission (CR) and 12 (6%) died during induction therapy. Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS relapse was low (4%). Compared with 222 patients treated with vincristine, doxorubicin, and dexamethasone (VAD) regimens, our patients had a better CR rate (91% v 75%, P <.01) and CR rate after one course (74% v 55%, P <.01) and better survival (P <.01), and a smaller percentage had more than 5% day 14 blasts (34% v 48%, P =.01). Previous prognostic models remained predictive for outcome with Hyper-CVAD therapy.
CONCLUSION: Hyper-CVAD therapy is superior to our previous regimens and should be compared with established regimens in adult ALL.

PMID 10653870  J Clin Oncol. 2000 Feb;18(3):547-61.
著者: Françoise Huguet, Thibaut Leguay, Emmanuel Raffoux, Xavier Thomas, Kheira Beldjord, Eric Delabesse, Patrice Chevallier, Agnes Buzyn, André Delannoy, Yves Chalandon, Jean-Paul Vernant, Marina Lafage-Pochitaloff, Agnès Chassevent, Véronique Lhéritier, Elizabeth Macintyre, Marie-Christine Béné, Norbert Ifrah, Hervé Dombret
雑誌名: J Clin Oncol. 2009 Feb 20;27(6):911-8. doi: 10.1200/JCO.2008.18.6916. Epub 2009 Jan 5.
Abstract/Text PURPOSE: Retrospective comparisons have suggested that adolescents or teenagers with acute lymphoblastic leukemia (ALL) benefit from pediatric rather than adult chemotherapy regimens. Thus, the aim of the present phase II study was to test a pediatric-inspired treatment, including intensified doses of nonmyelotoxic drugs, such as prednisone, vincristine, or L-asparaginase, in adult patients with ALL up to the age of 60 years.
PATIENTS AND METHODS: Between 2003 and 2005, 225 adult patients (median age, 31 years; range, 15 to 60 years) with Philadelphia chromosome-negative ALL were enrolled onto the Group for Research on Adult Acute Lymphoblastic Leukemia 2003 protocol, which included several pediatric options. Some adult options, such as allogeneic stem-cell transplantation for patients with high-risk ALL, were nevertheless retained.
RESULTS: were retrospectively compared with the historical France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) trial experience in 712 patients age 15 to 55 years. Results Complete remission rate was 93.5%. At 42 months, event-free survival (EFS) and overall survival (OS) rates were 55% (95% CI, 48% to 52%) and 60% (95% CI, 53% to 66%), respectively. Age remained an important bad prognostic factor, with 45 years of age as best cutoff. In older versus younger patients, there was a higher cumulative incidence of chemotherapy-related deaths (23% v 5%, respectively; P < .001) and deaths in first CR (22% v 5%, respectively; P < .001), whereas the incidence of relapse remained stable (30% v 32%, respectively). Complete remission rate (P = .02), EFS (P < .001), and OS (P < .001) compared favorably with the previous LALA-94 experience.
CONCLUSION: These results suggest that pediatric-inspired therapy markedly improves the outcome of adult patients with ALL, at least until the age of 45 years.

PMID 19124805  J Clin Oncol. 2009 Feb 20;27(6):911-8. doi: 10.1200/JCO・・・

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