Healy Fiona M, Dahal Lekh N, Jones Jack R E, Floisand Yngvar, Woolley John F
Department of Pharmacology & Therapeutics, University of Liverpool, Liverpool, United Kingdom.
Department of Molecular & Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
Front Oncol. 2021 Oct 29;11:769628. doi: 10.3389/fonc.2021.769628. eCollection 2021.
Myeloid malignancies are a heterogeneous group of clonal haematopoietic disorders, caused by abnormalities in haematopoietic stem cells (HSCs) and myeloid progenitor cells that originate in the bone marrow niche. Each of these disorders are unique and present their own challenges with regards to treatment. Acute myeloid leukaemia (AML) is considered the most aggressive myeloid malignancy, only potentially curable with intensive cytotoxic chemotherapy with or without allogeneic haematopoietic stem cell transplantation. In comparison, patients diagnosed with chronic myeloid leukaemia (CML) and treated with tyrosine kinase inhibitors (TKIs) have a high rate of long-term survival. However, drug resistance and relapse are major issues in both these diseases. A growing body of evidence suggests that Interferons (IFNs) may be a useful therapy for myeloid malignancies, particularly in circumstances where patients are resistant to existing front-line therapies and have risk of relapse following haematopoietic stem cell transplant. IFNs are a major class of cytokines which are known to play an integral role in the non-specific immune response. IFN therapy has potential as a combination therapy in AML patients to reduce the impact of minimal residual disease on relapse. Alongside this, IFNs can potentially sensitize leukaemic cells to TKIs in resistant CML patients. There is evidence also that IFNs have a therapeutic role in myeloproliferative neoplasms (MPNs) such as polycythaemia vera (PV) and primary myelofibrosis (PMF), where they can restore polyclonality in patients. Novel formulations have improved the clinical effectiveness of IFNs. Low dose pegylated IFN formulations improve pharmacokinetics and improve patient tolerance to therapies, thereby minimizing the risk of haematological toxicities. Herein, we will discuss recent developments and the current understanding of the molecular and clinical implications of Type I IFNs for the treatment of myeloid malignancies.
髓系恶性肿瘤是一组异质性的克隆性造血疾病，由起源于骨髓微环境的造血干细胞（HSCs）和髓系祖细胞异常引起。这些疾病中的每一种都是独特的，在治疗方面都有其自身的挑战。急性髓系白血病（AML）被认为是最具侵袭性的髓系恶性肿瘤，只有通过强化细胞毒性化疗（有或没有异基因造血干细胞移植）才有可能治愈。相比之下，被诊断为慢性髓系白血病（CML）并接受酪氨酸激酶抑制剂（TKIs）治疗的患者长期生存率较高。然而，耐药性和复发是这两种疾病的主要问题。越来越多的证据表明，干扰素（IFNs）可能是治疗髓系恶性肿瘤的一种有用疗法，特别是在患者对现有一线疗法耐药且有造血干细胞移植后复发风险的情况下。IFNs是一类主要的细胞因子，已知在非特异性免疫反应中起不可或缺的作用。IFN疗法在AML患者中作为联合疗法有潜力降低微小残留病对复发的影响。除此之外，IFNs可能使耐药CML患者的白血病细胞对TKIs敏感。也有证据表明IFNs在骨髓增殖性肿瘤（MPNs）如真性红细胞增多症（PV）和原发性骨髓纤维化（PMF）中具有治疗作用，在这些疾病中它们可以恢复患者的多克隆性。新型制剂提高了IFNs的临床疗效。低剂量聚乙二醇化IFN制剂改善了药代动力学并提高了患者对治疗的耐受性，从而将血液学毒性风险降至最低。在此，我们将讨论I型IFNs治疗髓系恶性肿瘤的分子和临床意义的最新进展及当前认识。
