Waselenko J K, Grever M R, Beer M, Lucas M A, Byrd J C
Hematology/Oncology Department, Brooke Army Medical Center, San Antonio, TX 78234, USA.
Semin Oncol. 2000 Apr;27(2 Suppl 5):44-51.
Renewed interest in chronic lymphocytic leukemia (CLL) has led to an unprecedented number of investigators contributing to all aspects of research in this disease. In fact, the evolution of research in the area of molecular aberrations in CLL and their impact on treatment resistance alone is striking. These data, along with the advent of the purine analogs, have been central to this paradigm shift. The inferior response rate, the abbreviated response duration, and the inability to prolong survival with alkylating agents such as chlorambucil have resulted in purine analogs being used as first- and second-line therapy for patients with CLL. In fact, patients treated with fludarabine have a higher overall and complete response rate as well as a disease-free survival advantage compared with patients treated with alkylator-based therapy. Pentostatin, the first purine analog to enter clinical trials, was never subjected to extensive schedule optimization despite its demonstrated efficacy and its paucity of significant myelosuppression compared with the other purine analogs. However, pentostatin induced a 25% to 30% response rate in heavily pretreated CLL patients, including some who had received prior fludarabine, suggesting possible non-cross-resistance. Based on preclinical data demonstrating synergistic activity when a DNA damaging agent (eg, an alkylating agent) is followed by an inhibitor of DNA repair (a purine analog), a number of purine analog/alkylator combinations have been and are presently being examined in a variety of lymphoid neoplasms. While the clinical data conflict, at least two phase II studies examining a combination of a purine analog and an alkylator in untreated patients with CLL have generated promising data. This report describes the scientific justification and the design of a new phase II study examining the combination of pentostatin and chlorambucil with granulocyte-macrophage colony-stimulating factor support for patients with untreated, treated, and fludarabine-refractory B-cell CLL.
对慢性淋巴细胞白血病（CLL）重新燃起的兴趣使得前所未有的众多研究人员投身于该疾病各个方面的研究。事实上，仅CLL分子异常领域的研究进展及其对治疗耐药性的影响就十分显著。这些数据，连同嘌呤类似物的出现，一直是这一范式转变的核心。使用诸如苯丁酸氮芥等烷化剂时反应率较低、反应持续时间缩短且无法延长生存期，这使得嘌呤类似物被用作CLL患者的一线和二线治疗药物。事实上，与接受基于烷化剂治疗的患者相比，接受氟达拉滨治疗的患者总体缓解率和完全缓解率更高，且具有无病生存优势。喷司他丁是首个进入临床试验的嘌呤类似物，尽管已证明其疗效且与其他嘌呤类似物相比严重骨髓抑制较少，但从未进行过广泛的给药方案优化。然而，喷司他丁在经过大量预处理的CLL患者中诱导出了25%至30%的缓解率，包括一些先前接受过氟达拉滨治疗的患者，提示可能存在非交叉耐药性。基于临床前数据表明，当DNA损伤剂（如烷化剂）之后使用DNA修复抑制剂（嘌呤类似物）时具有协同活性，目前已有多种嘌呤类似物/烷化剂组合正在多种淋巴瘤中进行研究。虽然临床数据存在矛盾，但至少有两项II期研究在未经治疗的CLL患者中检测嘌呤类似物与烷化剂的组合，已产生了有前景的数据。本报告描述了一项新的II期研究的科学依据和设计，该研究检测喷司他丁与苯丁酸氮芥联合粒细胞-巨噬细胞集落刺激因子支持治疗未经治疗过的、已接受过治疗的以及对氟达拉滨耐药的B细胞CLL患者。
