Chronic-Phase Chronic Myelogenous Leukemia
Treatment Options for Chronic-Phase Chronic Myelogenous Leukemia (CML)
Targeted therapy with tyrosine kinase inhibitors
High-dose therapy followed by allogeneic BMT or SCT
Biologic therapy with or without chemotherapy
Current Clinical Trials
Treatment Options for Chronic-Phase Chronic Myelogenous Leukemia (CML)
- Targeted therapy with tyrosine kinase inhibitors.
- High-dose therapy followed by allogeneic bone marrow transplant (BMT) or stem cell transplantation (SCT).
- Biologic therapy with or without chemotherapy.
- Splenectomy may be required and useful in patients having hematologic problems and physical discomfort from a massive spleen.
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
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.[10-18] 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.[15,16] 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.[19,20][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.[17,21]
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?[13,23,24]
- 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.[27,28] Most transplant series suggest improved survival when the procedure is performed within 1 year of diagnosis.[29-31][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.[33,34]
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.[28,39]
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.Biologic therapy with or without chemotherapy
Long-term data are available for initial treatment with interferon alpha. A meta-analysis of seven trials that randomly assigned patients to receive interferon or conventional chemotherapy (hydroxyurea or busulfan) demonstrated a 30% reduction in the annual death rate for patients who received interferon (P < .001).[Level of evidence: 1iiA] The annual death rate was reduced by 26% in the trials of interferon versus hydroxyurea (P = .001) and 36% in the trials of interferon versus busulfan (P = .007). Median survival was prolonged by 1 to 2 years; 5-year survival rate was 57% for patients treated with interferon and 42% for patients treated with chemotherapy (P < .001). Further analysis of the two trials, which included a three-way randomization between interferon, hydroxyurea, and busulfan, showed hydroxyurea to be superior to busulfan, decreasing the proportional odds of death by 24% (P = .02). About 20% of the chronic-phase patients treated with interferon alpha have complete cytogenetic remissions with temporary disappearance of Philadelphia chromosome (Ph1)-positive cells in the marrow, and in about 10% of the patients these cytogenetic responses are quite long lasting.[43-45] These data have only been published in the context of a review article, rather than a peer-reviewed research manuscript.
Long-term follow-up of the interferon-treated patients from a randomized trial that compared interferon with chemotherapy showed that the median survival had not been reached at 10 years for patients who had complete or major cytogenetic responses to interferon. Seventy-four percent of patients with complete cytogenetic responses and 55% of patients with major cytogenetic responses were alive and had shown no disease progression at date of publication (median follow-up time was not provided). Using molecular methods of analysis, however, small numbers of Ph1-positive cells can still be detected in the majority of patients having long-term cytogenetic remissions, and longer follow-up will be required to ascertain whether the disease will recur.
Patients older than 60 years with chronic-phase CML have a hematologic and cytogenetic response rate and duration of cytogenetic response similar to that in younger patients; however, the incidence of complications is greater in elderly patients. Interferon alpha has significant toxic effects that can result in dosage modification or discontinuation of therapy in many cases. A randomized, prospective trial of 407 patients compared two doses of interferon, 5 million units/m² daily versus 3 million units/m² daily; at a median follow-up of 53 months, no difference was seen in OS, progression-free survival, or number of major cytogenetic responses.[Level of evidence: 1iiA] As evidenced in the CLB-9013 study, common side effects included influenza-like syndrome, nausea, anorexia, weight loss, and neuropsychiatric symptoms, all of which were completely reversible with cessation of therapy. (Refer to the PDQ summaries on Nausea and Vomiting and Nutrition for information on some of these side effects.) Immune-mediated complications, such as hyperthyroidism, hemolysis, and connective tissue diseases may occur rarely after long-term treatment. Interferon alpha is quite costly, and daily subcutaneous injections can be troublesome. Pegylated interferon alpha is administered weekly; a randomized, noninferiority trial of 344 newly diagnosed CML patients could not rule out the possibility that pegylated interferon alpha may be slightly inferior to daily interferon alpha.[Level of evidence: 1iiDiv]
Patients whose disease is in cytogenetic remission should continue therapy for at least 2 to 3 years beyond remission, and perhaps indefinitely, as suggested by some investigators. After 1 year, patients with only a partial cytogenetic response should consider alternative therapy with imatinib mesylate or allogeneic BMT or SCT (if eligible). The French Chronic Myeloid Leukemia Study Group randomly assigned 721 patients to interferon and cytarabine versus interferon alone.[Level of evidence: 1iiA] Patients who received the combination had significantly more major cytogenetic responses (41% vs. 24%, P < .001) and improved 3-year survival (86% vs. 80%). Another trial by the Italian Cooperative Study Group on CML did not show a survival benefit for interferon plus cytarabine versus interferon alone.[Level of evidence: 1iiA] Both studies showed increased toxic effects for the combination versus interferon alone.[52,53] Interferon alpha is also effective for patients who have relapsed after allogeneic BMT.[54,55]Hydroxyurea
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.References
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