Treatment Option Overview
Treatment of patients with chronic myelogenous leukemia (CML) is usually initiated when the diagnosis is established, which is done by the presence of an elevated white blood cell (WBC) count, splenomegaly, thrombocytosis, and identification of the BCR/ABL (breakpoint cluster region/Abelson) translocation. The optimal frontline treatment for patients with chronic-phase CML is the subject of active clinical evaluation but involves specific inhibitors of the BCR/ABL tyrosine kinase.
In a randomized trial comparing imatinib mesylate with interferon plus cytarabine, with 5 years' median follow-up, imatinib mesylate induced complete cytogenetic responses in more than 80% of newly diagnosed patients; in addition, the annual rate of progression to accelerated phase or blast crisis dropped from 2% to less than 1% in the fourth year on the imatinib arm.[Level of evidence: 1iiDiii] However, most of these continually responding patients still showed detectable evidence of the BCR/ABL translocation by the most sensitive measurement of reverse transcriptase–polymerase chain reaction (RT–PCR).[3-5] The clinical implication of this finding after 10 years or more is unknown, but these results have changed clinical practice. Although evidence-based survival advantages are unavailable because of crossover in randomized trials, the overall survival rate for all patients at 5 years is 89%, with fewer than 50% of all deaths (4.5%) caused by CML.
Tyrosine kinase inhibitors with greater potency and selectivity for BCR/ABL than imatinib have been evaluated in newly diagnosed patients with CML. In a randomized, prospective study of 846 patients comparing nilotinib with imatinib, the rate of major molecular response at 12 months was 43% and 44% for 2-dose schedules of nilotinib and 22% for imatinib (P < .001 for both comparisons). The rate of complete cytogenetic response at 12 months was 80% and 78% for 2-dose schedules of nilotinib and 65% for imatinib (P < .001 for both comparisons).[Level of evidence: 1iiDiv] Progression to accelerated phase or blast crisis occurred in 11 patients on imatinib (4%) but only occurred in 2 patients (<1%, P = . 01) and 1 patient (<1%, P = .004) for the patients on 2-dose schedules of nilotinib.
Similarly, in a randomized, prospective study of 519 patients comparing dasatinib with imatinib, the rate of major molecular response at 12 months was 46% for dasatinib and 28% for imatinib (P < .0001). The rate of complete cytogenetic response at 12 months was 77% for dasatinib and 66% for imatinib (P = .007).[Level of evidence: 1iiDiv] Progression to accelerated-phase CML or blast crisis occurred in nine patients (3.5%) on imatinib and in five patients (1.9%) on dasatinib (not statistically different).
Although one of these two studies showed statistically significant decreased rates of progression to accelerated or blastic phase, which may ultimately translate into improved survival, the follow-up period with nilotinib and dasatinib has not been long enough to detect and confirm this prolonged survival with these agents. The preferred initial treatment for newly diagnosed patients with chronic-phase CML could be any of these specific inhibitors of the BCR/ABL tyrosine kinase.
The only consistently successful curative treatment of CML beyond 10 years' follow-up has been allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT). Long-term data beyond 10 years of therapy are available, and most long-term survivors show no evidence of the BCR/ABL translocation by any available test (e.g., cytogenetics, RT–PCR, or fluorescent in situ hybridization [FISH]). Many patients, however, are not eligible for this approach because of age, comorbid conditions, or lack of a suitable donor. In addition, substantial morbidity and mortality result from allogeneic BMT or SCT; a 15% to 30% treatment-related mortality can be expected, depending on whether a donor is related and on the presence of mismatched antigens.
Long-term data are also available for patients treated with interferon alpha.[11-13] Approximately 10% to 20% of these patients have a complete cytogenetic response with no evidence of BCR/ABL translocation by any available test, and the majority of these patients are disease free beyond 10 years. Maintenance of therapy with interferon is required, however, and some patients experience side effects that preclude continued treatment.
Newly diagnosed patients with very high levels of circulating leukocytes (WBC >100,000/mm3) require immediate therapy with imatinib mesylate to avoid cerebrovascular events or death from leukostasis. Leukophoresis and plateletpheresis are sometimes required for an even more emergent reduction of counts.References
- Sawyers CL: Chronic myeloid leukemia. N Engl J Med 340 (17): 1330-40, 1999. [PUBMED Abstract]
- 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 355 (23): 2408-17, 2006. [PUBMED Abstract]
- Bhatia R, Holtz M, Niu N, et al.: Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101 (12): 4701-7, 2003. [PUBMED Abstract]
- 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 (15): 1423-32, 2003. [PUBMED Abstract]
- Rosti G, Martinelli G, Bassi S, et al.: Molecular response to imatinib in late chronic-phase chronic myeloid leukemia. Blood 103 (6): 2284-90, 2004. [PUBMED Abstract]
- Kantarjian HM, Talpaz M, O'Brien S, et al.: Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 108 (6): 1835-40, 2006. [PUBMED Abstract]
- Saglio G, Kim DW, Issaragrisil S, et al.: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362 (24): 2251-9, 2010. [PUBMED Abstract]
- Kantarjian H, Shah NP, Hochhaus A, et al.: Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362 (24): 2260-70, 2010. [PUBMED Abstract]
- Wei G, Rafiyath S, Liu D: First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J Hematol Oncol 3: 47, 2010. [PUBMED Abstract]
- Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic myelogenous leukemia: playing the odds. J Clin Oncol 16 (9): 2897-903, 1998. [PUBMED Abstract]
- Ozer H, George SL, Schiffer CA, et al.: Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study 8583. Blood 82 (10): 2975-84, 1993. [PUBMED Abstract]
- 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 122 (4): 254-61, 1995. [PUBMED Abstract]
- 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 92 (5): 1541-8, 1998. [PUBMED Abstract]