Nilotinib和伊马替尼发挥协同增效作用

BCR-ABL+的白血病临床前模型中Nilotinib和伊马替尼发挥协同增效作用
波士顿Dana Farber癌症研究中心的Weisberg等报告,在BCR-ABL+的白血病临床前模型中,联合应用nilotinib和伊马替尼(imatinib)可发挥协同增效作用。[Blood 2007,109 (5): 2112]

因出现抵抗伊马替尼的BCR-ABL基因点突变而导致的药物抵抗在晚期慢性髓细胞性白血病(CML)患者中是一个显著的问题。BCR-ABL抑制剂 nilotinib比伊马替尼有更强的对抗BCR-ABL的效果,而且在对伊马替尼抵抗的BCR-ABL突变中仍然显示出活跃的对抗能力。Ⅰ期和Ⅱ期临床试验显示,nilotinib可以诱导之前伊马替尼治疗失败的患者出现缓解,提示两药序贯应用存在临床价值。但是,有几个原因提示同时应用这两个药物存在更大的吸引力,其中比较重要的原因是理论上同时应用两种BCR-ABL酪氨酸激酶抑制剂可能降低耐药突变克隆的发生率。

研究者分别在体外对表达BCR-ABL、伊马替尼敏感或抵抗的细胞系和体内小鼠白血病模型中研究了伊马替尼和nilotinib联合应用的效应。

结果显示,在伊马替尼敏感的细胞系中,伊马替尼和nilotinib联合表现出相加甚至轻度协同的效应,而无明显拮抗作用。在伊马替尼抵抗的细胞系中,二者联合显示出增强的抗白血病活性,尽管这一效果不如在高度伊马替尼抵抗的突变株T3151和Y253H中明显。

体外试验提示,与单独使用相比,伊马替尼和nilotinib同时使用显示出更强的诱导细胞凋亡、抑制细胞增殖和更显著抑制细胞内酪氨酸磷酸化的作用。小鼠体内研究表明,二者联合治疗显示出更强的抗肿瘤作用。

研究者认为,虽然伊马替尼和nilotinib的作用靶点都是BCR-ABL酪氨酸激酶,但两药联合应用在临床前模型中疗效突出,提示应该在临床中开始两药联合治疗BCR-ABL+ CML的研究。

Nilotinib Is Highly Active and Safe

Nilotinib Is Highly Active and Safe in Chronic Myelogenous Leukaemia Patients with Imatinib-Resistance or Intolerance -
New data demonstrated the efficacy and tolerability of Tasigna (nilotinib) in the treatment of Chronic myelogenous leukaemia (CML) patients with Imatinib-Resistance or Intolerance for whom there are few therapeutic options.

CML is a myeloproliferative disorder resulting from a chromosomal rearrangement leading to the formation of a novel fusion gene, BCR-ABL. The abnormal chromosome that causes CML is called the Philadelphia chromosome (Ph), and the resulting fusion gene encodes the BCR-ABL protein that has constitutive protein tyrosine kinase activity.

In the absence of treatment, CML progresses within several years from a chronic phase to an accelerated phase, and eventually culminates in blastic phase and death. Prior to imatinib introduction median survival of patients with accelerated phase CML was less than 18 months. The treatment of CML has been transformed by the introduction of imatinib, an inhibitor of the BCR-ABL tyrosine kinase. However, patients with CML in accelerated phase (CML-AP) who failed prior imatinib therapy have very limited therapeutic options.

Nilotinib (Tasigna) is a highly selective BCR-ABL tyrosine kinase inhibitor with a mechanism of action similar to imatinib but 30 times more potent in vitro versus sensitive cell lines. Two open-label Phase II studies were undertaken to evaluate the efficacy and safety of Tasigna in patients with imatinib resistant or intolerant CML in chronic phase (CP)1 and accelerated phase (AP)2 disease.

Study design

The open-label, uncontrolled, multicentre Phase II studies included 320 CP patients and 119 AP patients with imatinib resistant or intolerant CML. Median duration of treatment was 341 days for CP patients and 202 days for AP patients. Tasigna was administered on a continuous basis (400mg twice daily, 2 hours after a meal and with no food for at least one hour after administration) unless there was evidence of inadequate response or disease progression. Dose escalation to 600mg twice daily was allowed.

The primary endpoint in the CP patients was the rate of major cytogenetic response defined as elimination (complete cytogenetic response) or significant reduction of Ph+ haematopoietic cells. The primary endpoint in the AP patients was overall confirmed haematological response, defined as either a complete haematological response, no evidence of leukaemia or return to chronic phase.

Major cytogenetic response was observed in 56% of the CP patients

Major cytogenetic response was observed in 56.3% of the CP patients and 40.0% had complete cytogenetic response. Complete haematological remission at baseline was reported in 114 patients, the remaining, 76.2% achieved complete haematological remission in 1 month.

80% of AP patients were still alive after 12 months with Tasigna

In the AP group, a haematological response was observed in 47% of patients and a major cytogenetic response in 29% of patients. Overall survival rate among the 119 AP patients after 12 months of follow-up was 79%.

In both the CP and AP groups most responders achieved their major cytogenetic responses or hematologic responses rapidly (within 3 months of starting Tasigna treatment) and these were sustained (median duration has not been reached).

Tasigna had an acceptable safety and tolerability profile

Nonhaematologic adverse events were mostly mild to moderate. The most frequent Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia (27% in the CP group and 35% in the AP group), neutropenia (30% in CP and 21% in AP), and asymptomatic serum lipase elevation (15% in CP).

Conclusion

The studies showed that Tasigna produced significant hematologic and cytogenetic responses in imatinib-resistant and -intolerant patients with CML regardless the phase of the disease, chronic or accelerated.

This confirms that Tasigna is an effective and well-tolerated therapy which provides an important option for the treatment of CML patients with imatinib-resistance or -intolerance, whether the patients are in the chronic or accelerated phase of the disease.

1- Kantarjian HM et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 735.
2- Le Coutre P et al. Blood. 2008 Feb 15;111(4):1834-9. Epub 2007 Nov 29.

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