Chronic-Phase Chronic Myelogenous Leukemia (CML)
Treatment Options for Chronic-Phase CML
- Targeted therapy with tyrosine kinase inhibitors .
- High-dose therapy followed by allogeneic bone marrow transplant (BMT) or stem cell transplantation (SCT).
- Splenectomy may be required and useful in patients having hematologic problems and physical discomfort from a massive spleen.
Targeted therapy with tyrosine kinase inhibitors
A trial randomly assigning 1,106 previously untreated patients to imatinib mesylate or to interferon plus cytarabine documented a 76% complete cytogenetic response rate with imatinib mesylate versus 14% for interferon plus cytarabine at a median follow-up of 19 months.[1,2][Level of evidence: 1iiDiii] At 18 months, 96.7% of the imatinib group had avoided progression to accelerated-phase CML or blast crisis compared with 91.5% of the interferon plus cytarabine group (P < .001). Because 90% of the combination group had switched to imatinib by 18 months (mostly because of intolerance of side effects), a survival difference may never be observed. By the 5-year median follow-up of this trial, imatinib mesylate induced complete cytogenetic response in more than 80% of the participants, with the annual rate of progression to accelerated-phase CML or blast crisis dropping from 2% in the first year to less than 1% in the fourth year. In addition, the overall survival (OS) rate for all patients at 5 years is 89%, with fewer than 50% of all deaths (4.5%) caused by CML. More than 90% of completely responding patients still show detectable evidence of the BCR/ABL translocation, usually by reverse transcription-polymerase chain reaction (RT–PCR) or by fluorescence in situ hybridization of progenitor cell cultures.[3-5] The clinical implication of this finding after 10 years or more is unknown, but these results have changed clinical practice. Poor compliance is the predominant reason for inadequate molecular response to imatinib.
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 that compared nilotinib with imatinib, the rate of major molecular response at 24 months was 71% and 67% for two-dose schedules of nilotinib and 44% for imatinib (P < .0001 for both comparisons).[Level of evidence: 1iiDiv] Progression to accelerated-phase CML or blast crisis occurred in 17 patients on imatinib (14%), but this progression only occurred in two patients (<1%, P = .0003) and in five patients (1.8%, P = .0089), respectively, for those patients on two-dose schedules of nilotinib. Nilotinib-treated patients had a lower rate of treatment-emergent BCR/ABL mutations than did imatinib-treated patients.
Similarly, in a randomized, prospective study of 519 patients that compared 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 major molecular response at 24 months was 64% for dasatinib and 46% for imatinib (P < .0001).[Level of evidence: 1iiDiv] Progression to accelerated-phase CML or blast crisis occurred in 13 patients (5%) on imatinib and in six patients (2.3%) on dasatinib (not statistically different).
Although one of these two studies showed statistically significant decreased rates of progression to accelerated- or blastic-phase CML, 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.
Higher doses of imatinib mesylate, alternative tyrosine kinase inhibitors (such as dasatinib or nilotinib, and allogeneic SCT) are implemented for suboptimal response or progression and are under clinical evaluation as frontline approaches.[11-19] Currently in practice, dose escalation of imatinib is usually the first step taken for suboptimal response, but clinical trials are required to establish the relative efficacy and sequencing of dose escalation, dasatinib, and nilotinib.[16,17] Two studies looked at dose escalation of imatinib in almost 200 previously untreated patients, most of whom were of intermediate Sokal risk; 63% to 73% achieved a major molecular response by 18 to 24 months and only three patients showed progression to advanced phase in these preliminary phase II results.[20,21][Level of evidence: 3iiiDiv] Until randomized studies are performed, it is unclear whether the increased response with increased dosage will translate into longer durations of response or survival advantages.[18,22]
A single-center, retrospective analysis of 483 patients with chronic phase CML who were treated with imatinib (400 mg or 800 mg daily), dasatinib, or nilotinib, indicated that patients who have better than 35% t(9;22)+ cells at 3 months of therapy have inferior event-free, transformation-free, and OS rates compared with patients who have better early cytogenetic responses.
Among the many unanswered questions are the following:
- Will responses on tyrosine kinase inhibitors be durable beyond 10 years, and can we ever stop treatment with them? In a prospective, nonrandomized study, 100 patients in complete molecular remission stopped imatinib after more than 2 years of therapy; by 1 year, 61% of patients relapsed and all responded to the reintroduction of imatinib. Longer follow-up is required to see if some patients maintain a long-term remission after discontinuation of therapy.
- Should the newer tyrosine kinase inhibitors dasatinib or nilotinib replace imatinib as frontline therapy?
- Does time-to-response matter if a good response is obtained eventually?
- Does a good response in a high-risk patient overcome the adverse prognosis of the high-risk features?
- What is the role of allogeneic BMT or SCT for younger, eligible patients and when should it be offered?[14,25,26]
- Should other active agents be added to therapy with tyrosine kinase inhibitors?
All of these issues have led to an active reappraisal of recommendations for optimal frontline therapy for chronic-phase CML.
High-dose therapy followed by allogeneic BMT or SCT
The only consistently successful curative treatment of CML has been high-dose therapy followed by allogeneic BMT or SCT. Patients younger than 60 years with an identical twin or with HLA-identical siblings can be considered for BMT early in the chronic phase. Although the procedure is associated with considerable acute morbidity and mortality, 50% to 70% of patients transplanted in the chronic phase survive 2 to 3 years, and the results are better in younger patients, especially those younger than 20 years. The results of patients transplanted in the accelerated and blastic phases of the disease are progressively worse.[29,30] Most transplant series suggest improved survival when the procedure is performed within 1 year of diagnosis.[31-33][Level of evidence: 3iiiA] The data supporting early transplant, however, have never been confirmed in controlled trials. In a randomized, clinical trial, disease-free survival and OS were comparable when allogeneic transplantation followed preparative therapy with cyclophosphamide and total-body irradiation (TBI) or busulfan and cyclophosphamide without TBI. The latter regimen was associated with less graft-versus-host disease and fewer fevers, hospitalizations, and hospital days.[Level of evidence: 1iiA] Reduced-intensity conditioning allogeneic SCT is under evaluation in first or second remissions.[35,36]
About 20% of otherwise eligible CML patients lack a suitably matched sibling donor. HLA-matched unrelated donors or donors mismatched at one-HLA antigen can be found for about 50% of eligible participants through the National Marrow Donor Program. A retrospective review of 2,444 patients who received myeloablative allogeneic SCT showed OS at 15 years of 88% (95% confidence interval [CI], 86%–90%) for sibling-matched transplant and of 87% (95% CI, 83%–90%) for unrelated donor transplant. The cumulative incidences of relapse were 8% (95% CI, 7%–10%) for sibling-matched transplant and 2% (95% CI, 1%– 4%) for unrelated donor transplant.
Although the majority of relapses occur within 5 years of transplantation, relapses have occurred for as long as 15 years following BMT. In a molecular analysis of 243 patients who underwent allogeneic BMT over a 20-year interval, only 15% had no detectable BCR/ABL transcript by PCR analysis. The risk of relapse appears to be less in patients transplanted early in disease and in patients who develop chronic graft-versus-host disease.[30,41]
With the advent of imatinib, dasatinib, and nilotinib, the timing and sequence of allogeneic BMT or SCT has been cast in doubt. Allogeneic SCT is the preferred choice for patients presenting with accelerated-phase or blast-phase disease, for patients with a T3151 mutation (resistant to currently available tyrosine kinase inhibitors), and for patients with complete intolerance to the pharmacologic options.
In a prospective trial of 354 patients aged younger than 60 years, 123 of 135 patients with a matched, related donor underwent early allogeneic SCT while the others received interferon-based therapy and imatinib at relapse; some also underwent a matched, unrelated-donor transplant in remission. With a 9-year median follow-up, survival still favored the drug treatment arm (P = .049), but most of the benefit was early as a result of transplant-related mortality, with the survival curves converging by 8 years.[Level of evidence: 2A] Among the many unanswered questions are the following:
- Should younger eligible patients move quickly toward allogeneic SCT after induction failure by imatinib mesylate?
- Does the substantial toxicity and mortality of allogeneic transplantation render its early use obsolete?
Clinical trials and long-term results from ongoing trials will be required before these controversies are resolved.
Tyrosine kinase inhibitor-resistant CML
For patients resistant to the tyrosine kinase inhibitor, omacetaxine mepesuccinate (a cephalotaxine, formerly known as homoharringtonine, with activity independent of BCR/ABL) has shown a hematologic response rate of 67% and a median progression-free survival of 7 months in a small, phase II study of 46 patients.[Level of evidence: 3iiiDiv]
Hydroxyurea is given daily by mouth (1–3 g per day as a single dose on an empty stomach). Hydroxyurea is superior to busulfan in the chronic phase of CML, with significantly longer median survival and significantly fewer severe adverse effects. A dose of 40 mg/kg per day is often used initially and frequently results in a rapid reduction of the white blood cell (WBC) count. When the WBC count drops below 20,000 mm3, the hydroxyurea is often reduced and titrated to maintain a WBC count between 5,000 and 20,000. Hydroxyurea is currently used primarily to stabilize patients with hyperleukocytosis or as palliative therapy for patients who have not responded to other therapies.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with chronic phase chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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- 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]
- Marin D, Bazeos A, Mahon FX, et al.: Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 28 (14): 2381-8, 2010. [PUBMED Abstract]
- Kantarjian HM, Hochhaus A, Saglio G, et al.: Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 12 (9): 841-51, 2011. [PUBMED Abstract]
- Hochhaus A, Saglio G, Larson RA, et al.: Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 121 (18): 3703-8, 2013. [PUBMED Abstract]
- Kantarjian HM, Shah NP, Cortes JE, et al.: Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 119 (5): 1123-9, 2012. [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]
- Jabbour E, Cortes J, Kantarjian HM, et al.: Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood 108 (4): 1421-3, 2006. [PUBMED Abstract]
- Cortes JE, Jones D, O'Brien S, et al.: Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol 28 (3): 392-7, 2010. [PUBMED Abstract]
- Apperley JF, Cortes JE, Kim DW, et al.: Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol 27 (21): 3472-9, 2009. [PUBMED Abstract]
- Cortes JE, Jones D, O'Brien S, et al.: Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol 28 (3): 398-404, 2010. [PUBMED Abstract]
- Kantarjian HM, Larson RA, Guilhot F, et al.: Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 115 (3): 551-60, 2009. [PUBMED Abstract]
- Jabbour E, Cortes JE, Kantarjian HM: Suboptimal response to or failure of imatinib treatment for chronic myeloid leukemia: what is the optimal strategy? Mayo Clin Proc 84 (2): 161-9, 2009. [PUBMED Abstract]
- Jabbour E, Kantarjian HM, Jones D, et al.: Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 113 (10): 2154-60, 2009. [PUBMED Abstract]
- Cortes JE, Baccarani M, Guilhot F, et al.: Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol 28 (3): 424-30, 2010. [PUBMED Abstract]
- Rosti G, Palandri F, Castagnetti F, et al.: Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood 114 (24): 4933-8, 2009. [PUBMED Abstract]
- Castagnetti F, Palandri F, Amabile M, et al.: Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party. Blood 113 (15): 3428-34, 2009. [PUBMED Abstract]
- Cortes JE, Kantarjian HM, Goldberg SL, et al.: High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J Clin Oncol 27 (28): 4754-9, 2009. [PUBMED Abstract]
- Hehlmann R, Lauseker M, Jung-Munkwitz S, et al.: Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29 (12): 1634-42, 2011. [PUBMED Abstract]
- Jain P, Kantarjian H, Nazha A, et al.: Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities. Blood 121 (24): 4867-74, 2013. [PUBMED Abstract]
- Mahon FX, Réa D, Guilhot J, et al.: Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11 (11): 1029-35, 2010. [PUBMED Abstract]
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- Saussele S, Lauseker M, Gratwohl A, et al.: Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood 115 (10): 1880-5, 2010. [PUBMED Abstract]
- Preudhomme C, Guilhot J, Nicolini FE, et al.: Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 363 (26): 2511-21, 2010. [PUBMED Abstract]
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- Cortes J, Digumarti R, Parikh PM, et al.: Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol 88 (5): 350-4, 2013. [PUBMED Abstract]
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