Molecular discoveries and clinical advances over the past few decades have made the treatment of chronic myeloid leukemia (CML) one of the great success stories of modern medicine. Before the 1980s, the focus was on maintaining normal white blood cell counts with agents such as hydroxyurea and busulfan. With the use of interferon, treatment strategies turned more toward cytogenetic remission. In 1998, targeted therapy was introduced to this setting with the first studies of imatinib mesylate. Since then, treatment objectives have shifted toward the attainment of molecular remission. In this review, we consider the variety of approaches to treating CML, efforts to minimize treatment failures, and possible future directions in therapy.
When Drs. Nowell and Hungerford first suggested a causal relationship between a chromosome abnormality and chronic granulocytic leukemia (now termed chronic myeloid leukemia, or CML), an era of cancer genetics began. Over the course of the next 20 years, the Philadelphia chromosome, named after the city where it was discovered, became the hallmark of CML, and the focal point for many discoveries. In 1973, it was defined as t(9;22), a reciprocal chromosomal translocation. A decade later, laboratories in the Netherlands and the United States localized the ABL proto-oncogene on chromosome 9 and the breakpoint cluster region (BCR) on chromosome 22 as focal points of the fusion gene product.[3-5]
Subsequent molecular discoveries and clinical advances have made the treatment of CML one of the great success stories of modern medicine. The development of therapy for CML in the clinic largely matches the scientific discoveries in the laboratory. Before the 1980s, the focus was on maintaining normal white blood cell counts, typically with hydroxyurea and busulfan (Myleran). In the era of interferon, cytogenetic remission became the focal point of therapy. Targeted therapy was introduced in 1998 with the first studies of imatinib mesylate (Gleevec), and since then, the objectives of therapy have rapidly shifted toward the achievement of molecular remission.
Interferon and Bone Marrow Transplantation
In 1983, interferon-alpha was first found to have activity against CML. This finding was quickly expanded, and in early studies, hematologic and cytogenetic responses of 71% and 39%, respectively, were reached. Randomized studies comparing interferon-alpha to traditional chemotherapy with busulfan and hydroxyurea echoed these findings; interferon-alpha prolonged the time to disease progression by 28 months and led to some long-term complete responses. Dormant myeloid progenitors were seen in CML patients with interferon-alpha-induced remissions, and immunologic mechanisms leading to tumor dormancy were proposed as a cause of sustained remission with interferon-alpha therapy. Indeed, long-term remissions off therapy, perhaps indicative of cure, were noted in 7.6% of the interferon-treated patients.
Bone marrow transplant (BMT) is not intended to be a primary topic of discussion in this review (which focuses on nontransplant therapeutic approaches), but it is important to recognize the role of BMT in the management of CML. In some patients, BMT offered durable, long-term remissions, and in a significant proportion of patients who were candidates for transplant, the procedure was curative. The scope of BMT remained limited, given the restricted availability of matched-sibling and unrelated donors and the associated transplant-related morbidity and mortality.[11-13] A regimen of interferon alfa-2b (Intron A) plus cytarabine offered the first real survival advantage in the treatment of CML,[7,14] and this approach was augmented by judicious use of transplantation, which still provides benefit in select patients who fail targeted therapy.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Nowell P, Hungerford D: A minute chromosome in human chronic granulocytic leukemia. Science 132:1497-1499, 1960.
2. Rowley JD: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining (letter). Nature 243:290-293, 1973.
3. Groffen J, Stephenson JR, Heisterkamp N, et al: Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36:93-99, 1984.
4. Heisterkamp N, Stephenson JR, Groffen J, et al: Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature 306:239-242, 1983.
5. Bartram CR, de Klein A, Hagemeijer A, et al: Translocation of c-ab1 oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature 306:277-280, 1983.
6. Talpaz M, McCredie KB, Mavligit GM, et al: Leukocyte interferon-induced myeloid cytoreduction in chronic myelogenous leukemia. Blood 62:689-692, 1983.
7. Talpaz M, Kantarjian HM, McCredie KB, et al: Clinical investigation of human alpha interferon in chronic myelogenous leukemia. Blood 69:1280-1288, 1987.
8. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. N Engl J Med 330:820-825, 1994.
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 94:1383-1389, 1994.
10. Kantarjian HM, O'Brien S, Cortes J, et al: Imatinib mesylate therapy improves survival in patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in the chronic phase: Comparison with historic data. Cancer 98:2636-2642, 2003.
11. Gratwohl A, Hermans J, Niederwieser D, et al: Bone marrow transplantation for chronic myeloid leukemia: Long-term results. Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation. Bone Marrow Transplant 12:509-516, 1993.
12. Bortin MM, Horowitz MM, Rowlings PA, et al: 1993 progress report from the International Bone Marrow Transplant Registry. Advisory Committee of the International Bone Marrow Transplant Registry. Bone Marrow Transplant 12:97-104, 1993.
13. Lamparelli T, Van Lint MT, Gualandi F, et al: Bone marrow transplantation for chronic myeloid leukemia (CML) from unrelated and sibling donors: Single center experience. Bone Marrow Transplant 20:1057-1062, 1997.
14. Druker BJ, Tamura S, Buchdunger E, et al: Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561-566, 1996.
15. Lugo TG, Pendergast AM, Muller AJ, et al: Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247:1079-1082, 1990.
16. Carroll M, Ohno-Jones S, Tamura S, et al: CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood 90:4947-4952, 1997.
17. Druker BJ, Talpaz M, Resta DJ, et al: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031-1037, 2001.
18. Sawyers CL, Hochhaus A, Feldman E, et al: Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: Results of a phase II study. Blood 99:3530-3539, 2002.
19. Ottmann OG, Druker BJ, Sawyers CL, et al: A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100:1965-1971, 2002.
20. Braziel RM, Launder TM, Druker BJ, et al: Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months' experience. Blood 100:435-441, 2002.
21. Kantarjian HM, O'Brien S, Cortes JE, et al: Treatment of philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res 8:2167-2176, 2002.
22. Kantarjian HM, Cortes J, O'Brien S, et al: Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 99:3547-3553, 2002.
23. Hughes TP, Kaeda J, Branford S, et al: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1423-1432, 2003.
24. O'Brien SG, Guilhot F, Larson RA, et al: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994-1004, 2003.
25. Guilhot F, Roy L, Guilhot J, et al: Retrospective comparison of imatinib versus interferon plus cytarabine (IFN/Ara-C) for chronic myelogenous leukemia (CML) patients in chronic phase (CP) (abstract 165). Blood 106:52a, 2005.
26. Kantarjian H, Talpaz M, O'Brien S, et al: High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 103:2873-2878, 2004.
27. Piazza RG, Magistroni V, Andreoni F, et al: Imatinib dose increase up to 1200 mg daily can induce new durable complete cytogenetic remissions in relapsed Ph+ chronic myeloid leukemia patients. Leukemia 19:1985-1987, 2005.
28. Hughes T, Branford S, Reynolds J, et al: Maintenance of imatinib dose intensity in the first six months of therapy for newly diagnosed patients with CML is predictive of molecular response, independent of the ability to increase dose at a later point (abstract 164). Blood 106:51a, 2005.
29. Corbin AS, La Rosee P, Stoffregen EP, et al: Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood 101:4611-4614, 2003.
30. Azam M, Latek RR, Daley GQ: Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 112:831-843, 2003.
31. Gorre ME, Mohammed M, Ellwood K, et al: Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876-880, 2001.
32. Shah NP, Nicoll JM, Nagar B, et al: Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2:117-125, 2002.
33. Al-Ali HK, Heinrich MC, Lange T, et al: High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patients with secondary resistance to imatinib. Hematol J 5:55-60, 2004.
34. Shah NP, Tran C, Lee FY, et al: Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305:399-401, 2004.
35. O'Hare T, Walters DK, Stoffregen EP, et al: In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 65:4500-4505, 2005.
36. O'Hare T, Corbin AS, Druker BJ: Targeted CML therapy: Controlling drug resistance, seeking cure. Curr Opin Genet Dev 16:92-99, 2006.
37. Wilson MB, Schreiner SJ, Choi HJ, et al: Selective pyrrolo-pyrimidine inhibitors reveal a necessary role for Src family kinases in Bcr-Abl signal transduction and oncogenesis. Oncogene 21:8075-8088, 2002.
38. Sawyers C, Kantarjian H, Shah N, et al: Dasatinib (BMS354825) in patients with chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ALL) who are resistant or intolerant to imatinib: Update of phase I study (abstract 38). Blood 106:16a, 2005.
39. Kantarjian HM, Ottman O, Cortes J, et al: AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has significant activity in imatinib-resistant chronic myeloid leukemia (CML) or Philadelphia-chromosome positive acute lymphoid leukemia (Ph+ALL) (abstract 37). Blood ;106:15a-16a, 2005.
40. Guilhot F, Apperley JF, Shah N, et al: A phase II study of dasatinib in patients with accelerated phase chronic myeloid leukemia (CML) who are resistant or intolerant to imatinib: First results of the CA180005 'START-A' study (abstract 39). Blood 106:16a, 2005.
41. Hochhaus A, Baccarani M, Sawyers C, et al: A phase II study of dasatinib in patients with chronic phase chronic myeloid leukemia Philadelphia chromosome-positive CML resistant or intolerant to imatinib: First results of the CA180013 'START-C' study (abstract 41). Blood 106:17a, 2005.
42. Talpaz M, Rousselot P, Kim DW, et al: A phase II study of dasatinib in patients with chronic myeloid leukemia (CML) in myeloid blast crisis who are resistant or intolerant to imatinib: First results of the CA180006 'START-B' study (abstract 40). Blood 106:16a, 2005.
43. Chu S, Xu H, Shah NP, et al: Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 105:2093-2098, 2005.
44. Copland M, Fraser AR, Harrison SJ, et al: Targeting the silent minority: Emerging immunotherapeutic strategies for eradication of malignant stem cells in chronic myeloid leukaemia. Cancer Immunol Immunother 54:297-306, 2005.
45. Copland M, Jorgensen HG, Holyoake TL: Evolving molecular therapy for chronic myeloid leukaemia-are we on target? Hematology 10:349-359, 2005.
46. Usuki K, Iijima K, Iki S, et al: CML cytogenetic relapse after cessation of imatinib therapy. Leuk Res 29:237-238, 2005.
47. Mauro MJ, Druker BJ, Maziarz RT: Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission. Leuk Res 28(suppl 1):S71-S73, 2004.
48. Copland M, Hamilton A, Elrick LJ, et al: Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML, but does not eliminate the quiescent fraction. Blood e-pub (available at www.bloodjournal.org): February 9, 2006.
49. Chandra J, Tracy J, Loegering D, et al: Adaphostin-induced oxidative stress overcomes BCR/ABL mutation-dependent and -independent imatinib resistance. Blood 107:2501-2506, 2006.
50. Adrian FJ, Ding Q, Sim T, et al: Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat Chem Biol 2:95-102, 2006.
51. Bartholomeusz GA, Donato N, Estrov Z, et al: Activation of a novel proteasomal independent BCR/ABL degradation pathway by WP1130 induces apoptosis in CML cells (abstract 2862). Blood 106:802a, 2005.