今日の臨床サポート

急性前骨髄球性白血病

著者: 横山泰久 筑波大学医学医療系血液内科

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:2022/10/26
患者向け説明資料

概要・推奨   

  1. APLでは、FISHないしはRT-PCRを用いたPML-RARAの検出による早期診断が勧められる(推奨度1OJG)
  1. 治療前白血球数が予後予測因子である(推奨度1OJG)
  1. 未治療APLの初回治療ではATRAと化学療法の併用療法が推奨される(推奨度1CJ)
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  1. 骨髄細胞のPML-RARA 測定が微少残存病変(MRD)の検出に有用である(推奨度1OJG)
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  1. 亜ヒ酸による再寛解APL例では亜ヒ酸による地固め療法後、骨髄PML-RARA陰性例には自家移植、骨髄PML-RARA陽性例には同種移植が勧められる(推奨度2OJG)
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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。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※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、実際の保険適応の査定において保険適応及び保険適応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応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:
横山泰久 : 未申告[2022年]
監修:木崎昌弘 : 講演料(武田薬品工業,ヤンセンファーマ,小野薬品工業,ブリストル・マイヤーズスクイブ),研究費・助成金など(武田薬品工業),奨学(奨励)寄付など(協和キリン,旭化成ファーマ,第一三共,中外製薬,日本新薬,武田薬品工業)[2022年]

改訂のポイント:
  1. WHO分類に従い疾患情報について加筆修正を行った。
  1. 造血器腫瘍診療ガイドライン 2018年版補訂版に基づき、海外の状況を含め標準療法について加筆修正を行った。
  1. 定期レビューを行い、診断、予後評価、治療、フォローアップ、再発例の治療など、全般に加筆修正を行った。

病態・疫学・診察

疾患情報  
  1. 急性前骨髄球性白血病(APL)は急性骨髄性白血病(AML)の1病型で、AMLの10~15%を占める[1]
  1. WHO分類ではAPL with PML-RARAとされ、染色体転座t(15;17)由来のPML-RARA遺伝子をほぼ全て(> 98%)の症例に認める[2]
  1. 例外的にPML以外の遺伝子とRARA遺伝子の融合がみられる場合がある(variant RARA translocations)。
APLの染色体転座とATRAおよび亜ヒ酸の反応性:<図表>
  1. 形態的には細胞質に豊富な顆粒をもった異常なAPL細胞(芽球・前骨髄球)の増加を認め、またアウエル小体を多数有するFaggot細胞がみられることも特徴的である(hypergranular type, FAB分類M3)。一部は顆粒が微細で目立たずアウエル小体も欠くmicrogranular variant(FAB分類M3v)であり、形態診断が難しい。
  1. APL(M3)例の骨髄塗抹標本のメイギムザ染色:<図表>
  1. APL(M3v)例の骨髄塗抹標本のメイギムザ染色:<図表>
  1. 過剰線溶を伴う播種性血管内凝固(DIC)を来しやすく、出血症状での発症や脳出血等の致死的出血による早期死亡が多い[3]
  1. t(15;17)陽性APLの初発症状と血液・凝固異常:<図表>
  1. PML-RARA遺伝子に由来するPML-RARα蛋白を標的とする全トランス型レチノイン酸(ATRA)および亜ヒ酸(ATO)による分化誘導療法が有効である[1][4]。variant RARA translocationsでは治療反応性が異なる[5]
APLの染色体転座とATRAおよび亜ヒ酸の反応性:<図表>
  1. ATRAと化学療法の併用療法による寛解導入療法および寛解後療法が本邦での標準治療である[6]
  1. 初発APLの診断と治療のアルゴリズム:アルゴリズム
  1. ATRAとATOの併用(ATRA + ATO)療法が海外では標準療法であり[4][7]、本邦でも早期導入が望まれる(本邦保険適用外)。
  1. 寛解導入療法における出血や分化症候群に対する支持療法が重要である。
 
問診・診察のポイント  
  1. 出血症状での発症が多いので全身の皮下出血や口腔内出血などに注意する。抜歯後の止血困難や、女性では過多月経も多い。また、消化管出血、肺出血、脳出血などの臓器出血の有無にも注意して問診、診察を行う。

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文献 

Hugues de Thé, Pier Paolo Pandolfi, Zhu Chen
Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure.
Cancer Cell. 2017 Nov 13;32(5):552-560. doi: 10.1016/j.ccell.2017.10.002.
Abstract/Text Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.

Copyright © 2017 Elsevier Inc. All rights reserved.
PMID 29136503
Lijun Wen, Yang Xu, Li Yao, Nana Wang, Qinrong Wang, Tianhui Liu, Jinlan Pan, Jiannong Cen, Huifeng Zhou, Miao Miao, Yang W Shao, Xiaonan Wang, Xiaoxia Wang, Changgeng Ruan, Depei Wu, Suning Chen
Clinical and molecular features of acute promyelocytic leukemia with variant retinoid acid receptor fusions.
Haematologica. 2019 May;104(5):e195-e199. doi: 10.3324/haematol.2018.205369. Epub 2018 Sep 20.
Abstract/Text
PMID 30237272
Masamitsu Yanada, Tadashi Matsushita, Norio Asou, Yuji Kishimoto, Motohiro Tsuzuki, Yasuhiro Maeda, Kentaro Horikawa, Masaya Okada, Shigeki Ohtake, Fumiharu Yagasaki, Tadashi Matsumoto, Yukihiko Kimura, Katsuji Shinagawa, Masako Iwanaga, Yasushi Miyazaki, Ryuzo Ohno, Tomoki Naoe
Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome.
Eur J Haematol. 2007 Mar;78(3):213-9. doi: 10.1111/j.1600-0609.2006.00803.x. Epub 2007 Jan 16.
Abstract/Text BACKGROUND: Even after the introduction of all-trans retinoic acid (ATRA), early hemorrhagic death remains a major cause of remission induction failure for acute promyelocytic leukemia (APL).
METHODS: To investigate severe hemorrhagic complications during remission induction therapy with respect to incidence, risk factors, and influence on outcome. Results were analyzed for 279 patients enrolled in the APL97 study conducted by the Japan Adult Leukemia Study Group (JALSG).
RESULTS: Severe hemorrhage occurred in 18 patients (6.5%). Although most of them were receiving frequent transfusions, the targeted levels of platelet counts (30 x 10(9)/L) and plasma fibrinogen (1.5 g/L) for this study were reached at the day of bleeding in only 71% and 40%, respectively. Nine of them succumbed to an early death, while the remaining nine patients eventually achieved complete remission (CR). The 5-yr event-free survival rate was 68.1% for those who did not suffer severe hemorrhage, and 31.1% for those who did (P < 0.0001). For patients who achieved CR, on the other hand, there was no difference in disease-free survival between patients with and without severe hemorrhage (P = 0.6043). Risk factor analysis identified three pretreatment variables associated with severe hemorrhage: initial fibrinogen level, white blood cell count, and performance status. Additionally, patients with severe hemorrhage were more easily prone to develop retinoic acid syndrome or pneumonia than patients without hemorrhage.
CONCLUSIONS: These results indicate that fatal hemorrhage represents a major obstacle in curing APL, and that patients with such high-risk features may benefit from more aggressive supportive care.

PMID 17241371
Francesco Lo-Coco, Giuseppe Avvisati, Marco Vignetti, Christian Thiede, Sonia Maria Orlando, Simona Iacobelli, Felicetto Ferrara, Paola Fazi, Laura Cicconi, Eros Di Bona, Giorgina Specchia, Simona Sica, Mariadomenica Divona, Alessandro Levis, Walter Fiedler, Elisa Cerqui, Massimo Breccia, Giuseppe Fioritoni, Helmut R Salih, Mario Cazzola, Lorella Melillo, Angelo M Carella, Christian H Brandts, Enrica Morra, Marie von Lilienfeld-Toal, Bernd Hertenstein, Mohammed Wattad, Michael Lübbert, Matthias Hänel, Norbert Schmitz, Hartmut Link, Maria Grazia Kropp, Alessandro Rambaldi, Giorgio La Nasa, Mario Luppi, Fabio Ciceri, Olimpia Finizio, Adriano Venditti, Francesco Fabbiano, Konstanze Döhner, Michaela Sauer, Arnold Ganser, Sergio Amadori, Franco Mandelli, Hartmut Döhner, Gerhard Ehninger, Richard F Schlenk, Uwe Platzbecker, Gruppo Italiano Malattie Ematologiche dell'Adulto, German-Austrian Acute Myeloid Leukemia Study Group, Study Alliance Leukemia
Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.
N Engl J Med. 2013 Jul 11;369(2):111-21. doi: 10.1056/NEJMoa1300874.
Abstract/Text BACKGROUND: All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.
METHODS: We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%.
RESULTS: Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity.
CONCLUSIONS: ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).

PMID 23841729
Miguel A Sanz, Pierre Fenaux, Martin S Tallman, Elihu H Estey, Bob Löwenberg, Tomoki Naoe, Eva Lengfelder, Hartmut Döhner, Alan K Burnett, Sai-Juan Chen, Vikram Mathews, Harry Iland, Eduardo Rego, Hagop Kantarjian, Lionel Adès, Giuseppe Avvisati, Pau Montesinos, Uwe Platzbecker, Farhad Ravandi, Nigel H Russell, Francesco Lo-Coco
Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet.
Blood. 2019 Apr 11;133(15):1630-1643. doi: 10.1182/blood-2019-01-894980. Epub 2019 Feb 25.
Abstract/Text Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion-based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid- and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.

© 2019 by The American Society of Hematology.
PMID 30803991
Norio Asou, Yuji Kishimoto, Hitoshi Kiyoi, Masaya Okada, Yasukazu Kawai, Motohiro Tsuzuki, Kentaro Horikawa, Mitsuhiro Matsuda, Katsuji Shinagawa, Tohru Kobayashi, Shigeki Ohtake, Miki Nishimura, Masatomo Takahashi, Fumiharu Yagasaki, Akihiro Takeshita, Yukihiko Kimura, Masako Iwanaga, Tomoki Naoe, Ryuzo Ohno, Japan Adult Leukemia Study Group
A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARalpha transcript after consolidation therapy: the Japan Adult Leukemia Study Group (JALSG) APL97 study.
Blood. 2007 Jul 1;110(1):59-66. doi: 10.1182/blood-2006-08-043992. Epub 2007 Mar 20.
Abstract/Text To examine the efficacy of intensified maintenance chemotherapy, we conducted a prospective multicenter trial in adult patients with newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Of the 302 registered, 283 patients were assessable and 267 (94%) achieved complete remission. Predicted 6-year overall survival in all assessable patients and disease-free survival in patients who achieved complete remission were 83.9% and 68.5%, respectively. A total of 175 patients negative for PML-RARalpha at the end of consolidation were randomly assigned to receive either intensified maintenance chemotherapy (n = 89) or observation (n = 86). Predicted 6-year disease-free survival was 79.8% for the observation group and 63.1% for the chemotherapy group, showing no statistically significant difference between the 2 groups (P = .20). Predicted 6-year survival of patients assigned to the observation was 98.8%, which was significantly higher than 86.2% in those allocated to the intensified maintenance (P = .014). These results indicate that the intensified maintenance chemotherapy did not improve disease-free survival, but rather conferred a significantly poorer chance of survival in acute promyelocytic leukemia patients who have become negative for the PML-RARalpha fusion transcript after 3 courses of intensive consolidation therapy.

PMID 17374742
David Grimwade, Jelena V Jovanovic, Robert K Hills, Elizabeth A Nugent, Yashma Patel, Rajinder Flora, Daniela Diverio, Katy Jones, Hannah Aslett, Elaine Batson, Kristian Rennie, Roger Angell, Richard E Clark, Ellen Solomon, Francesco Lo-Coco, Keith Wheatley, Alan K Burnett
Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy.
J Clin Oncol. 2009 Aug 1;27(22):3650-8. doi: 10.1200/JCO.2008.20.1533. Epub 2009 Jun 8.
Abstract/Text PURPOSE: Molecular diagnostics and early assessment of treatment response that use methodologies capable of detecting submicroscopic disease can distinguish subgroups of patients with leukemia at differing relapse risk. Such information is being incorporated into risk-stratified protocols; however, there are few data concerning prospective use of sequential minimal residual disease (MRD) monitoring to identify more precisely those patients destined to experience relapse, which would allow more tailored therapies.
METHODS: Real-time quantitative polymerase chain reaction (RQ-PCR) assays to detect leukemia-specific transcripts (ie, PML-RARA, RARA-PML) were used to prospectively analyze 6,727 serial blood and marrow samples from 406 patients with newly diagnosed acute promyelocytic leukemia (APL) who were receiving all-trans-retinoic acid and anthracycline-based chemotherapy.
RESULTS: MRD monitoring according to the recommended schedule successfully identified the majority of patients subject to relapse and provided the most powerful predictor of relapse-free survival (RFS) in multivariable analysis (hazard ratio, 17.87; 95% CI, 6.88 to 46.41; P < .0001); MRD monitoring was far superior to presenting WBC (hazard ratio, 1.02; 95% CI, 1.00 to 1.03; P = .02), which is currently widely used to guide therapy. In patients who were predicted to experience relapse on the basis of MRD monitoring, early treatment intervention with arsenic trioxide prevented progression to overt relapse in the majority, and the RFS rate at 1 year from molecular relapse was 73%. By using this strategy, 3-year cumulative incidence of clinical relapse was only 5% in the Medical Research Council AML15 trial.
CONCLUSION: Rigorous sequential RQ-PCR monitoring provides the strongest predictor of RFS in APL and, when coupled with pre-emptive therapy, provides a valid strategy to reduce rates of clinical relapse. This provides a model for development of a more individualized approach to management of other molecularly defined subtypes of acute leukemia.

PMID 19506161
M A Sanz, F Lo Coco, G Martín, G Avvisati, C Rayón, T Barbui, J Díaz-Mediavilla, G Fioritoni, J D González, V Liso, J Esteve, F Ferrara, P Bolufer, C Bernasconi, M Gonzalez, F Rodeghiero, D Colomer, M C Petti, J M Ribera, F Mandelli
Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups.
Blood. 2000 Aug 15;96(4):1247-53.
Abstract/Text Preliminary independent reports of the Italian GIMEMA and the Spanish PETHEMA trials for newly diagnosed acute promyelocytic leukemia (APL) indicated a similarly high antileukemic efficacy in terms of complete remission and disease-free survival rates. To better investigate these studies and the prognostic factors influencing relapse risk, this study analyzed the updated results of 217 patients with PML/RAR alpha-positive APL enrolled in GIMEMA (n = 108) and PETHEMA (n = 109). All patients received identical induction (AIDA schedule) and maintenance. For consolidation, GIMEMA patients received 3 courses including idarubicin/cytarabine, mitoxantrone/etoposide, and idarubicin/cytarabine/thioguanine, whereas PETHEMA patients received the same drugs and dose schedule of idarubicin and mitoxantrone with the omission of nonintercalating agents. Depending on whether molecular relapses were classified as censored or uncensored events, the 3-year Kaplan-Meier estimates of relapse-free survival (RFS) for the combined series were 90 +/- 2% and 86 +/- 2%, respectively. Minor differences observed between the 2 patient cohorts were negligible. Multivariate regression analysis of RFS showed that initial leukocyte (WBC) and platelet counts were the only variables with independent prognostic value. The resulting predictive model for RFS demonstrated its capability of segregating patients into low-risk (WBC count 40 x 10(9)/L), intermediate-risk (WBC count 10 x 10(9)/L) groups, with distinctive RFS curves (P <.0001). The conclusions are that omission of nonanthracycline drugs from the AIDA regimen is not associated with reduced antileukemic efficacy and a simple predictive model may be used for risk-adapted therapy in this disease. (Blood. 2000;96:1247-1253)

PMID 10942364
N Asou, K Adachi, J Tamura, A Kanamaru, S Kageyama, A Hiraoka, E Omoto, H Akiyama, K Tsubaki, K Saito, K Kuriyama, H Oh, K Kitano, S Miyawaki, K Takeyama, O Yamada, K Nishikawa, M Takahashi, S Matsuda, S Ohtake, H Suzushima, N Emi, R Ohno
Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group.
J Clin Oncol. 1998 Jan;16(1):78-85.
Abstract/Text PURPOSE: We conducted a multicenter study of differentiation therapy with all-trans retinoic acid (ATRA) followed by intensive chemotherapy in patients with newly diagnosed acute promyelocytic leukemia (APL) and analyzed the prognostic factors for predicting complete remission (CR), event-free survival (EFS), and disease-free survival (DFS).
PATIENTS AND METHODS: All patients received ATRA until CR. If patients had an initial leukocyte count greater than 3.0 x 10(9)/L, they received daunorubicin (DNR) and behenoyl cytarabine (BHAC). During therapy, if patients showed blast and promyelocyte counts greater than 1.0 x 10(9)/L, they received additional DNR and BHAC. After achieving CR, patients received three courses of consolidation and six courses of maintenance/intensification chemotherapy.
RESULTS: Of 198 registered, 196 were assessable (age range, 15 to 86 years; median, 46) and 173 (88%) achieved CR. Multivariate analysis showed that no or minor purpura at diagnosis (P = .0046) and age less than 30 years (P = .0076) were favorable factors for achievement of CR. Predicted 4-year overall survival and EFS rates were 74% and 54%, respectively, and the 4-year predicted DFS rate for 173 CR patients was 62%. Multivariate analysis showed that age less than 30 years (P = .0003) and initial leukocyte count less than 10 x 10(9)/L (P = .0296) were prognostic factors for longer EFS, and initial leukocyte count less than 10.0 x 10(9)/L was a sole significant prognostic factor for longer DFS (P = .0001).
CONCLUSION: Our results show that age, hemorrhagic diathesis, and initial leukocyte count are prognostic factors for APL treated with ATRA followed by intensive chemotherapy.

PMID 9440726
Alan K Burnett, Nigel H Russell, Robert K Hills, David Bowen, Jonathan Kell, Steve Knapper, Yvonne G Morgan, Jennie Lok, Angela Grech, Gail Jones, Asim Khwaja, Lone Friis, Mary Frances McMullin, Ann Hunter, Richard E Clark, David Grimwade, UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group
Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial.
Lancet Oncol. 2015 Oct;16(13):1295-305. doi: 10.1016/S1470-2045(15)00193-X. Epub 2015 Sep 14.
Abstract/Text BACKGROUND: Acute promyelocytic leukaemia is a chemotherapy-sensitive subgroup of acute myeloid leukaemia characterised by the presence of the PML-RARA fusion transcript. The present standard of care, chemotherapy and all-trans retinoic acid (ATRA), results in a high proportion of patients being cured. In this study, we compare a chemotherapy-free ATRA and arsenic trioxide treatment regimen with the standard chemotherapy-based regimen (ATRA and idarubicin) in both high-risk and low-risk patients with acute promyelocytic leukaemia.
METHODS: In the randomised, controlled, multicentre, AML17 trial, eligible patients (aged ≥16 years) with acute promyelocytic leukaemia, confirmed by the presence of the PML-RARA transcript and without significant cardiac or pulmonary comorbidities or active malignancy, and who were not pregnant or breastfeeding, were enrolled from 81 UK hospitals and randomised 1:1 to receive treatment with ATRA and arsenic trioxide or ATRA and idarubicin. ATRA was given to participants in both groups in a daily divided oral dose of 45 mg/m(2) until remission, or until day 60, and then in a 2 weeks on-2 weeks off schedule. In the ATRA and idarubicin group, idarubicin was given intravenously at 12 mg/m(2) on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m(2) on days 1-4 of course 2; mitoxantrone at 10 mg/m(2) on days 1-4 of course 3, and idarubicin at 12 mg/m(2) on day 1 of the final (fourth) course. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0·3 mg/kg on days 1-5 of each course, and at 0·25 mg/kg twice weekly in weeks 2-8 of course 1 and weeks 2-4 of courses 2-5. High-risk patients (those presenting with a white blood cell count >10 × 10(9) cells per L) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m(2) intravenously). Neither maintenance treatment nor CNS prophylaxis was given to patients in either group. All patients were monitored by real-time quantitative PCR. Allocation was by central computer minimisation, stratified by age, performance status, and de-novo versus secondary disease. The primary endpoint was quality of life on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 global health status. All analyses are by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN55675535.
FINDINGS: Between May 8, 2009, and Oct 3, 2013, 235 patients were enrolled and randomly assigned to ATRA and idarubicin (n=119) or ATRA and arsenic trioxide (n=116). Participants had a median age of 47 years (range 16-77; IQR 33-58) and included 57 high-risk patients. Quality of life did not differ significantly between the treatment groups (EORTC QLQ-C30 global functioning effect size 2·17 [95% CI -2·79 to 7·12; p=0·39]). Overall, 57 patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3-4 toxicities. After course 1 of treatment, grade 3-4 alopecia was reported in 23 (23%) of 98 patients in the ATRA and idarubicin group versus 5 (5%) of 95 in the ATRA and arsenic trioxide group, raised liver alanine transaminase in 11 (10%) of 108 versus 27 (25%) of 109, oral toxicity in 22 (19%) of 115 versus one (1%) of 109. After course 2 of treatment, grade 3-4 alopecia was reported in 25 (28%) of 89 patients in the ATRA and idarubicin group versus 2 (3%) of 77 in the ATRA and arsenic trioxide group; no other toxicities reached the 10% level. Patients in the ATRA and arsenic trioxide group had significantly less requirement for most aspects of supportive care than did those in the ATRA and idarubicin group.
INTERPRETATION: ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with acute promyelocytic leukaemia, with a high cure rate and less relapse than, and survival not different to, ATRA and idarubicin, with a low incidence of liver toxicity. However, no improvement in quality of life was seen.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 26384238
Lionel Adès, Agnes Guerci, Emmanuel Raffoux, Miguel Sanz, Patrice Chevallier, Simona Lapusan, Christian Recher, Xavier Thomas, Consuelo Rayon, Sylvie Castaigne, Olivier Tournilhac, Stephane de Botton, Norbert Ifrah, Jean-Yves Cahn, Eric Solary, Claude Gardin, Nathalie Fegeux, Dominique Bordessoule, Augustin Ferrant, Sandrine Meyer-Monard, Norbert Vey, Herve Dombret, Laurent Degos, Sylvie Chevret, Pierre Fenaux, European APL Group
Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience.
Blood. 2010 Mar 4;115(9):1690-6. doi: 10.1182/blood-2009-07-233387. Epub 2009 Dec 17.
Abstract/Text Acute promyelocytic leukemia (APL) is highly curable with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.2% to 33%, 23.4%, and 13.4% with no maintenance, maintenance using intermittent ATRA, continuous 6 mercaptopurine plus methotrexate, and both treatments, respectively (P < .001). Maintenance particularly benefited patients with white blood cell (WBC) count higher than 5 x 10(9)/L (5000/microL). Early addition of CT to ATRA significantly improved 10-year event-free survival (EFS), but without significant effect on overall survival (OS). The 10-year cumulative incidence of deaths in complete response (CR), resulting mainly from myelosuppression, was 5.7%, 15.4%, and 21.7% in patients younger than 55, 55 to 65, and older than 65 years, respectively, supporting the need for less myelosuppressive treatments, particularly for consolidation therapy. This study is registered at http://clinicaltrials.gov as NCT00599937.

PMID 20018913
Yasmin Abaza, Hagop Kantarjian, Guillermo Garcia-Manero, Elihu Estey, Gautam Borthakur, Elias Jabbour, Stefan Faderl, Susan O'Brien, William Wierda, Sherry Pierce, Mark Brandt, Deborah McCue, Rajyalakshmi Luthra, Keyur Patel, Steven Kornblau, Tapan Kadia, Naval Daver, Courtney DiNardo, Nitin Jain, Srdan Verstovsek, Alessandra Ferrajoli, Michael Andreeff, Marina Konopleva, Zeev Estrov, Maria Foudray, David McCue, Jorge Cortes, Farhad Ravandi
Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab.
Blood. 2017 Mar 9;129(10):1275-1283. doi: 10.1182/blood-2016-09-736686. Epub 2016 Dec 21.
Abstract/Text The combination of all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of standard-risk patients with newly diagnosed acute promyelocytic leukemia (APL). A recent study demonstrated the efficacy of this regimen with added gemtuzumab ozogamicin (GO) in high-risk patients. We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without GO. For induction, all patients received ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg daily) with a dose of GO (9 mg/m2 on day 1) added to high-risk patients (white blood cell count, >10 × 109/L), as well as low-risk patients who experienced leukocytosis during induction. Once in complete remission, patients received 4 cycles of ATRA plus ATO consolidation. One hundred eighty-seven patients, including 54 with high-risk and 133 with low-risk disease, have been treated. The complete remission rate was 96% (52 of 54 in high-risk and 127 of 133 in low-risk patients). Induction mortality was 4%, with only 7 relapses. Among low-risk patients, 60 patients (45%) required either GO or idarubicin for leukocytosis. Median duration of follow-up was 47.6 months. The 5-year event-free, disease-free, and overall survival rates are 85%, 96%, and 88%, respectively. Late hematological relapses beyond 1 year occurred in 3 patients. Fourteen deaths occurred beyond 1 year; 12 were related to other causes. This study confirms the durability of responses with this regimen.

© 2017 by The American Society of Hematology.
PMID 28003274
Uwe Platzbecker, Giuseppe Avvisati, Laura Cicconi, Christian Thiede, Francesca Paoloni, Marco Vignetti, Felicetto Ferrara, Mariadomenica Divona, Francesco Albano, Fabio Efficace, Paola Fazi, Marco Sborgia, Eros Di Bona, Massimo Breccia, Erika Borlenghi, Roberto Cairoli, Alessandro Rambaldi, Lorella Melillo, Giorgio La Nasa, Walter Fiedler, Peter Brossart, Bernd Hertenstein, Helmut R Salih, Mohammed Wattad, Michael Lübbert, Christian H Brandts, Mathias Hänel, Christoph Röllig, Norbert Schmitz, Hartmut Link, Chiara Frairia, Enrico Maria Pogliani, Claudio Fozza, Alfonso Maria D'Arco, Nicola Di Renzo, Agostino Cortelezzi, Francesco Fabbiano, Konstanze Döhner, Arnold Ganser, Hartmut Döhner, Sergio Amadori, Franco Mandelli, Gerhard Ehninger, Richard F Schlenk, Francesco Lo-Coco
Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial.
J Clin Oncol. 2017 Feb 20;35(6):605-612. doi: 10.1200/JCO.2016.67.1982. Epub 2016 Oct 31.
Abstract/Text Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 109/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.

PMID 27400939
E Di Bona, G Avvisati, G Castaman, M Luce Vegna, V De Sanctis, F Rodeghiero, F Mandelli
Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia.
Br J Haematol. 2000 Mar;108(4):689-95.
Abstract/Text A total of 622 consecutive patients with acute promyelocytic leukaemia (APL) treated within the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) group during 1989-97 have been reviewed to assess the clinical effectiveness of all-trans retinoic acid (ATRA) on the incidence of early haemorrhagic deaths and on APL-associated coagulopathy. Of them, 499 were treated with idarubicin plus ATRA (study A) and 123 with Idarubicin alone (study B). In both studies, similar guidelines for supportive treatment were used. Haemorrhagic symptoms were evaluated according to a reproducible score system. Deaths occurring within 10 d of starting treatment were 19 (3.8%) in study A and nine (7.3%) in study B (P = 0.09), with 15 (3%) and five (4.1%) (P not significant) due to haemorrhage. Overall, induction mortality was 7.6% and 16.2% respectively (P < 0.003). In study A, days with platelet counts 30 x 109/l (P < 0.001) in both studies, and by a haemorrhagic score of 3 in study A (P < 0.001). Although the reduction of early fatal haemorrhages was not significant, a substantial clinical improvement was evident in terms of reduction of the severity of bleeding symptoms, blood product consumption and overall induction mortality when ATRA was combined with idarubicin.

PMID 10792270
Katsuji Shinagawa, Masamitsu Yanada, Toru Sakura, Yasunori Ueda, Masashi Sawa, Junichi Miyatake, Nobuaki Dobashi, Minoru Kojima, Yoshihiro Hatta, Nobuhiko Emi, Shigehisa Tamaki, Hiroshi Gomyo, Etsuko Yamazaki, Katsumichi Fujimaki, Norio Asou, Keitaro Matsuo, Shigeki Ohtake, Yasushi Miyazaki, Kazunori Ohnishi, Yukio Kobayashi, Tomoki Naoe
Tamibarotene as maintenance therapy for acute promyelocytic leukemia: results from a randomized controlled trial.
J Clin Oncol. 2014 Nov 20;32(33):3729-35. doi: 10.1200/JCO.2013.53.3570. Epub 2014 Sep 22.
Abstract/Text PURPOSE: The introduction of all-trans-retinoic acid (ATRA) has significantly improved outcomes for acute promyelocytic leukemia (APL), although a subset of patients still suffer relapse. The purpose of this study was to evaluate the role of maintenance therapy with the synthetic retinoid tamibarotene in APL.
PATIENTS AND METHODS: Patients with newly diagnosed APL in molecular remission at the end of consolidation therapy were randomly assigned to receive ATRA or tamibarotene, both orally, for 14 days every 3 months for up to 2 years.
RESULTS: A total of 347 patients were enrolled. Of the 344 eligible patients, 319 (93%) achieved complete remission. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment. The relapse-free survival (RFS) rate at 4 years was 84% for the ATRA arm and 91% for the tamibarotene arm (hazard ratio [HR], 0.54; 95% CI, 0.26 to 1.13). When the analysis was restricted to 52 high-risk patients with an initial WBC count ≥ 10.0 × 10(9)/L, the intergroup difference was statistically significant, with 4-year RFS rates of 58% for the ATRA arm and 87% for the tamibarotene arm (HR, 0.26; 95% CI, 0.07 to 0.95). For patients with non-high-risk disease, the HR was 0.82 (95% CI, 0.32 to 2.01). The test for interaction between treatment effects and these subgroups resulted in P = .075. Both treatments were generally well tolerated.
CONCLUSION: In this trial, no difference was detected between ATRA and tamibarotene for maintenance therapy. In an exploratory analysis, there was a suggestion of improved efficacy of tamibarotene in high-risk patients, but this requires further study.

© 2014 by American Society of Clinical Oncology.
PMID 25245439
Lionel Adès, Sylvie Chevret, Emmanuel Raffoux, Stephane de Botton, Agnes Guerci, Arnaud Pigneux, Anne Marie Stoppa, Thierry Lamy, Francoise Rigal-Huguet, Anne Vekhoff, Sandrine Meyer-Monard, Frederic Maloisel, Eric Deconinck, Augustin Ferrant, Xavier Thomas, Nathalie Fegueux, Christine Chomienne, Herve Dombret, Laurent Degos, Pierre Fenaux, European Acute Promyelocytic Leukemia Group
Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group.
J Clin Oncol. 2006 Dec 20;24(36):5703-10. doi: 10.1200/JCO.2006.08.1596. Epub 2006 Nov 20.
Abstract/Text PURPOSE: Several phase II studies have suggested that cytarabine (AraC) was not required in the treatment of newly diagnosed acute promyelocytic leukemia (APL) patients receiving all-trans-retinoic acid (ATRA), an anthracycline, and maintenance therapy, and we aimed at confirming this finding in a randomized trial.
PATIENTS AND METHODS: Newly diagnosed APL patients younger than age 60 years with a WBC count of less than 10,000/microL were randomly assigned to receive either ATRA combined with and followed by three daunorubicin (DNR) plus AraC courses and a 2-year maintenance regimen (AraC group) or the same treatment but without AraC (no AraC group). Patients older than age 60 years and patients with initial WBC count of more than 10,000/microL were not randomly assigned but received risk-adapted treatment, with higher dose of AraC and CNS prophylaxis in patients with WBC counts more than 10,000/microL.
RESULTS: Overall, 328 (96.5%) of 340 patients achieved complete remission (CR). In the AraC and the no AraC groups, the CR rates were 99% and 94% (P = .12), the 2-year cumulative incidence of relapse (CIR) rates were 4.7% and 15.9% (P = .011), the event-free survival (EFS) rates were 93.3% and 77.2% (P = .0021), and survival rates were 97.9% and 89.6% (P = .0066), respectively. In patients younger than age 60 years with WBC counts more than 10,000/microL, the CR, 2-year CIR, EFS, and survival rates were 97.3%, 2.9%, 89%, and 91.9%, respectively.
CONCLUSION: These results support a role for AraC in addition to ATRA and anthracyclines in the treatment of newly diagnosed APL, at least using DNR at the cumulative dose we used and with the consolidation and maintenance regimens we used.

PMID 17116939
Lionel Adès, Miguel A Sanz, Sylvie Chevret, Pau Montesinos, Patrice Chevallier, Emmanuel Raffoux, Edo Vellenga, Agnès Guerci, Arnaud Pigneux, Francoise Huguet, Consuelo Rayon, Anne Marie Stoppa, Javier de la Serna, Jean-Yves Cahn, Sandrine Meyer-Monard, Thomas Pabst, Xavier Thomas, Stéphane de Botton, Ricardo Parody, Juan Bergua, Thierry Lamy, Anne Vekhoff, Silvia Negri, Norbert Ifrah, Hervé Dombret, Augustin Ferrant, Dominique Bron, Laurent Degos, Pierre Fenaux
Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results.
Blood. 2008 Feb 1;111(3):1078-84. doi: 10.1182/blood-2007-07-099978. Epub 2007 Nov 1.
Abstract/Text All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 x 10(9)/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 x 10(9)/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 x 10(9)/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

PMID 17975017
Miguel A Sanz, Pau Montesinos, Chelo Rayón, Alexandra Holowiecka, Javier de la Serna, Gustavo Milone, Elena de Lisa, Salut Brunet, Vicente Rubio, José M Ribera, Concha Rivas, Isabel Krsnik, Juan Bergua, José González, Joaquín Díaz-Mediavilla, Rafael Rojas, Félix Manso, Gert Ossenkoppele, José D González, Bob Lowenberg, PETHEMA and HOVON Groups
Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome.
Blood. 2010 Jun 24;115(25):5137-46. doi: 10.1182/blood-2010-01-266007. Epub 2010 Apr 14.
Abstract/Text A risk-adapted strategy based on all-trans retinoic acid (ATRA) and anthracycline monochemotherapy (PETHEMA LPA99 trial) has demonstrated a high antileukemic efficacy in acute promyelocytic leukemia. We designed a new trial (LPA2005) with the objective of achieving stepwise improvements in outcome. Between July 2005 and April 2009, low- and intermediate-risk patients (leukocytes < 10 x 10(9)/L) received a reduced dose of mitoxantrone for the second consolidation course, whereas high- risk patients younger than 60 years of age received cytarabine combined with ATRA and idarubicin in the first and third consolidation courses. Of 372 patients attaining complete remission after ATRA plus idarubicin (92.5%), 368 proceeded to consolidation therapy. For low- and intermediate-risk patients, duration of neutropenia and thrombocytopenia and hospital stay were significantly reduced without sacrificing antileukemic efficacy, compared with the previous LPA99 trial. For high-risk patients, the 3-year relapse rate was significantly lower in the LPA2005 trial (11%) than in the LPA99 (26%; P = .03). Overall disease-free survival was also better in the LPA2005 trial (P = .04). In conclusion, the lower dose of mitoxantrone resulted in a significant reduction of toxicity and hospital stay while maintaining the antileukemic activity, and the combination of ATRA, idarubicin, and cytarabine for high-risk acute promyelocytic leukemia significantly reduced the relapse rate in this setting. Registered at http://www.clinicaltrials.gov as NCT00408278.

PMID 20393132
Miguel A Sanz, Edo Vellenga, Chelo Rayón, Joaquín Díaz-Mediavilla, Concha Rivas, Elena Amutio, Jesús Arias, Guillermo Debén, Andrés Novo, Juan Bergua, Javier de la Serna, Javier Bueno, Silvia Negri, José M Beltrán de Heredia, Guillermo Martín
All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia.
Blood. 2004 Dec 1;104(12):3490-3. doi: 10.1182/blood-2004-04-1642. Epub 2004 Aug 3.
Abstract/Text Therapeutic results in elderly patients with acute promyelocytic leukemia (APL) have been generally reported as less effective than for younger patients. Patients 60 years or older with APL who were enrolled in 2 successive multicenter PETHEMA studies received induction therapy with all-trans retinoic acid (ATRA) and idarubicin, consolidation with 3 anthracycline monochemotherapy courses with or without ATRA, and maintenance with ATRA and low-dose chemotherapy. Eighty-seven of 104 patients achieved complete remission (84%). Eighty-six proceeded to consolidation therapy (2 withdrew after the first and second courses). Deaths in remission occurred during consolidation and maintenance therapy in 3 and 4 patients, respectively. One patient showed molecular persistence after consolidation and 5 had a relapse. The 6-year cumulative incidence of relapse, leukemia-free survival, and disease-free survival were 8.5%, 91%, and 79%, respectively. A significantly higher incidence of low-risk patients found among the elderly, as compared to younger patients, may partially account for the low relapse rate observed. This study confirms the high antileukemic efficacy, low toxicity, and high degree of compliance of protocols using ATRA and anthracycline monochemotherapy for induction and consolidation therapy in elderly patients.

PMID 15292063
F Mandelli, R Latagliata, G Avvisati, P Fazi, F Rodeghiero, F Leoni, M Gobbi, F Nobile, E Gallo, R Fanin, S Amadori, M Vignetti, G Fioritoni, F Ferrara, A Peta, R Giustolisi, G Broccia, M C Petti, F Lo-Coco, Italian GIMEMA Cooperative Group
Treatment of elderly patients (> or =60 years) with newly diagnosed acute promyelocytic leukemia. Results of the Italian multicenter group GIMEMA with ATRA and idarubicin (AIDA) protocols.
Leukemia. 2003 Jun;17(6):1085-90. doi: 10.1038/sj.leu.2402932.
Abstract/Text In all, 134 elderly patients (median age 66 years, range 60-75 years) with newly diagnosed acute promyelocytic leukemia (APL) were enrolled in two successive protocols of the Italian multicenter group GIMEMA. All patients received an identical induction with all-trans retinoic acid and idarubicin; 116 (86%) entered complete remission (CR), two (2%) were resistant and 16 (12%) died during induction. After CR, 106 patients received further therapy whereas 10 did not, because of refusal (n=5) or toxicity (n=5). Consolidation consisted of three chemotherapy courses in the AIDA protocol (AIDA, 67 patients) or, since 1997, of an amended protocol including only the first cycle (amended AIDA, aAIDA, 39 patients). In the AIDA group, 43 patients (64%) completed consolidation, while seven (11%) and 17 (25%) patients were withdrawn after first and second courses, respectively; nine patients (13%) died in CR and 12 (18%) relapsed. In the aAIDA group, all patients received the assigned treatment; two patients (5%) died in CR and six (15%) relapsed. In the AIDA and aAIDA series, the 3-year overall and discase-free survival rates were 81 and 83% (P=NS), 73 and 72% (P=NS), respectively. We highlight here the frequency and severity of complications linked to intensive chemotherapy in this clinical setting and suggest that, in APL of the elderly, less intensive postremission therapy allows significant reduction of severe treatment-related toxicity and may be equally effective.

PMID 12764372
Bayard L Powell, Barry Moser, Wendy Stock, Robert E Gallagher, Cheryl L Willman, Richard M Stone, Jacob M Rowe, Steven Coutre, James H Feusner, John Gregory, Stephen Couban, Frederick R Appelbaum, Martin S Tallman, Richard A Larson
Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710.
Blood. 2010 Nov 11;116(19):3751-7. doi: 10.1182/blood-2010-02-269621. Epub 2010 Aug 12.
Abstract/Text Arsenic trioxide (As(2)O(3)) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As(2)O(3) consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As(2)O(3) consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As(2)O(3) arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As(2)O(3) arm, 90% compared with 70% at 3 years (P < .0001). The addition of As(2)O(3) consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

PMID 20705755
Elyce Cardonick, Audrey Iacobucci
Use of chemotherapy during human pregnancy.
Lancet Oncol. 2004 May;5(5):283-91. doi: 10.1016/S1470-2045(04)01466-4.
Abstract/Text When cancer is diagnosed in a pregnant woman, life-saving chemotherapy for the mother poses life-threatening concerns for the developing fetus. Depending on the type of cancer and the stage at diagnosis, chemotherapy cannot necessarily be delayed until after delivery. Women diagnosed with acute lymphoblastic leukaemia who decline both termination and chemotherapy often die with the previable fetus in utero. Safe use of chemotherapy, especially during the second and third trimester, have been reported, and pregnant women with cancer can accept therapy without definite neonatal harm. Here, we review the use of chemotherapy in pregnancy by trimester of exposure and summarise neonatal outcomes, including malformations, perinatal complications, and oldest age of neonatal follow-up. We will also discuss the modes of action of the drugs used and look at the multiagent regimens recommended for use during pregnancy.

PMID 15120665
Pau Montesinos, Juan M Bergua, Edo Vellenga, Chelo Rayón, Ricardo Parody, Javier de la Serna, Angel León, Jordi Esteve, Gustavo Milone, Guillermo Debén, Concha Rivas, Marcos González, Mar Tormo, Joaquín Díaz-Mediavilla, Jose D González, Silvia Negri, Elena Amutio, Salut Brunet, Bob Lowenberg, Miguel A Sanz
Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors.
Blood. 2009 Jan 22;113(4):775-83. doi: 10.1182/blood-2008-07-168617. Epub 2008 Oct 22.
Abstract/Text Differentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid (ATRA). Detailed knowledge about DS has remained limited. We present an analysis of the incidence, characteristics, prognostic factors, and outcome of 739 APL patients treated with ATRA plus idarubicin in 2 consecutive trials (Programa Español de Tratamientos en Hematología [PETHEMA] LPA96 and LPA99). Overall, 183 patients (24.8%) experienced DS, 93 with a severe form (12.6%) and 90 with a moderate form (12.2%). Severe but not moderate DS was associated with an increase in mortality. A bimodal incidence of DS was observed, with peaks occurring in the first and third weeks after the start of ATRA therapy. A multivariate analysis indicated that a WBC count greater than 5 x 10(9)/L and an abnormal serum creatinine level correlated with an increased risk of developing severe DS. Patients receiving systematic prednisone prophylaxis (LPA99 trial) in contrast to those receiving selective prophylaxis with dexamethasone (LPA96 trial) had a lower incidence of severe DS. Patients developing severe DS showed a reduced 7-year relapse-free survival in the LPA96 trial (60% vs 85%, P = .003), but this difference was not apparent in the LPA99 trial (86% vs 88%).

PMID 18945964
Hitoshi Minamiguchi, Hiroyuki Fujita, Yoshiko Atsuta, Norio Asou, Toru Sakura, Yasunori Ueda, Masashi Sawa, Nobuaki Dobashi, Yasuhiro Taniguchi, Rikio Suzuki, Yoshihito Uchino, Akihiro Tomita, Shigehisa Tamaki, Maki Hagihara, Katsumichi Fujimaki, Masamitsu Yanada, Yoshinobu Maeda, Masako Iwanaga, Noriko Usui, Yukio Kobayashi, Shigeki Ohtake, Hitoshi Kiyoi, Itaru Matsumura, Yasushi Miyazaki, Tomoki Naoe, Akihiro Takeshita, Japan Adult Leukemia Study Group
Predictors of early death, serious hemorrhage, and differentiation syndrome in Japanese patients with acute promyelocytic leukemia.
Ann Hematol. 2020 Dec;99(12):2787-2800. doi: 10.1007/s00277-020-04245-6. Epub 2020 Sep 2.
Abstract/Text Significant advancements have been achieved with regard to the outcomes of acute promyelocytic leukemia (APL) patients through the introduction of all-trans retinoic acid; however, early hemorrhagic death and differentiation syndrome remain the major causes of remission induction failure in patients with APL. To investigate early death, serious hemorrhage, and differentiation syndrome during remission induction therapy in terms of incidence, risk factors, influence on outcomes, and prophylactic effects of several new anticoagulants, the results of 344 patients enrolled in the Acute Promyelocytic Leukemia 204 study conducted by the Japan Adult Leukemia Study Group were analyzed. Early death was observed in 16 patients (4.7%), of whom 14 had serious hemorrhage and 2 had differentiation syndrome. Serious hemorrhage and differentiation syndrome of grade 2 or higher were observed in 21 and 54 patients, respectively. Patients who achieved complete remission had a 7-year disease-free survival of 84.8% if they did not experience serious hemorrhage and 40.0% if they experienced serious hemorrhage during remission induction therapy (P = 0.001). Risk factor analyses showed that higher white blood cell count was associated with early death, higher white blood cell count and lower platelet count with serious hemorrhage, and leukocytosis during induction therapy and higher body surface area with differentiation syndrome. In conclusion, these results indicate that patients with such high-risk features may benefit from more intensive supportive care. The hemorrhagic risk was not relieved by the introduction of new anticoagulants. Further studies are required to establish the predictive impact of body surface area on differentiation syndrome. This trial is registered with UMIN-CTR as C000000154 on September 13, 2005.

PMID 32879992
S R Frankel, A Eardley, G Lauwers, M Weiss, R P Warrell
The "retinoic acid syndrome" in acute promyelocytic leukemia.
Ann Intern Med. 1992 Aug 15;117(4):292-6.
Abstract/Text OBJECTIVE: To describe a novel complication of therapy with all-trans retinoic acid in patients with acute promyelocytic leukemia.
DESIGN: Case series.
SETTING: Comprehensive cancer center.
PATIENTS: Consecutive patients with a morphologic diagnosis of acute promyelocytic leukemia who underwent remission induction treatment with all-trans retinoic acid, 45 mg/m2 body surface area per day.
MEASUREMENTS AND RESULTS: Nine of 35 patients (26%; 95% CI, 9% to 52%) with acute promyelocytic leukemia who were treated with all-trans retinoic acid developed a syndrome consisting primarily of fever and respiratory distress. Additional prominent signs and symptoms included weight gain, lower-extremity edema, pleural or pericardial effusions, and episodic hypotension. The onset of this symptom complex occurred from 2 to 21 days after starting treatment. Three deaths occurred; post-mortem examinations in two patients showed pulmonary interstitial infiltration with maturing myeloid cells. Six other patients survived, each achieving complete remission (five patients with all-trans retinoic acid only; 1 patient with chemotherapy). In six of the nine cases, the onset of the syndrome was preceded by an increase in peripheral blood leukocytes to a level of at least 20 x 10(9) cells/L. Certain therapeutic interventions, including leukapheresis, temporary cessation of therapy with all-trans retinoic acid, and cytotoxic chemotherapy in moderate doses were not useful after respiratory distress was established. However, the administration of high-dose corticosteroid therapy (dexamethasone, 10 mg IV intravenously every 12 hours for 3 or more days) early in the course of the syndrome resulted in prompt symptomatic improvement and full recovery in three of four patients.
CONCLUSIONS: The use of all-trans retinoic acid to induce hematologic remission in patients with acute promyelocytic leukemia is associated in some patients with the development of a potentially lethal syndrome that is not uniformly accompanied by peripheral blood leukocytosis. Early recognition of the symptom complex of fever and dyspnea, combined with prompt corticosteroid treatment, may decrease morbidity and mortality associated with this syndrome.

PMID 1637024
S De Botton, H Dombret, M Sanz, J S Miguel, D Caillot, R Zittoun, M Gardembas, A Stamatoulas, E Condé, A Guerci, C Gardin, K Geiser, D C Makhoul, O Reman, J de la Serna, F Lefrere, C Chomienne, C Chastang, L Degos, P Fenaux
Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. The European APL Group.
Blood. 1998 Oct 15;92(8):2712-8.
Abstract/Text All trans-retinoic acid (ATRA) syndrome is a life-threatening complication of uncertain pathogenesis that can occur during the treatment of acute promyelocytic leukemia (APL) by ATRA. Since its initial description, however, no large series of ATRA syndrome has been reported in detail. We analyzed cases of ATRA syndrome observed in an ongoing European trial of treatment of newly diagnosed APL. In this trial, patients 65 years of age or less with an initial white blood cell count (WBC) less than 5,000/microL were initially randomized between ATRA followed by chemotherapy (CT) (ATRA-->CT group) or ATRA with CT started on day 3; patients with WBC greater than 5,000/microL received ATRA and CT from day 1; patients aged 66 to 75 received ATRA-->CT. In patients with initial WBC less than 5, 000/microL and allocated to ATRA-->CT, CT was rapidly added if WBC was greater than 6,000, 10,000, 15,000/microL by days 5, 10, and 15 of ATRA treatment. A total of 64 (15%) of the 413 patients included in this trial experienced ATRA syndrome during induction treatment. Clinical signs developed after a median of 7 days (range, 0 to 35 days). In two of them, they were in fact present before the onset of ATRA. In 11 patients, they occurred upon recovery from the phase of aplasia due to the addition of CT. Respiratory distress (89% of the patients), fever (81%), pulmonary infiltrates (81%), weight gain (50%), pleural effusion (47%), renal failure (39%), pericardial effusion (19%), cardiac failure (17%), and hypotension (12%) were the main clinical signs, and 63 of the 64 patients had at least three of them. Thirteen patients required mechanical ventilation and two dialysis. A total of 60 patients received CT in addition to ATRA as per protocol or based on increasing WBC; 58 also received high dose dexamethasone (DXM); ATRA was stopped when clinical signs developed in 30 patients. A total of 55 patients (86%) who experienced ATRA syndrome achieved complete remission (CR), as compared with 94% of patients who had no ATRA syndrome (P = .07) and nine (14%) died of ATRA syndrome (5 cases), sepsis (2 cases), leukemic resistance (1 patient), and central nervous system (CNS) bleeding (1 patient). None of the patients who achieved CR and received ATRA for maintenance had ATRA syndrome recurrence. No significant predictive factors of ATRA syndrome, including pretreatment WBC, could be found. Kaplan Meier estimates of relapse, event-free survival (EFS), and survival at 2 years were 32% +/- 10%, 63% +/- 8%, and 68% +/- 7% in patients who had ATRA syndrome as compared with 15% +/- 3%, 77% +/- 2%, and 80% +/- 2% in patients who had no ATRA syndrome (P = .05, P = .003, and P = .03), respectively. In a stepwise Cox model that also included pretreatment prognostic variables, ATRA syndrome remained predictive for EFS and survival. In conclusion, in this multicenter trial where CT was rapidly added to ATRA in case of high or increasing WBC counts and DXM generally also used at the earliest clinical sign, the incidence of ATRA syndrome was 15%, but ATRA syndrome was responsible for death in only 1.2% of the total number of patients treated. However, occurrence of ATRA syndrome was associated with lower EFS and survival.

Copyright 1998 by The American Society of Hematology.
PMID 9763554
M S Tallman, J W Andersen, C A Schiffer, F R Appelbaum, J H Feusner, A Ogden, L Shepherd, J M Rowe, C François, R S Larson, P H Wiernik
Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome.
Blood. 2000 Jan 1;95(1):90-5.
Abstract/Text We examined the incidence, clinical course, and outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) who developed the retinoic acid syndrome (RAS) treated on the Intergroup Protocol 0129, which prospectively evaluated the role of alltrans retinoic acid (ATRA) alone during induction and as maintenance therapy. Forty-four of 167 (26%) patients receiving ATRA for induction developed the syndrome at a median of 11 days of ATRA (range, 2-47). The median white blood cell (WBC) count was 1,450/microL at diagnosis and was 31,000/microL (range, 6,800-72,000/microL) at the time the syndrome developed. ATRA was discontinued in 36 of the 44 patients (82%) and continued in 8 patients (18%), with subsequent resolution of the syndrome in 7 of the 8. ATRA was resumed in 19 of the 36 patients (53%) in whom ATRA was stopped and not in 17 (47%). The syndrome recurred in 3 of those 19 patients, with 1 death attributable to resumption of the drug. Ten of these 36 patients received chemotherapy without further ATRA, and 8 achieved complete remission (CR). Among 7 patients in whom ATRA was not restarted and were not treated with chemotherapy, 5 achieved CR and 2 died. Two deaths were definitely attributable to the syndrome. No patient receiving ATRA as maintenance developed the syndrome. (Blood. 2000;95:90-95)

PMID 10607690
Miguel A Sanz, David Grimwade, Martin S Tallman, Bob Lowenberg, Pierre Fenaux, Elihu H Estey, Tomoki Naoe, Eva Lengfelder, Thomas Büchner, Hartmut Döhner, Alan K Burnett, Francesco Lo-Coco
Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet.
Blood. 2009 Feb 26;113(9):1875-91. doi: 10.1182/blood-2008-04-150250. Epub 2008 Sep 23.
Abstract/Text The introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized the management and outcome of this disease. Several treatment strategies using these agents, usually in combination with chemotherapy, but also without or with minimal use of cytotoxic agents, have provided excellent therapeutic results. Cure of APL patients, however, is also dependent on peculiar aspects related to the management and supportive measures that are crucial to counteract life-threatening complications associated with the disease biology and molecularly targeted treatment. The European LeukemiaNet recently appointed an international panel of experts to develop evidence- and expert opinion-based guidelines on the diagnosis and management of APL. Together with providing current indications on genetic diagnosis, modern risk-adapted front-line therapy and salvage treatment, the review contains specific recommendations for the identification and management of most important complications such as the bleeding disorder, APL differentiation syndrome, QT prolongation and other ATRA- and ATO-related toxicities, as well as for molecular assessment of response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women.

PMID 18812465
Kazuyuki Shigeno, Kensuke Naito, Naohi Sahara, Miki Kobayashi, Satoki Nakamura, Sinya Fujisawa, Kaori Shinjo, Akihiro Takeshita, Ryuzo Ohno, Kazunori Ohnishi
Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies.
Int J Hematol. 2005 Oct;82(3):224-9. doi: 10.1532/IJH97.05044.
Abstract/Text Recently, arsenic trioxide (ATO) has been proved to induce complete remission (CR) at a high rate in patients with acute promyelocytic leukemia (APL). We prospectively investigated the safety and efficacy of ATO therapy in patients with relapsed and refractory APL and examined the duration of CR and the postremission therapies. Initially, 0.15 mg/kg ATO was administered until bone marrow remission to a maximum of 60 days. After the patient achieved CR, 1 additional ATO course at the same dosage was administered for 25 days. Of 34 patients, 31 (91%) achieved CR. PML-RAR3 messenger RNA was not detected in the bone marrow of 18 (72%) of the 25 patients evaluated by reverse transcriptase-polymerase chain reaction analysis. At a median follow-up of 30 months, the estimated 2-year overall survival rate was 56%, and the estimated 2-year event-free survival rate was 17%. During the ATO therapy, QTc prolongation was observed in most cases. Fifteen patients developed ventricular tachycardia, and 1 of them showed torsades de pointes. Other adverse events were nausea, water retention, APL differentiation syndrome, skin eruption, liver dysfunction, and peripheral neuropathy, all of which were quite tolerable. ATO therapy was remarkably effective for relapsed APL; however, postremission therapies were necessary to maintain a durable remission.

PMID 16207595
Masamitsu Yanada, Motohiro Tsuzuki, Hiroyuki Fujita, Katsumichi Fujimaki, Shin Fujisawa, Kazutaka Sunami, Masafumi Taniwaki, Akira Ohwada, Kosuke Tsuboi, Akio Maeda, Akihiro Takeshita, Shigeki Ohtake, Yasushi Miyazaki, Yoshiko Atsuta, Yukio Kobayashi, Tomoki Naoe, Nobuhiko Emi, Japan Adult Leukemia Study Group
Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia.
Blood. 2013 Apr 18;121(16):3095-102. doi: 10.1182/blood-2012-11-466862. Epub 2013 Feb 14.
Abstract/Text The optimal treatments for relapsed acute promyelocytic leukemia (APL) remain equivocal. We conducted a phase 2 study to evaluate the efficacy and feasibility of a sequential treatment consisting of induction and consolidation with arsenic trioxide (ATO), peripheral blood stem cell (PBSC) harvest after high-dose cytarabine chemotherapy, and autologous hematopoietic cell transplantation (HCT). Between 2005 and 2009, 35 patients (26 with hematologic and 9 with molecular relapse) were enrolled. Induction therapy resulted in complete remission in 81% of those with hematologic relapse, and most patients became negative for PML-RARα after the first ATO consolidation course, but 4 remained positive. Administration of the second ATO consolidation course further decreased the transcript levels in 3 patients. In total, 25 patients proceeded to PBSC harvest, all of whom successfully achieved the target CD34+ cell doses, and 23 underwent autologous HCT with PML-RARα-negative PBSC graft. Posttransplant relapse occurred in 3 patients, and there was no transplant-related mortality. With a median follow-up of 4.9 years, the 5-year event-free and overall survival rates were 65% and 77%, respectively. These findings demonstrate the outstanding efficacy and feasibility of the sequential treatment featuring ATO and autologous HCT for relapsed APL. This study was registered at http://www.umin.ac.jp/ctr/ as #C000000302.

PMID 23412094
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
Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients.
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
T Tobita, A Takeshita, K Kitamura, K Ohnishi, M Yanagi, A Hiraoka, T Karasuno, M Takeuchi, S Miyawaki, R Ueda, T Naoe, R Ohno
Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid.
Blood. 1997 Aug 1;90(3):967-73.
Abstract/Text Differentiation therapy with all-trans retinoic acid (ATRA) has marked a major advance and become the first choice drug in the treatment of acute promyelocytic leukemia (APL). However, patients who relapse from ATRA-induced complete remission (CR) have difficulty in obtaining a second CR with a second course of ATRA therapy alone. We tested the efficacy of a new synthetic retinoid, Am80, in APL that had relapsed from CR induced by ATRA in a prospective multicenter study. Am80 is approximately 10 times more potent than ATRA as an in vitro differentiation inducer, is more stable to light, heat, and oxidation than ATRA, has a low affinity for cellular retinoic acid binding protein, and does not bind to retinoic acid receptor-gamma. Patients received Am80, 6 mg/m2, orally alone daily until CR. Of 24 evaluable patients, 14 (58%) achieved CR. The interval from the last ATRA therapy was not different between CR and failure cases. The clinical response was well correlated with the in vitro response to Am80 in patients examined. Adverse events included 1 retinoic acid syndrome, 1 hyperleukocytosis, 9 xerosis, 8 cheilitis, 16 hypertriglyceridemia, and 15 hypercholesterolemia, but generally milder than those of ATRA, which all patients had received previously. Am80 is effective in APL relapsed from ATRA-induced CR and deserves further trials, especially in combination with chemotherapy.

PMID 9242525
Francesco Lo-Coco, Giuseppe Cimino, Massimo Breccia, Nélida I Noguera, Daniela Diverio, Erica Finolezzi, Enrico M Pogliani, Eros Di Bona, Concetta Micalizzi, Mariagrazia Kropp, Adriano Venditti, Agostino Tafuri, Franco Mandelli
Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia.
Blood. 2004 Oct 1;104(7):1995-9. doi: 10.1182/blood-2004-04-1550. Epub 2004 Jun 8.
Abstract/Text The anti-CD33 antibody calicheamicinconjugate gemtuzumab ozogamicin (GO) was used to treat 16 patients with acute promyelocytic leukemia (APL) who had relapsed at the molecular level. Of these patients, 8 were experiencing a first, 5 a second, 2 a third, and 1 a fourth relapse. GO was administered at 6 mg/m2 for 2 doses, and patients achieving a new molecular remission (MR) (ie, negativity of the reverse transcriptase-polymerase chain reaction [RT-PCR] test for PML/RARalpha) received a third dose. MR was obtained in 9 (91%) of 11 patients tested after 2 doses and in 13 (100%) of 13 patients tested after the third dose. Of the 3 remaining patients, 1 achieved MR after one GO administration and received no further therapy owing to hepatic toxicity, and 2 showed disease progression during treatment. Quantitative RT-PCR studies showed that responding patients experienced a dramatic decline (at least 2 logs) of the PML/RARalpha transcript after the first GO dose. Of 14 responders, 7 remained in sustained MR for a median of 15 months (range, 7-31 months) while 7 experienced relapse at 3 to 15 months. GO was administered again in 2 patients with relapse, and both obtained a new MR. These data indicate that GO is highly effective as a single treatment for patients with molecularly relapsed APL including those with very advanced disease.

PMID 15187030
Rajasekar Thirugnanam, Biju George, Ezhil Chendamarai, Kavitha M Lakshmi, Poonkuzhali Balasubramanian, Auro Viswabandya, Alok Srivastava, Mammen Chandy, Vikram Mathews
Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen.
Biol Blood Marrow Transplant. 2009 Nov;15(11):1479-84. doi: 10.1016/j.bbmt.2009.07.010. Epub 2009 Sep 1.
Abstract/Text In patients with relapsed acute promyelocytic leukemia (APL), the best consolidation regimen following induction of remission with arsenic trioxide (ATO) remains to be defined. Since January 2000, 37 patients with relapsed APL were treated at our center. The median age was 34 years (range, 6-57 years), and there were 20 males (54.1%). The median duration of first remission was 20.3 months (range, 2.9-81.2 months). Relapse was treated with single-agent ATO in 22 patients (59.5%), ATO+ATRA in 5 patients (13.5%), and ATO+ATRA + anthracycline in 10 patients (27%). Thirty-three patients (89%) achieved molecular remission after induction and a consolidation course. Fourteen patients opted to undergo autologous stem cell transplantation (SCT), and the remaining 19 patients received monthly cycles of ATO as a single agent (n=13) or ATO+ATRA (n=6) for 6 months. At a median follow-up of 32 months, the 5-year Kaplan-Meier estimate of event-free survival (EFS) was 83.33% +/- 15.21% in those who underwent autologous SCT versus 34.45% +/- 11.24% in those who did not (P=.001; log-rank test). Following remission induction with ATO-based regimens in patients with relapsed APL, consolidation with autologous SCT is associated with a significantly superior clinical outcome compared with ATO- and ATO+ATRA-based maintenance regimens.

PMID 19822309
C Ganzel, V Mathews, K Alimoghaddam, A Ghavamzadeh, D Kuk, S Devlin, H Wang, M-J Zhang, D Weisdorf, D Douer, J M Rowe, E Polge, J Esteve, A Nagler, M Mohty, M S Tallman
Autologous transplant remains the preferred therapy for relapsed APL in CR2.
Bone Marrow Transplant. 2016 Sep;51(9):1180-3. doi: 10.1038/bmt.2016.96. Epub 2016 Apr 18.
Abstract/Text Despite their favorable prognosis, 10-20% of acute promyelocytic leukemia (APL) patients relapse. Reinduction therapy is often followed by autologous hematopoietic cell transplantation (auto-HCT). Arsenic trioxide (ATO) has become part of standard reinduction and is often followed by auto-HCT. Data on patients in CR2 were collected from two large transplant registries (Center for International Blood and Marrow Transplant Research (CIBMTR) and European Group for Blood and Marrow Transplant (EBMT)) and two specialty referral centers. The outcome of patients in CR2 who received only ATO-based therapy as reinduction was retrospectively compared with those who got an auto-HCT, with or without ATO. Prognostic factors included age, disease risk, extramedullary disease and duration of CR1. Of 207 evaluable patients, the median age was 31.5 years, 15.3% had extramedullary disease and median WBC at diagnosis was 4.8 × 10(9)/L. Sixty-seven patients received ATO alone and 140 underwent auto-HCT. The groups were comparable for age, gender, extramedullary disease, risk group and duration of CR1. At 5 years, overall survival (OS) was 42% and 78% for the ATO-only and auto-HCT groups, respectively (P<0.001). In addition, OS was associated with longer duration of CR1 (P=0.002), but not with disease risk at diagnosis. These data suggest that auto-HCT for APL patients in CR2 results in better OS than ATO-based therapy alone.

PMID 27088379
S de Botton, A Fawaz, S Chevret, H Dombret, X Thomas, M Sanz, A Guerci, J San Miguel, J de la Serna, A M Stoppa, O Reman, A Stamatoulas, M Fey, J Y Cahn, J J Sotto, J H Bourhis, A Parry, C Chomienne, L Degos, P Fenaux
Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group.
J Clin Oncol. 2005 Jan 1;23(1):120-6. doi: 10.1200/JCO.2005.03.127. Epub 2004 Nov 8.
Abstract/Text PURPOSE: To retrospectively determine the outcome of acute promyelocytic leukemia (APL) patients who underwent autologous or allogeneic stem-cell transplantation (SCT) during second complete remission.
PATIENTS AND METHODS: Of 122 relapsing patients included in two successive multicenter APL trials who achieved hematological second complete remission (generally after a salvage regimen of all-trans-retinoic acid [ATRA] combined with chemotherapy), 73 (60%) received allogeneic (n = 23) or autologous (n = 50) SCT.
RESULTS: Seven-year relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) in the autologous SCT group were 79.4%, 60.6%, and 59.8%, respectively, with a transplant-related mortality (TRM) of 6%. Of the 28 and two patients autografted with negative and positive, respectively, reverse transcriptase-polymerase chain reaction before auto SCT, three (11%) and one relapsed, respectively. In the allogeneic SCT group, 7-year RFS, EFS, and OS were 92.3%, 52.2%, and 51.8%, respectively, with 39% TRM. OS was significantly better in the autologous SCT group than in the allogeneic SCT group (P = .04), whereas RFS and EFS did not differ significantly (P = .19 and P = .11, respectively). In patients not receiving transplantation, 7-year RFS, EFS, and OS were 38%, 30.4%, and 39.5%, respectively.
CONCLUSION: These retrospective data suggest that autologous SCT is very effective in APL relapsing after treatment with ATRA if performed in molecular remission. Allogeneic SCT yields few relapses, but it is associated with high TRM when performed after salvage with very intensive chemotherapy. Salvage with arsenic trioxyde, which has lower toxicity, should further improve the outcome of relapsing APL, especially before allogeneic SCT.

PMID 15534358
M A Sanz, M Labopin, N-C Gorin, J de la Rubia, W Arcese, G Meloni, A Bacigalupo, P Alessandrino, E Carreras, A Iriondo, N Novitzky, P Jacobs, G Bandini, F Lo-Coco, F Frassoni, V Rocha, Acute Leukemia Working Party (ALWP) of European Cooperative Group for Blood and Marrow Transplantation (EBMT)
Hematopoietic stem cell transplantation for adults with acute promyelocytic leukemia in the ATRA era: a survey of the European Cooperative Group for Blood and Marrow Transplantation.
Bone Marrow Transplant. 2007 Apr;39(8):461-9. doi: 10.1038/sj.bmt.1705620. Epub 2007 Feb 26.
Abstract/Text We performed a survey of the European Cooperative Group for Blood and Marrow Transplantation to analyze the outcome of 625 acute promyelocytic leukemia (APL) patients transplanted with auto- or allogeneic-hematopoietic stem cell transplantation (autoHSCT, alloHSCT) after 1993, in first (CR1) or in second complete remission (CR2). Leukemia-free survival (LFS) at 5 years in CR1 was 69% for 149 patients autografted and 68% for 144 patients allografted, whereas in CR2, LFS was 51% in 195 autoHSCT and 59% in 137 alloHSCT recipients, respectively. In the group of autoHSCT for CR1 (n=149), higher relapse incidence (RI) was associated with shorter time from diagnosis to transplant (<7.6 months); transplant-related mortality (TRM) was increased in older patients (>47 years), whereas for CR2, longer time from diagnosis to transplant (>18 months) was associated with increased LFS and decreased RI. In the alloHSCT group for CR1 (n=144), age (<33 years) was associated with increased LFS and decreased TRM and for CR2 (n=137), the use of mobilized peripheral blood stem cells was associated with decreased TRM. Female recipient, a female donor to male recipient and transplants performed before 1997 were associated with decreased RI. In conclusion, HSCT still appears to have a role in APL, especially for patients in CR2.

PMID 17322930
Jennifer L Holter Chakrabarty, Morel Rubinger, Jennifer Le-Rademacher, Hai-Lin Wang, Andrew Grigg, George B Selby, Jeffrey Szer, Jacob M Rowe, Daniel J Weisdorf, Martin S Tallman
Autologous is superior to allogeneic hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission.
Biol Blood Marrow Transplant. 2014 Jul;20(7):1021-5. doi: 10.1016/j.bbmt.2014.03.025. Epub 2014 Mar 30.
Abstract/Text To identify favored choice of transplantation in patients with acute promyelocytic leukemia (APL) in second complete remission, we studied 294 patients with APL in second complete remission (CR2) receiving allogeneic (n = 232) or autologous (n = 62) hematopoietic cell transplantation (HCT) reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR) from 1995 to 2006, including 155 with pre-HCT PML/RAR∝ status (49% of allogeneic and 66% of autologous). Patient characteristics and transplantation characteristics, including treatment-related mortality, overall survival (OS), and disease-free survival, were collected and analyzed for both univariate and multivariate outcomes. With median follow-up of 115 (allogeneic) and 72 months (autologous), 5-year disease-free survival (DFS) favored autologous with 63% (49% to 75%), compared with allogeneic at 50% (44% to 57%) (P = .10). OS was 75% (63% to 85%) versus 54% (48% to 61%) (P = .002), for autologous and allogeneic transplantation, respectively. Multivariate analysis showed significantly worse DFS after allogeneic HCT (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.16 to 3.06; P = .011) and age > 40 years (HR, 2.30; 95% CI, 1.44 to 3.67; P = .0005). OS was significantly worse after allogeneic HCT (HR, 2.66; 95% CI, 1.52 to 4.65; P= .0006); age > 40 (HR, 3.29; 95% CI, 1.95 to 5.54; P < .001), and first complete remission < 12 months (HR, 1.56; 95% CI, 1.07 to 2.26; P = .021). Positive pre-HCT PML-RAR∝ status in 17 of 114 allogeneic and 6 of 41 receiving autologous transplantation did not influence relapse, treatment failure, or survival in either group. The survival advantage for autografting was attributable to increased treatment-related mortality (TRM) in the allogeneic group of 30% compared to 2% in the autologous group, in addition to the added mortality associated with GVHD. We conclude that autologous HCT yields superior OS for APL in CR2. Long-term DFS in autologous recipients, even with minimal residual disease-positive grafts, remains an important subject for further study.

Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
PMID 24691221

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