Schrappe M, Aricò M, Harbott J, Biondi A, Zimmermann M, Conter V, Reiter A, Valsecchi M G, Gadner H, Basso G, Bartram C R, Lampert F, Riehm H, Masera G
Department of Pediatric Hematology and Oncology, Medizinische Hochschule Hannover, Hannover, Germany.
Blood. 1998 Oct 15;92(8):2730-41.
Among 4,760 acute lymphoblastic leukemia (ALL) patients enrolled from 1986 to 1995 in two subsequent trials of the BFM and AIEOP study group, 61 patients were found to have Philadelphia chromosome-positive (Ph+) ALL. These patients were analyzed for presenting features and treatment outcome to identify specific prognostic factors. Treatment stratification was based on initial cell mass and early response as determined by blast count in peripheral blood after a 7-day induction prephase with prednisone and one dose of intrathecal methotrexate on day 1. All patients were treated by similar intensive Berlin-Frankfurt-Münster (BFM) protocols. The median age of Ph+ patients was 7.5 years, the median white blood cell count (WBC) was 75 x 10(9)/L, 77% of patients had common ALL, and 29% coexpressed myeloid markers. After a median observation time of 4.2 years, 29 of 61 patients are alive (survival probability [pSUR] at 4 years, 0.49; standard error [SE], 0.06), and 24 of 61 are in first complete remission (CR1; probability of event-free survival [pEFS] at 4 years, 0.38; SE, 0.06). Twenty (35%) of 57 evaluable patients had >/=1,000 leukemic blasts per microliter of blood on day 8 of induction (defined as prednisone-poor-response [PPR]). These patients were older (10.0 v 6.88 years; P = .02) and had a higher WBC (144 v 29 x 10(9)/L; P = .0016) as compared with patients with prednisone good response (PGR; <1,000 blasts/microL at day 8). Only 2 of 20 patients (10%) with PPR remained in CR1 and alive: 6 patients with PPR did not survive after allogeneic bone marrow transplantation (BMT) due to recurring disease (n = 3) and toxicity (n = 3), and 12 nontransplanted patients died due to progression (n = 5) or relapse (n = 7). In contrast, 26 (70%) of the 37 patients with PGR are alive. Of 18 patients transplanted by allo-BMT, 1 relapsed (now in CR2) and 4 died after BMT. Among the 19 patients with PGR treated by chemotherapy alone, 8 remained in CR1 and 11 relapsed, of which 4 are in CR2 or CR3. The prednisone response emerged as the only independent prognostic factor for survival in Cox regression analysis. Thus, two thirds of Ph+ childhood ALL cases can be identified early by PGR, which, when treated with intensive BFM chemotherapy, with or without BMT, have a significantly lower risk of treatment failure. With a median continuous complete remission (CCR) time of 4.1 years, pEFS for PGR is 0.55 (SE, 0.08) compared with 0.10 (SE, 0.07) in patients with PPR (P = .0001). PGR is also an indicator for treatment responsiveness and durable second remission after relapse, which in turn may provide a second chance for BMT.
在1986年至1995年期间，BFM和AIEOP研究组的两项后续试验纳入的4760例急性淋巴细胞白血病（ALL）患者中，发现61例患者为费城染色体阳性（Ph+）ALL。对这些患者的临床表现和治疗结果进行分析，以确定特定的预后因素。治疗分层基于初始细胞量和早期反应，早期反应通过在使用泼尼松进行7天诱导前期和第1天给予一剂鞘内甲氨蝶呤后外周血原始细胞计数来确定。所有患者均采用类似的强化柏林-法兰克福-明斯特（BFM）方案进行治疗。Ph+患者的中位年龄为7.5岁，中位白细胞计数（WBC）为75×10⁹/L，77%的患者为普通ALL，29%的患者共表达髓系标志物。经过4.2年的中位观察期后，61例患者中有29例存活（4年生存率[pSUR]为0.49；标准误差[SE]为0.06），61例中有24例处于首次完全缓解（CR1；4年无事件生存率[pEFS]为0.38；SE为0.06）。57例可评估患者中有20例（35%）在诱导第8天每微升血液中白血病原始细胞≥1000个（定义为泼尼松反应不佳[PPR]）。与泼尼松反应良好（PGR；诱导第8天原始细胞<1000个/微升）的患者相比，这些患者年龄更大（10.0岁对6.88岁；P = 0.02），WBC更高（144×10⁹/L对29×10⁹/L；P = 0.0016）。PPR的20例患者中只有2例（10%）仍处于CR1且存活：6例PPR患者在异基因骨髓移植（BMT）后因疾病复发（n = 3）和毒性（n = 3）未存活，12例未进行移植的患者因病情进展（n = 5）或复发（n = 7）死亡。相比之下，37例PGR患者中有26例（70%）存活。在18例接受异基因BMT移植的患者中，1例复发（现处于CR2），4例在BMT后死亡。在19例仅接受化疗的PGR患者中，8例仍处于CR1，11例复发，其中4例处于CR2或CR3。在Cox回归分析中，泼尼松反应成为生存的唯一独立预后因素。因此，三分之二的Ph+儿童ALL病例可通过PGR早期识别，这些病例在接受强化BFM化疗（无论是否进行BMT）时，治疗失败风险显著降低。PGR患者的中位持续完全缓解（CCR）时间为4.1年，pEFS为0.55（SE为0.08），而PPR患者为0.10（SE为0.07）（P = 0.0001）。PGR也是治疗反应性和复发后持久二次缓解的指标，这反过来可能为BMT提供第二次机会。
