UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

干扰素α在慢性髓系白血病治疗中的应用

Authors
Robert S Negrin, MD
Charles A Schiffer, MD
Section Editor
Richard A Larson, MD
Deputy Editor
Rebecca F Connor, MD
Translators
杨林花, 主任医师

引言

从1981年起，在干扰素α(interferon alpha, IFNα)用于慢性髓系白血病(chronic myeloid leukemia, CML)的治疗方面已开展了广泛的研究，最初采用部分纯化的IFNα[1]，之后使用重组的IFNα-2a[2]。在酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)甲磺酸伊马替尼问世之前，IFN曾被作为大多数CML患者的首选非移植治疗。然而，随着TKI的不断发展，以及与TKI相比，IFN的毒性较高，使得IFN这一药物在CML治疗中的应用有很大程度的减少。

本文将讨论IFNα在CML治疗中的应用。其他治疗选择将单独讨论。 (参见“慢性髓系白血病的治疗概述”和“慢性髓系白血病慢性期的初始治疗”和“加速期慢性髓系白血病的治疗”和“急变期慢性髓系白血病的治疗”和“酪氨酸激酶抑制剂在慢性髓系白血病中的临床应用”和“慢性髓系白血病的造血干细胞移植”)

干扰素α

使用IFNα-2a单药治疗CML的大部分患者获得血液学缓解(hematologic remission, HR)，然而仅有少部分(13%-27%)患者获得细胞遗传学完全缓解(complete cytogenetic remission，CCR；即常规细胞遗传学检测手段检测不到任何Ph+中期分裂相)[3,4]。

在较年轻患者以及Sokal风险分组较低的患者中，细胞遗传学缓解率较高[5,6]。虽然细胞遗传学缓解程度可随时间推移而增加，但是如果治疗的第1年内未见Ph染色体中期分裂相百分比下降，则给予进一步治疗也很少见获得细胞遗传学缓解的情况。

少数患者的细胞遗传学缓解可持续较长时间；获得主要细胞遗传学缓解的患者生存期似乎更长[7]。由于IFN有明显的副作用，许多临床医生选择对治疗约1年后无细胞遗传学改善的患者停用IFN。两项研究发现，应用IFNα获得CCR患者的10年生存率为72%-78%[3,4]。对大部分应用IFNα获得CCR的患者使用更敏感的聚合酶链反应(polymerase chain reaction, PCR)技术仍可检测到疾病的分子学证据[4,8-10]，但是有时也会有维持长期细胞遗传学缓解状态的患者在停用IFN后无复发。由于该观察结果和一些其他因素，目前有正在进行和计划进行的临床试验将IFNα用于CML的后期治疗，以增加缓解深度，从而使得更大部分患者可以停用TKI。

         

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: 2017-06 . | This topic last updated: 2017-01-13.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Talpaz M, McCredie KB, Mavligit GM, Gutterman JU. Leukocyte interferon-induced myeloid cytoreduction in chronic myelogenous leukemia. Blood 1983; 62:689.
  2. Talpaz M, Kantarjian HM, McCredie K, et al. Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha A in chronic myelogenous leukemia. N Engl J Med 1986; 314:1065.
  3. Bonifazi F, de Vivo A, Rosti G, et al. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood 2001; 98:3074.
  4. Kantarjian HM, O'Brien S, Cortes JE, et al. Complete cytogenetic and molecular responses to interferon-alpha-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer 2003; 97:1033.
  5. Sokal JE, Baccarani M, Russo D, Tura S. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 1988; 25:49.
  6. Sokal risk score calculator available online at www.roc.se/sokal.asp (Accessed on April 03, 2006).
  7. Talpaz M, Kantarjian H, Kurzrock R, et al. Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia. Philadelphia chromosome-positive patients. Ann Intern Med 1991; 114:532.
  8. Lee MS, Kantarjian H, Talpaz M, et al. Detection of minimal residual disease by polymerase chain reaction in Philadelphia chromosome-positive chronic myelogenous leukemia following interferon therapy. Blood 1992; 79:1920.
  9. Talpaz M, Estrov Z, Kantarjian H, et al. Persistence of dormant leukemic progenitors during interferon-induced remission in chronic myelogenous leukemia. Analysis by polymerase chain reaction of individual colonies. J Clin Invest 1994; 94:1383.
  10. Chomel JC, Brizard F, Veinstein A, et al. Persistence of BCR-ABL genomic rearrangement in chronic myeloid leukemia patients in complete and sustained cytogenetic remission after interferon-alpha therapy or allogeneic bone marrow transplantation. Blood 2000; 95:404.
  11. Kantarjian HM, Smith TL, O'Brien S, et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med 1995; 122:254.
  12. Schofield JR, Robinson WA, Murphy JR, Rovira DK. Low doses of interferon-alpha are as effective as higher doses in inducing remissions and prolonging survival in chronic myeloid leukemia. Ann Intern Med 1994; 121:736.
  13. Kluin-Nelemans HC, Buck G, le Cessie S, et al. Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups. Blood 2004; 103:4408.
  14. Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group. Blood 1994; 84:4064.
  15. Italian Cooperative Study Group on Chronic Myeloid Leukemia, Tura S, Baccarani M, et al. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med 1994; 330:820.
  16. Allan NC, Richards SM, Shepherd PC. UK Medical Research Council randomised, multicentre trial of interferon-alpha n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. The UK Medical Research Council's Working Parties for Therapeutic Trials in Adult Leukaemia. Lancet 1995; 345:1392.
  17. Ohnishi K, Ohno R, Tomonaga M, et al. A randomized trial comparing interferon-alpha with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood 1995; 86:906.
  18. Sacchi S, Kantarjian H, O'Brien S, et al. Immune-mediated and unusual complications during interferon alfa therapy in chronic myelogenous leukemia. J Clin Oncol 1995; 13:2401.
  19. Zuber J, Martinez F, Droz D, et al. Alpha-interferon-associated thrombotic microangiopathy: a clinicopathologic study of 8 patients and review of the literature. Medicine (Baltimore) 2002; 81:321.
  20. Mahon FX, Delbrel X, Cony-Makhoul P, et al. Follow-up of complete cytogenetic remission in patients with chronic myeloid leukemia after cessation of interferon alfa. J Clin Oncol 2002; 20:214.
  21. Gale RP, Hehlmann R, Zhang MJ, et al. Survival with bone marrow transplantation versus hydroxyurea or interferon for chronic myelogenous leukemia. The German CML Study Group. Blood 1998; 91:1810.
  22. Long-term follow-Up of the italian trial of interferon-alpha versus conventional chemotherapy in chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Blood 1998; 92:1541.
  23. Sokal JE, Leong SS, Gomez GA. Preferential inhibition by cytarabine of CFU-GM from patients with chronic granulocytic leukemia. Cancer 1987; 59:197.
  24. Sokal JE, Gockerman JP, Bigner SH. Evidence for a selective antileukemic effect of cytosine arabinoside in chronic granulocytic leukemia. Leuk Res 1988; 12:453.
  25. Robertson MJ, Tantravahi R, Griffin JD, et al. Hematologic remission and cytogenetic improvement after treatment of stable-phase chronic myelogenous leukemia with continuous infusion of low-dose cytarabine. Am J Hematol 1993; 43:95.
  26. Kantarjian HM, Keating MJ, Estey EH, et al. Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine. J Clin Oncol 1992; 10:772.
  27. Thaler J, Fluckinger T, Huber H, et al. Treatment of 11 patients with chronic myelogenous leukemia with interferon-alpha-2C and low-dose cytosine arabinoside. Leuk Res 1993; 17:711.
  28. Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med 1997; 337:223.
  29. Baccarani M, Rosti G, de Vivo A, et al. A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia. Blood 2002; 99:1527.
  30. del Cañizo MC, Fisac MP, Galende J, et al. Continuous oral cytarabine ocfosfate with interferon-alpha-2b for patients with newly diagnosed chronic myeloid leukaemia: a pilot study. Br J Haematol 2001; 115:541.
  31. Garcia-Manero G, Talpaz M, Giles FJ, et al. Treatment of Philadelphia chromosome-positive chronic myelogenous leukemia with weekly polyethylene glycol formulation of interferon-alpha-2b and low-dose cytosine arabinoside. Cancer 2003; 97:3010.
  32. Talpaz M, Rakhit A, Rittweger K, et al. Phase I evaluation of a 40-kDa branched-chain long-acting pegylated IFN-alpha-2a with and without cytarabine in patients with chronic myelogenous leukemia. Clin Cancer Res 2005; 11:6247.
  33. Molldrem JJ, Lee PP, Wang C, et al. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med 2000; 6:1018.
  34. Burchert A, Neubauer A. Interferon alpha and T-cell responses in chronic myeloid leukemia. Leuk Lymphoma 2005; 46:167.
  35. Palandri F, Castagnetti F, Iacobucci I, et al. The response to imatinib and interferon-alpha is more rapid than the response to imatinib alone: a retrospective analysis of 495 Philadelphia-positive chronic myeloid leukemia patients in early chronic phase. Haematologica 2010; 95:1415.
  36. Burchert A, Müller MC, Kostrewa P, et al. Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia. J Clin Oncol 2010; 28:1429.
  37. Preudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 2010; 363:2511.
  38. Hanfstein B, Müller MC, Hehlmann R, et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia 2012; 26:2096.
  39. Palandri F, Iacobucci I, Castagnetti F, et al. Front-line treatment of Philadelphia positive chronic myeloid leukemia with imatinib and interferon-alpha: 5-year outcome. Haematologica 2008; 93:770.
  40. Guilhot F, Preudhomme C, Guilhot J, et al. Significant higher rates of undetectable molecular residual disease and molecular responses with pegylated form of interferon a2a in combination with imatinib for the treatment of newly diagnosed chronic phase chronic myeloid leukemia patients: confirmatory results at 18 months of part 1 of the spirit phase III randomized trial of the French CML Group (abstract 340). Blood 2009; 114:144s.
  41. Pletsch N, Saussele S, Lauseker M, et al. Optimization of imatinib therapy by combination. 5 year survival and response results of the pilot phase of the randomized German CML study IV (abstract 862). Blood 2009; 114:355.
  42. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355:2408.
  43. Branford S, Hughes T, Milner A, et al. Efficacy and safety of imatinib in patients with chronic myeloid leukemia and complete or near-complete cytogenetic response to interferon-alpha. Cancer 2007; 110:801.
  44. Malagola M, Breccia M, Skert C, et al. Long term outcome of Ph+ CML patients achieving complete cytogenetic remission with interferon based therapy moving from interferon to imatinib era. Am J Hematol 2014; 89:119.