重组α-2C干扰素治疗慢性粒细胞白血病：体外定向造血前体细胞（BFU-E、CFU-GM、CFU-Meg）敏感性与临床反应的关系

Recombinant interferon-alpha-2C in chronic myelogenous leukaemia: relationship of sensitivity of committed haematopoietic precursor cells in vitro (BFU-E, CFU-GM, CFU-Meg) and clinical response.

作者信息

Geissler D, Gastl G, Aulitzky W, Tilg H, Gaggl S, Konwalinka G, Huber C

机构信息

Department of Internal Medicine, University Hospital, Innsbruck, Austria.

出版信息

Leuk Res. 1990;14(7):629-36. doi: 10.1016/0145-2126(90)90018-5.

DOI:10.1016/0145-2126(90)90018-5

PMID:2388474

Abstract

In an ongoing phase-II trial we aimed to predict clinical responsiveness of Philadelphia chromosome positive (Ph1+) chronic myelogenous leukaemia (CML) to recombinant IFN-alpha-2C (rIFN-alpha-2C) by pretesting in vitro. From five normal controls and 14 CML patients in chronic phase, bone marrow samples were taken before treatment and tested for antiproliferative activity by rIFN-alpha-2C, using a microagar culture system for BFU-E, CFU-GM, and CFU-Meg. Light-density nucleated bone marrow cells were stimulated for BFU-E and CFU-Meg colony formation with Alpha medium containing 20% serum obtained from a patient with severe aplastic anaemia. CFU-GM growth was induced with conditioned medium from the cell line GCT. In normal controls BFU-E, CFU-GM and CFU-Meg colony formation was inhibited by rIFN-alpha-2C in a dose-dependent manner. BFU-E proved to be the most sensitive cell lineage (IC50: 65; range: 53-116 U/ml) whereas CFU-GM was about 20 times less sensitive (IC50: 643; range: 480-897 U/ml). The sensitivity of CFU-Meg ranged between these two colony types with 50% growth inhibition at an IFN concentration of 160 (range: 68-246 U/ml). A heterogeneous response to rIFN-alpha-2C in vitro was seen in CML patients. Three of the 14 patients were 'resistant' to rIFN-alpha-2C in vitro with IC50 values for BFU-E, CFU-GM and/or CFU-Meg colony formation greater than 10(4) U/ml. Patients were subsequently treated with a daily dose of rIFN-alpha-2C of 5 x 10(6) U. Four patients achieved a complete and six achieved a partial haematological response. Of the four non-responders three rapidly progressed into blastic crisis. Thus it was seen that treatment failure to interferon was accompanied by IFN-resistance in vitro of BFU-E, CFU-GM and/or CFU-Meg colony formation by bone marrow precursors (p less than 0.01). These results suggest a predictive value of IFN-sensitivity testing in vitro in Ph1 + CML.

摘要

在一项正在进行的II期试验中，我们旨在通过体外预测试来预测费城染色体阳性（Ph1 +）慢性粒细胞白血病（CML）对重组干扰素-α-2C（rIFN-α-2C）的临床反应性。从5名正常对照者和14名慢性期CML患者中，在治疗前采集骨髓样本，并使用用于BFU-E、CFU-GM和CFU-Meg的微琼脂培养系统，检测rIFN-α-2C的抗增殖活性。用含有从一名严重再生障碍性贫血患者获得的20%血清的α培养基刺激低密度有核骨髓细胞，以形成BFU-E和CFU-Meg集落。用细胞系GCT的条件培养基诱导CFU-GM生长。在正常对照中，rIFN-α-2C以剂量依赖性方式抑制BFU-E、CFU-GM和CFU-Meg集落形成。BFU-E被证明是最敏感的细胞系（IC50：65；范围：53 - 116 U/ml），而CFU-GM的敏感性约低20倍（IC50：643；范围：480 - 897 U/ml）。CFU-Meg的敏感性介于这两种集落类型之间，在IFN浓度为160（范围：68 - 246 U/ml）时生长抑制50%。在CML患者中观察到对rIFN-α-2C的体外反应存在异质性。14名患者中有3名在体外对rIFN-α-2C“耐药”，其BFU-E、CFU-GM和/或CFU-Meg集落形成的IC50值大于10(4) U/ml。随后患者接受每日剂量为5 x 10(6) U的rIFN-α-2C治疗。4名患者实现完全缓解，6名患者实现部分血液学缓解。在4名无反应者中，有3名迅速进展为急变期。因此可以看出，干扰素治疗失败与骨髓前体细胞的BFU-E、CFU-GM和/或CFU-Meg集落在体外对IFN耐药相关（p < 0.01）。这些结果表明体外IFN敏感性测试对Ph1 + CML具有预测价值。