Sick C, Schultheis B, Pasternak G, Kottke I, Hörner S, Heissig B, Hehlmann R
Katharina-Kasper-Kliniken, St. Marienkrankenhaus, Medizinische Klinik, Frankfurt, Germany.
Ann Hematol. 2001 Jan;80(1):9-16. doi: 10.1007/s002770000237.
The mechanism and target cell of the life-prolonging effect of interferon-alpha (IFN-alpha) in chronic myelogenous leukemia (CML) are controversial. We studied the influence of IFN-alpha treatment on the frequency of malignant hematopoietic precursor cells in the peripheral blood (PB) of CML patients during the course of the disease. PB 10-day colony-forming cells (PB-CFCs) were assessed with regard to their quantity, lineage distribution, and BCR-ABL status, as determined by fluorescence in situ hybridization (FISH). PB-CFC numbers were determined in 39 patients (29 in the chronic phase, 6 in an advanced stage, and 4 with progression to an advanced stage during follow-up). Thirty-one patients were evaluated either once or several times to determine the BCR-ABL status of the colonies. BCR-ABL negative PB-CFCs were detectable at diagnosis in 5 of 11 patients. A major reduction of BCR-ABL positive colonies to <25% of PB-CFCs was observed in 10/13 determinable IFN-alpha treated patients in early and late chronic phases, indicating a high proportion of BCR-ABL negativity at the clonogenic cell level. In contrast, only 3 of these patients had a cytogenetic response of <25% Philadelphia chromosome (Ph1)-positive metaphases in bone marrow cytogenetics. Treatment with IFN-alpha and/or hydroxyurea (HU) during chronic phase was accompanied by a reduction of PB-CFCs to subnormal levels (median 24 CFCs/ml) compared to controls (median 207 CFCs/ml), untreated patients in chronic phase (median 25,979 CFCs/ml), and patients with advanced disease (median 6,047 CFCs/ml). In blast crisis (6 patients), all colonies tested were BCR-ABL positive. Our results show that IFN-alpha treatment leads to a marked reduction of malignant myeloid precursor cells in the PB of CML patients, which exceeds the degree of cytogenetic remission. This offers an explanation for the good therapeutic efficacy and even life-prolonging effect of IFN-alpha, which is also observed in cytogenetic non-responders.
α干扰素（IFN-α）对慢性粒细胞白血病（CML）的延长生命作用机制及靶细胞存在争议。我们研究了IFN-α治疗对CML患者疾病过程中外周血（PB）中恶性造血前体细胞频率的影响。通过荧光原位杂交（FISH）确定PB 10天集落形成细胞（PB-CFCs）的数量、谱系分布及BCR-ABL状态。对39例患者（29例慢性期、6例晚期、4例随访期间进展为晚期）的PB-CFCs数量进行了测定。对31例患者进行了一次或多次评估以确定集落的BCR-ABL状态。11例患者中5例在诊断时可检测到BCR-ABL阴性的PB-CFCs。在慢性期早期和晚期，13例可测定的接受IFN-α治疗的患者中有10例观察到BCR-ABL阳性集落大幅减少至PB-CFCs的<25%，表明在克隆形成细胞水平上BCR-ABL阴性比例很高。相比之下，这些患者中只有3例骨髓细胞遗传学中费城染色体（Ph1）阳性中期细胞的细胞遗传学反应<25%。与对照组（中位数207个CFCs/ml）、慢性期未治疗患者（中位数25,979个CFCs/ml）及晚期疾病患者（中位数6,047个CFCs/ml）相比，慢性期使用IFN-α和/或羟基脲（HU）治疗伴随着PB-CFCs减少至低于正常水平（中位数24个CFCs/ml）。在急变期（6例患者），所有检测的集落均为BCR-ABL阳性。我们的结果表明，IFN-α治疗导致CML患者PB中恶性髓系前体细胞显著减少，这超过了细胞遗传学缓解程度。这为IFN-α良好的治疗效果甚至延长生命作用提供了解释，在细胞遗传学无反应者中也观察到了这种现象。
