Bassan R, Lerede T, Buelli M, Borleri G, Bellavita P, Rambaldi A, Barbui T
Division of Hematology, Ospedali Riuniti, Bergamo, Italy.
Haematologica. 1998 May;83(5):422-7.
High-dose cytarabine (HIDAC) and new anthracycline-type drugs (mitoxantrone, idarubicin) are the mainstay of several active regimens against relapsed and refractory acute myeloid leukemia (AML). The present study was undertaken to assess the feasibility, toxicity, and antileukemic activity of carboplatin (CBDCA) added to a combination of the two former agents.
Two regimens (R) of CBDCA plus HIDAC and either mitoxantrone or idarubicin (crossover) were sequentially evaluated. R-1 consisted of CBDCA 300 mg/m2/d (24-hour infusion) on days 1-4, HIDAC 1 g/m2/bd on days 1-5, and mitoxantrone/idarubicin 12/6 mg/m2/d on days 1-3, followed by granulocyte colony-stimulating factor (G-CSF). R-2, an attenuated-toxicity regimen, consisted of CBDCA and G-CSF as above, HIDAC on alternate days (1, 3, 5), and mitoxantrone/idarubicin 8/5 mg/m2/dose. Intended post-remission therapy included a similar, lower intensity course and a myeloablative phase supported by an allogeneic or autologous blood cell transplant.
Twenty-nine patients (median age 53 years, one child) formed the study group: 10 (34%) had a primary refractory disease (8 to idarubicin-cytarabine-etoposide, ICE), 6 (21%) were at second or subsequent relapse, and 5 (17%) had a first remission lasting < 12 months. In addition, 4 patients (14%) had received prior HIDAC and 10 (34%) were relapsing after a bone marrow/blood cell transplant. Twelve patients were treated with R-1 and 17 with R-2. The complete response rate was 25% with R-1 and 53% with R-2, due to a significantly lower death rate by pancytopenic complications (p = 0.023). The probability of response by risk class was: primary refractory 30% (43% with R-2), > 2nd relapse 33% (50% with R-2), 1st relapse < 12 months 40% (50% with R-2), 1st relapse > 12 months 50% (75% with R-2), prior HIDAC 75%, and prior transplant 30% (33% with R-2). Seven patients could undergo an autologous (n = 5) or allogeneic (n = 2) bone marrow/peripheral blood cell transplant after one consolidation cycle. Overall survival was 4.2 months, significantly longer in responders (complete and partial: median 11 months) than non-responders (p < 0.001). Median duration of complete remission was 10 months and 2-year probability 0.31, but no patient remained disease-free at 3 years.
R-2 was well tolerated, exerted a significant activity in high-risk AML, and is amenable to further improvements. However, the lack of long-term disease-free survivors indicates the need for innovative post-remission strategies.
大剂量阿糖胞苷（HIDAC）和新型蒽环类药物（米托蒽醌、伊达比星）是几种针对复发和难治性急性髓系白血病（AML）的有效方案的主要组成部分。本研究旨在评估在上述两种药物联合方案中加入卡铂（CBDCA）的可行性、毒性和抗白血病活性。
依次评估了两种CBDCA联合HIDAC以及米托蒽醌或伊达比星（交叉使用）的方案（R）。R-1方案包括第1 - 4天给予CBDCA 300 mg/m²/d（24小时静脉输注），第1 - 5天给予HIDAC 1 g/m²/每日两次，第1 - 3天给予米托蒽醌/伊达比星12/6 mg/m²/d，随后给予粒细胞集落刺激因子（G-CSF）。R-2方案是一种低毒性方案，包括上述的CBDCA和G-CSF，HIDAC隔日使用（第1、3、5天），米托蒽醌/伊达比星8/5 mg/m²/剂量。缓解后治疗计划包括一个类似的、强度较低的疗程以及一个由异基因或自体血细胞移植支持的清髓阶段。
29例患者（中位年龄53岁，1例儿童）组成研究组：10例（34%）为原发性难治性疾病（8例对伊达比星 - 阿糖胞苷 - 依托泊苷，ICE方案耐药），6例（21%）处于第二次或后续复发，5例（17%）首次缓解持续时间<12个月。此外，4例患者（14%）曾接受过HIDAC治疗，10例（34%）在骨髓/血细胞移植后复发。12例患者接受R-1方案治疗，17例接受R-2方案治疗。R-1方案完全缓解率为25%，R-2方案为53%，原因是全血细胞减少并发症导致的死亡率显著降低（p = 0.023）。按风险类别划分的缓解概率为：原发性难治性30%（R-2方案为43%），>第二次复发33%（R-2方案为50%），首次复发<12个月40%（R-2方案为50%），首次复发>12个月50%（R-2方案为75%），曾接受HIDAC治疗75%，曾接受移植30%（R-2方案为33%）。7例患者在一个巩固周期后可接受自体（n = 5）或异基因（n = 2）骨髓/外周血细胞移植。总生存期为4.2个月，缓解者（完全缓解和部分缓解：中位生存期11个月）明显长于未缓解者（p < 0.001）。完全缓解的中位持续时间为10个月，2年概率为0.31，但3年时无患者无病生存。
R-2方案耐受性良好，对高危AML有显著活性，且适合进一步改进。然而，缺乏长期无病生存者表明需要创新的缓解后治疗策略。
