The diagnosis of CML is made in approximately 20% of affected individuals by detecting a high white blood cell count on routine blood testing. Patients are usually without symptoms and often have difficulty understanding the serious nature of their disease since they do not feel ill.
CML is generally not considered to be a curable cancer with current optimal treatment (treatment with the targeted agents Gleevec® (imatinib) or Tasigna® (nilotinib)), but survival is prolonged and ultimate outcomes are still being determined. Allogeneic stem cell transplantation can eradicate the abnormal clone of cells and cure many patients who fail or are intolerant to initial treatment but is associated with significant treatment related morbidity and mortality. All current therapies, other than stem cell transplantation, are aimed at controlling the growth of abnormal cells and attempting to delay the transformation or progression from the chronic phase to the blastic phase resembling acute leukemia.
A variety of factors ultimately influence a patient’s decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms, increase a patient’s chance of cure, or prolong a patient’s survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.
The following is a general overview of the treatment of CML in the chronic phase. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.
Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials.
Gleevec was the first targeted therapy to produce significant cytogenetic and molecular responses in the majority of newly diagnosed patients with CML in chronic phase. More recently, Tasigna was also approved for this use, and may prove to be even more effective than Gleevec. Tasigna was originally approved for CML patients who were resistant or intolerant to Gleevec. The optimal use and timing of allogeneic stem cell transplants, which was until recently a common up-front therapy, is now less clear.
Treatment of Chronic Phase CML with Gleevec or Tasigna
The majority of CML cases are caused by a specific genetic abnormality, referred to as the Philadelphia chromosome. The Philadelphia chromosome occurs through a switching of specific genetic information. The gene that results from this genetic switching produces a protein called the Bcr-Abl tyrosine kinase. The Bcr-Abl tyrosine kinase influences cellular function and growth in an uncontrolled manner, leading to excessive replication and growth of cells – the hallmark trait of cancer.
Gleevec and Tasigna each bind to a specific site on the Bcr-Abl tyrosine kinase and blocks the growth effects of the protein. This, in turn, halts the excessive replication and growth of cancer cells.
Gleevec and Tasigna were compared in a study of adults with newly diagnosed, Philadelphia chromosome-positive CML in chronic phase.1 Patients were treated with Gleevec 400 mg per day or with one of two doses of Tasigna. Rates of major molecular response and complete cytogenetic response were higher among patients treated with Tasigna than among patients treated with Gleevec. These results suggest that Tasigna may be even more effective than Gleevec for the initial treatment of CML, but the study is ongoing and long-term results are not yet available.
Gleevec in Children with Newly Diagnosed CML
On September 27, 2006, the United States Food and Drug Administration (FDA) approved Gleevec for use in children with newly diagnosed CML. Approval was based on the treatment of 51 children with newly diagnosed CML enrolled in a phase II clinical trial. Complete hematological responses were observed in 78% of patients and complete cytogenetic responses in 65%. A required phase IV trial will continue to obtain long-term data.2 A more recent report from the Children’s Oncology Group has confirmed that Gleevec is well tolerated in previously untreated children with CML and produces outcomes similar to adults.3
Discontinuation of Gleevec
At the present time the consequences of stopping treatment with Gleevec are poorly understood. Generally, patients who have a complete cytogenetic response without a substantial molecular response are continued on therapy.
Options for Failure of or Intolerance to Gleevec
A small but significant fraction of patients will develop Gleevec resistance or are intolerant to the drug. Patients who fail or are intolerant to Gleevec now have alternatives other than allogeneic stem cell transplantation for treatment. Some patients who are receiving 400 mg of Gleevec per day will respond to increasing the dose to 800 mg per day. There are also two newer agents that have been developed for the treatment of patients with CML: Tasigna® (nilotinib) and Sprycel® (dasatinib) appear to be effective for the treatment of patients who fail Gleevec.
Sprycel for Gleevec Failures
Sprycel is a tyrosine kinase inhibitor that appears to have much greater activity against Bcr-Abl than Gleevec. It has been approved by the U.S. FDA for the treatment of patients with CML who are resistant to or intolerant of Gleevec. The FDA cited four single-arm studies involving over 400 patients who were no longer responsive to Gleevec. The response rate to Sprycel was 45% for patients in chronic phase of CML with responses lasting 6 months or more. Evidence from a randomized trial suggests that Sprycel may be more effective than increased doses of Gleevec in patients resistant to Gleevec.4 The major side effect of Sprycel is low white blood cell counts5 which can be prevented by the use of white blood cell boosters such as Neulasta.
Tasigna for Gleevec Failures
Tasigna is another drug that targets the Bcr-Abl protein. Tasigna has been approved for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase, as well as for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant to or intolerant to prior therapy that included Gleevec. In a study of 280 Gleevec-resistant or Gleevec-intolerant patients with chronic phase CML, Tasigna substantially reduced or eliminated Philadelphia chromosome-positive cells (major cytogenetic response) in 48% of patients.6
Allogeneic Stem Cell Transplantation
Prior to the development of Gleevec and other targeted therapies, many doctors believed that early allogeneic stem cell transplantation was the treatment of choice for patients under age 60 with suitable family donors and for those under age 45 with an HLA-matched unrelated donor. Patients transplanted in chronic phase in some transplant centers have a 10% chance of dying of the treatment in the first year and a 5-year survival of 80%. Delay in transplant has been shown to adversely affect outcome. Go to Allogeneic Stem Cell Transplant to learn about the procedure, donor selection, selecting a transplant center and specific results in CML patients.
Status of Allogeneic Stem Cell Transplant in the Gleevec Era
Over the past several years, most transplant centers have seen a marked reduction in the number of allogeneic stem cell transplants performed for chronic phase CML because patients have opted for initial Gleevec treatment. At the present time, few patients with CML receive an allogeneic stem cell transplant without a trial of Gleevec. This situation is made even more complicated by the success of the newer targeted agents Sprycel and Tasigna. Both these agents are reasonably effective in treating patients with Gleevec resistance or intolerance. Thus, it is likely that allogeneic stem cell transplants may be pushed back even farther in the treatment scheme for patients with CML in chronic phase.
Researchers from the Fred Hutchinson Cancer Research Center have reported the outcomes of patients with CML who had received at least 3 months of Gleevec prior to an allogeneic stem cell transplant.7 They compared the outcomes of patients transplanted in chronic phase who had not received Gleevec with comparable patients who had received Gleevec. The median time from diagnosis to transplant was 1.7 years for the Gleevec group and approximately one year for the comparison group. The 3-year survival was 74% for both groups, which may be less than has been observed previously for patients transplanted within one year of diagnosis. The researchers also looked at the outcomes of patients in the Gleevec group who had complete cytogenetic information. Three-year overall survival of patients who had a major or complete cytogenetic remission was 97% while the survival of patients with minor or minimal cytogenetic response or loss of response was 58%. These data suggest that patients who truly fail Gleevec have aggressive disease which may be difficult to eradicate with an allogeneic stem cell transplant.
Strategies to Improve Treatment
While significant progress has been made in the treatment of chronic phase CML, many patients still succumb to their disease and better treatment strategies are still needed. Future progress in the treatment of chronic phase CML will result from continued participation in appropriate clinical studies. Currently, there are several areas of active exploration aimed at improving the treatment of leukemia.
Dosage of Gleevec
The dose of Gleevec that is commonly used is 400 mg/day. Recent data suggest that a higher dose of 800 mg/day improves overall responses and as well as the rapidity of response. Researchers from MD Anderson Cancer Center have reported that increasing the dose of Gleevec to 400 mg twice daily improves the response rate as measured by cytogenetics and PCR in patients with CML in chronic phase.8 The major side effects were an increased incidence of low white blood cell counts and platelet levels compared to the low-dose group. Low white blood cell counts can be corrected by the use of white blood cell boosters such as Neulasta® (pegfilgrastim).
Sprycel in Newly Diagnosed Patients
Sprycel is being compared to Gleevec for the initial treatment of CML in a study of 519 patients with newly diagnosed, Philadelphia chromosome-positive, chronic-phase CML.9 After one year, rates of complete cytogenetic response rate and major molecular response were higher among patients treated with Sprycel than patients treated with Gleevec. These results suggest that Sprycel may be more effective than Gleevec for the initial treatment of CML. Researchers will continue to follow the study participants in order to determine whether there are differences in progression-free and overall survival between study groups.
Monitoring of Treatment
Monitoring of treatment with cytogenetics and PCR is essential for optimal treatment of patients with CML. This is made easier by performing these tests on peripheral blood rather than bone marrow.
The main supportive care drugs for use with the current tyrosine kinase inhibitors are Neupogen and Neulasta. For more information, go to Managing Side Effects.
1 Saglio G, Kim D-W, Issaragrisil S et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. New England Journal of Medicine. 2010;362:2251-2259.
2 Champagne MA, Capdeville R, Krailo MK, et al. Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome positive leukemia: Results from a Children’s Oncology Group phase I study. Blood 2004;104:2655-2660.
3 Champagne MA, Fu C, Chang M, et al. Imatinib in children with newly diagnosed chronic phase chronic myelogenous leukemia (CP CML): AAML0123COG study. Blood 2006;108:607a, abstract 2140.
4 Shah N, Pasquini R, Rousselot P, et al. Dasatinib (Sprycel®) vs. escalated dose of imatinib (im) in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) resistant to imatinib: Results of the CA180-017 START-R randomized study. Blood 2006;108:53a, abstract 167.
5 Quintas-Cardama A, Kantarajian HM, Nicaise C, et al. Cytopenias in patients (pts) with chronic myelogenous leukemia (CML) in chronic phase (CP) treated with dasatinib (Sprycel®): clinical features and management, including outcome after hematopoietic growth factor. Blood 2006;108:613a, abstract 2163
6 Kantarjian HM, Giles F, Gattermann et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood early online publication. August 22, 2007.
7 Oehler VG, Gooley T, Snyder DS, et al. The effects of imatinib mesylate treatment before allogeneic stem cell transplant for chronic myeloid leukemia. Blood 2006;October 24 Epub ahead of print.
8 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. The New England Journal of Medicine 2004;103:2873-2878.
9 Kantarjian H, Shah NP, Hochhaus A et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. New England Journal of Medicine. 2010; 362:2260-2270.
Copyright © 2021 CancerConnect. All Rights Reserved.