Kodama Yuichi, Manabe Atsushi, Kawasaki Hirohide, Kato Itaru, Kato Keisuke, Sato Atsushi, Matsumoto Kimikazu, Kato Motohiro, Hiramatsu Hidefumi, Sano Hideki, Kaneko Takashi, Oda Megumi, Saito Akiko M, Adachi Souichi, Horibe Keizo, Mizutani Shuki, Ishii Eiichi, Shimada Hiroyuki
Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan.
Pediatr Blood Cancer. 2017 Aug;64(8). doi: 10.1002/pbc.26423. Epub 2017 Jan 13.
In the tyrosine kinase inhibitor (TKI) era, outcomes after salvage therapy for relapsed or refractory Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) remain unclear.
The clinical courses of 19 patients with relapse (n = 13) or induction failure (n = 6) in the Japanese Pediatric Leukemia/Lymphoma Study Group Ph+ ALL04 study were retrospectively reviewed.
Fifteen male and four female patients had a median age of 8 (range 4-15) years at relapse or induction failure. Patients received imatinib in combination with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and methotrexate and cytarabine (MTX/Ara-C) (n = 9), imatinib in combination with other chemotherapy (n = 5), chemotherapy without imatinib (n = 2), imatinib alone (n = 2), or no additional chemotherapy (n = 1). Two patients underwent hematopoietic stem cell transplantation (HSCT) without achieving complete remission (CR) and died of leukemia. The remaining 17 patients achieved CR with salvage therapies and underwent HSCT whilst in CR: 10 patients remain alive in CR, five died of transplantation-related complications, and two died of relapse. In six of seven patients with available data on minimal residual disease (MRD), imatinib in combination with the first course of hyper-CVAD was more effective in achieving a favorable MRD response compared with the Ph+ ALL04 induction regimen.
This study suggested that cross-resistance to imatinib failed to develop after conventional chemotherapy. Imatinib in combination with chemotherapy including hyper-CVAD+MTX/Ara-C was effective and safe for relapsed or refractory Ph+ ALL patients who received frontline therapy without imatinib.
在酪氨酸激酶抑制剂（TKI）时代，复发或难治性费城染色体阳性（Ph+）急性淋巴细胞白血病（ALL）挽救治疗后的结局仍不明确。
回顾性分析了日本儿童白血病/淋巴瘤研究组Ph+ ALL04研究中19例复发（n = 13）或诱导失败（n = 6）患者的临床病程。
15例男性和4例女性患者在复发或诱导失败时的中位年龄为8岁（范围4 - 15岁）。患者接受伊马替尼联合超分割环磷酰胺、长春新碱、多柔比星和地塞米松（hyper-CVAD）以及甲氨蝶呤和阿糖胞苷（MTX/Ara-C）（n = 9）、伊马替尼联合其他化疗（n = 5）、不使用伊马替尼的化疗（n = 2）、单独使用伊马替尼（n = 2）或不进行额外化疗（n = 1）。2例患者未达到完全缓解（CR）即接受了造血干细胞移植（HSCT），并死于白血病。其余17例患者通过挽救治疗达到CR，并在CR期间接受了HSCT：10例患者仍处于CR状态存活，5例死于移植相关并发症，2例死于复发。在7例有微小残留病（MRD）可用数据的患者中，6例患者显示，与Ph+ ALL04诱导方案相比，伊马替尼联合首个疗程的hyper-CVAD在实现良好的MRD反应方面更有效。
本研究表明，传统化疗后未出现对伊马替尼的交叉耐药。伊马替尼联合包括hyper-CVAD + MTX/Ara-C在内的化疗对未接受伊马替尼一线治疗的复发或难治性Ph+ ALL患者有效且安全。
