Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Treatment options:

1. Since tyrosine kinase activity is required for the transforming function of the BCR/ABL (breakpoint cluster region/Abelson) fusion protein, a specific inhibitor of the kinase could be an effective treatment for patients with chronic myelogenous leukemia (CML).[1,2] Imatinib mesylate is a compound that inhibits the BCR/ABL oncoprotein, which is pathogenic in CML. In 454 patients with chronic phase CML, who had previously not responded to interferon, imatinib mesylate induced major cytogenetic responses in 60% of patients and complete hematologic response in 95% of patients, with 89% of patients free of progression to accelerated-phase or blastic-phase with a median follow-up of 18 months.[3][Level of evidence: 3iiiDiv] In 261 patients with chronic-phase CML treated with imatinib mesylate after failure of interferon, at 45 months' median follow-up, 75% remained alive in chronic phase on imatinib with a 4-year complete molecular response (no detectable BCR/ABL by reverse transcriptase–polymerase chain reaction [RT–PCR]) rate of 26%.[4][Level of evidence: 3iiiDiv] In a retrospective review of 284 patients treated with imatinib mesylate after failure of interferon, the molecular response after 3 years of treatment was equally good whether the patient attained complete cytogenetic response early (≤1 year) or late (>1 year).[5][Level of evidence: 3iiiDiv] Responses were also seen in patients with myeloid and lymphoid blast crises, though the responses appear more durable for the myeloid blast phenotype.[6][Level of evidence: 3iiiDiv] These results demonstrate activity that appears greater than that of any other agent used in the treatment of CML.

   A trial randomizing 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.[7,8][Level of evidence: 1iiDiii] At 18 months, 96.7% of the imatinib group had avoided progression to accelerated-phase 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 or blast crisis dropping from 2% in the first year to less than 1% in the fourth year.[8] 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 RT–PCR or by fluorescence in situ hybridization of progenitor cell cultures.[9-11] The clinical implication of this finding after 10 years or more is unknown, but these results have changed clinical practice. Although evidence-based survival benefits are unavailable because of crossover in randomized trials, the preferred initial treatment for newly diagnosed patients in chronic phase involves imatinib mesylate.[12,13]

   Higher doses of imatinib mesylate, alternative tyrosine kinase inhibitors such as dasatinib or nilotinib, and allogeneic stem cell transplantation are implemented for suboptimal response or progression and are under clinical evaluation as frontline approaches.[14-18] In a trial of 114 previously untreated patients given twice the usual dose of imatinib mesylate (400 mg twice daily), with 15 months' median follow-up, no patient had progressed to accelerated or blast phase, and 63% showed no detectable evidence of the BCR/ABL translocation by RT–PCR.[19][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.

   Newly diagnosed patients with chronic phase CML should be offered clinical trials.

   Among the many unanswered questions are the following:

   • What is the best dose of imatinib mesylate and should it be combined with other agents (such as interferon-alpha and/or cytarabine)?
   • What is the role of allogeneic bone marrow transplantation (BMT) or SCT for younger, eligible patients and when should it be offered after initiation of imatinib mesylate?[20]
   • Will responses on imatinib mesylate be durable beyond 10 years and can we ever stop imatinib? An anecdotal report of 12 patients who attained complete molecular remission by RT–PCR for at least 2 years describes the results of discontinuation of imatinib. With 18 months' follow-up, six patients remained in complete molecular remission. All of the six patients who had disease that became detectable responded to reintroduction of imatinib.[21][Level of evidence: 3iiiDiv]
   • Will 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?

   All of these issues have led to an active reappraisal of recommendations for optimal frontline therapy for chronic phase CML.

   In patients with blast crisis who have relapsed following treatment with imatinib mesylate, imatinib resistance was associated with reactivation of BCR/ABL signal transduction, either by point mutation or gene amplification of the BCR/ABL kinase domain.[22]




2. The only consistently successful curative treatment of CML has been high-dose therapy followed by allogeneic BMT or SCT.[23] Patients younger than 60 years with an identical twin or with human leukocyte antigen (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.[24,25] Most transplant series suggest improved survival when the procedure is performed within 1 year of diagnosis.[26-28][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 (DFS) 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.[29][Level of evidence: 1iiA] Reduced-intensity conditioning allogeneic SCT is under evaluation in first or second remissions.[30]

   About 20% of otherwise eligible CML patients lack a suitably matched sibling donor.[31] 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.[31] Major obstacles still exist to using unrelated donors, especially in older patients. Two retrospective series following allogeneic BMT from an HLA-matched unrelated donor showed a 5-year relapse rate of 3% to 10% and a 5-year OS rate of 31% to 57%, and most of the deaths were treatment related.[25][Level of evidence: 3iiiA][28] Patients with unrelated donor transplants were generally younger and had a longer interval from diagnosis to transplant. Although the majority of relapses occur within 5 years of transplantation, relapses have occurred for as long as 15 years following BMT.[32] 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.[33] The risk of relapse appears to be less in patients transplanted early in disease and in patients who develop chronic graft-versus-host disease.[25,34] BMT from an unrelated donor is associated with a higher risk of posttransplant graft failure and infection (viral and fungal). The incidence of relapse is lower with BMT from unrelated donors than it is from sibling donors.

   With the advent of imatinib mesylate, the timing and sequence of allogeneic BMT or SCT has been cast in doubt. In a prospective trial of 354 patients aged younger than 60 years, 123 of 135 patients with a matched related donor underwent early allogeneic stem cell transplantation while the others received interferon-based therapy and imatinib at relapse; some also underwent a matched unrelated donor transplant in remission.[35] With a 9-year median follow-up, survival still favored the nonmatched donor 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.[35][Level of evidence: 2A] Among the many unanswered questions are the following:

   • Should younger eligible patients move quickly toward allogeneic SCT after induction by imatinib mesylate or should transplantation be considered at first signs of molecular relapse?
   • 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.




3. 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).[36][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).[36] 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.[37-39] These data have only been published in the context of a review article, rather than a peer-reviewed research manuscript.[39]

   Long-term follow-up of the interferon-treated patients from a randomized trial comparing 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.[40] 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.[41] 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.[42][Level of evidence: 1iiA] As evidenced in the CALGB-9013 study, common side effects include influenza-like syndrome, nausea, anorexia, weight loss, and neuropsychiatric symptoms, all of which are completely reversible with cessation of therapy.[43] Immune-mediated complications, such as hyperthyroidism, hemolysis, and connective tissue diseases may occur rarely after long-term treatment.[44] 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.[45][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 randomized 721 patients to interferon and cytarabine versus interferon alone.[46][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.[47][Level of evidence: 1iiA] Both studies showed increased toxic effects for the combination versus interferon alone.[46,47] Interferon-alpha is also effective for patients who have relapsed after allogeneic BMT.[48,49]




4. 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.[50] 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.



5. Splenectomy may be required and useful in patients having hematologic problems and physical discomfort from a massive spleen.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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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