Chronic myeloid leukemia (CML) is the abnormal growth of relatively mature myeloid white blood cells. The disease is associated with a chromosomal abnormality in which genetic material from chromosome 9 is transferred to chromosome 22. The chromosome containing the genetic switch is called the Philadelphia chromosome; this chromosome plays a role in the development of CML.
The exchange of genetic information that produces the Philadelphia chromosome brings together two genes: the BCR (breakpoint cluster region) gene on chromosome 22 and the ABL (Ableson leukemia virus) gene on chromosome 9. The combination of these two genes into the single BCR-ABL gene results in the production of a protein that contributes to uncontrolled cell growth.
Chronic myeloid leukemia normally progresses from the chronic phase to an accelerated phase and ultimately, into a blastic or acute leukemia phase over a period of several years. Some patients, however, will be in accelerated phase at the time of initial diagnosis.
The diagnosis of accelerated phase requires at least one of the following:
- Persistent presence of 10-30% myeloblasts in marrow or peripheral blood
- Major increase of white blood cell count to over 50,000
- Platelet counts that are increased or decreased
- Red blood cell levels that are low despite treatment
- Progressive enlargement of the spleen
- Tumor nodules outside the bone marrow or spleen
- Any abnormal chromosome in addition to the Philadelphia chromosome
- Persistent unexplained fever or bone pain.
Patients may progress to the accelerated phase of CML without experiencing any symptoms. The diagnosis can be made on the basis of peripheral blood or bone marrow findings only.
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The following is a general overview of the treatment of chronic myeloid leukemia for patients who have progressed to the accelerated 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.
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When CML progresses to the accelerated phase, the leukemia cells may look like either myeloid or lymphoid cells and generally respond poorly to treatment. Historically, intensive chemotherapy regimens used for the treatment of acute myeloid leukemia were used and 25-35% of patients in accelerated phase achieved a remission of relatively short duration. In 2001, the oral tyrosine kinase inhibitor, Gleevec® (imatinib) was approved for the treatment of accelerated and blastic phase CML. Since then, Gleevec has been the primary initial treatment for most patients with newly diagnosed CML in chronic phase. Thus, most of the patients who now have CML in accelerated phase have failed Gleevec treatment.
Treatment of Accelerated Phase CML in Patients Not Exposed to Gleevec
Gleevec is a commonly used treatment for the subset of patients with accelerated phase CML who have not received Gleevec in the past. Researchers affiliated with the STI571 Study Group (IRIS) have reported the results of four years of follow-up of over 1,000 CML patients with advanced disease that had previously been treated with interferon.1 Patients were treated with Gleevec initially at a dose of 400 mg, but escalating to 600 or 800 mg per day. Survival was 82% among patients in chronic phase and 38% for patients in accelerated phase. Overall survival was more than 50% among those patients in accelerated phase who achieved a partial or complete cytogenetic response to Gleevec. Recent data suggest that Gleevec given at initial doses of 600 mg or 800 mg per day may produce optimal results.23
Certain subsets of patients in accelerated phase may have particularly good outcomes after treatment with Gleevec. According to the results of a study of 176 patients in accelerated phase, four-year survival after treatment with Gleevec was 53%.4 Among patients who had a cytogenetic response and were not anemic, four-year survival was 88%. This suggests that long-term disease control with Gleevec is possible in a subset of CML patients in accelerated phase.
For patients who are candidates for allogeneic stem cell transplantation, Gleevec may be given to reduce the extent of disease prior to transplantation.
Treatment of CML in Accelerated Phase after Gleevec Failure
Currently the overwhelming majority of patients entering the accelerated phase of CML will have received Gleevec in the chronic phase. Patients who fail or are intolerant to Gleevec now have several alternatives to consider. These include an increased dose of Gleevec; treatment with two new oral tyrosine kinase inhibitors that have been developed for the treatment of patients with CML: Tasigna® (nilotinib) and Sprycel® (dasatinib); and allogeneic stem cell transplant.
Treatment of Accelerated Phase of CML with Sprycel: 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.
Researchers from UCLA and the M.D. Anderson Cancer Center have reported that Sprycel has significant activity in patients with Philadelphia chromosome-positive CML or ALL who have disease resistant to Gleevec.5 In addition, researchers associated with the CA 180-005 ‘START A’ phase II study reported outcomes of patients with Gleevec-intolerant or resistant patients in the accelerated phase of CML treated with Sprycel.6 Thirteen percent of patients had failed a stem cell transplant. Complete cytogenetic response was achieved in 34% of patients who had not received a prior transplant and 17% in patients who had received a prior transplant. The one year survival was over 80% for transplanted and non-transplanted patients.
Treatment of Accelerated Phase of CML with Tasigna: Tasigna is another drug that targets the Bcr-Abl protein. Tasigna has been approved for the treatment of Philadelphia chromosome-positive chronic phase or accelerated phase CML in adult patients who are resistant to, or intolerant of, prior treatment that includes Gleevec.
Results from a multicenter international trial suggest that Tasigna is a safe and active drug for the treatment of patients with CML or ALL who fail Gleevec.78 Frequently seen side effects were different from those seen with Gleevec and included rash, liver damage and low blood cell counts.
Tasigna may also prove to be useful in patients who are resistant to Sprycel. A study reported at the 2006 meeting of the American Society of Hematology evaluated Tasigna in patients who had failed both Gleevec and Sprycel. 9 The study included 50 patients with accelerated or blast crisis of CML. The results of the study suggest that Tasigna has significant activity in patients who have failed Gleevec and Sprycel and may overcome Sprycel resistance.
Allogeneic Stem Cell Transplantation: Prior to the use of Gleevec, selected patients in accelerated phase of CML treated with high-dose chemotherapy and allogeneic stem cell transplant (using stem cells from a related donor) had a 5-year survival of up to 45%. There has been significant recent progress in the selection of compatible unrelated stem cell donors and the use of umbilical cord blood making allogeneic stem cell transplantation a practical therapeutic choice for most patients with CML in accelerated phase. The use of reduced intensity transplant regimens has also extended the age of transplantation up to 70 years for patients who are in generally good health. While allogeneic stem cell transplants offer the possibility of a cure, the risks and benefits of the procedure will need to be considered on an individual basis.
There are limited data concerning the outcome of allogeneic stem cell transplants among patients in the accelerated phase of CML who have failed Gleevec. Recently, researchers from the Fred Hutchinson Cancer Research Center have reported that CML patients receiving an allogeneic stem cell transplant after Gleevec treatment have similar outcomes to CML patients who received an allogeneic stem cell transplant without prior Gleevec treatment 10 Three-year survival was 45 percent in both groups of patients. These researchers suggest that pre-treatment with Gleevec did not adversely affect survival.
Strategies to Improve Treatment
While significant progress has been made in the treatment of CML in accelerated phase, many patients still succumb to leukemia and better treatment strategies are still needed. Future progress in the treatment of CML in accelerated will result from continued participation in appropriate clinical studies. Currently, there are several areas of active exploration aimed at improving the treatment of leukemia.
Allogeneic Stem Cell Transplant: Strategies designed to reduce the toxicity and improve the outcomes of allogeneic stem cell transplants are an active area of study for patients with accelerated phase of CML. In addition, studies continue to be performed to increase the sources of stem cells for patients who do not have related donors. Umbilical cord blood is one potential source. For more information go to Allogeneic Stem Cell Transplants.
Immunotherapy: Immunotherapy agents have been evaluated in the treatment of patients with minimal residual disease. Results from a phase II trial indicate that the investigative immunotherapy agent GVAX provides promising and durable responses, including long-term molecular remissions, among patients with CML with residual disease while on therapy with Gleevec.11 Unfortunately, the pharmaceutical company sponsoring this study has cancelled plans for further testing of this agent.
Fortunately, other researchers are also developing vaccines for the treatment of CML. Researchers at the Memorial Sloan-Kettering Cancer Center developed and are testing a vaccine which has proven safe and effective in developing an immune responses in patients with CML.12 Researchers from the MD Anderson Cancer Center have reported that patients who have an immune response to the vaccine have improved progression-free survival.13 Researchers from Italy have also developed a vaccine which has been tested in a small number of patients being treated with Gleevec or interferon.14 These researchers suggested that the vaccine produced further reductions in residual molecular disease. Finally, researchers from England have tested a vaccine in patients with CML in the chronic phase; the vaccine appears to improve control of CML in patients responding to Gleevec.15
These vaccine studies are important as they offer an alternative approach to the eradication of minimal residual disease in patients with CML responding to Gleevec or other agents. Vaccines can theoretically kill clones of cells that are drug resistant. Another advantage of vaccines is that they are relatively non-toxic with few side effects.
Development of New Kinase Inhibitors: There are now two agents for treating Gleevec failures: Sprycel and Tasigna. Researchers are continuing to develop new kinase inhibitors with greater activity than those used currently.
Phase I-II Chemotherapy Trials: New chemotherapy drugs continue to be developed and evaluated in phase I-II trials for patients with recurrent cancers. The purpose of phase I trials is to evaluate new drugs in order to determine the best way of administering the drug and whether the drug has any anti-cancer activity in patients. Phase II trials further evaluate new therapies that appear to have promising anti-leukemia activity.
Researchers from MD Anderson Cancer have reported that the chemotherapy drug, homoharringtonine, has significant activity in patients with CML who have failed Gleevec.16
Supportive Care: Supportive care refers to treatments designed to prevent and control the side effects of cancer and its treatment. Side effects not only cause patients discomfort, but also may prevent the optimal delivery of therapy at its planned dose and schedule. In order to achieve optimal outcomes from treatment and improve quality of life, it is imperative that side effects resulting from cancer and its treatment are appropriately managed. Side effects of the tyrosine kinase inhibitors Gleevec, Sprycel and Tasigna are predominantly low white blood cell counts and anemia. Neupogen® (filgrastim) and Neulasta® (pegfilgrastim) can be used to prevent or treat low white blood cell counts17 and Procrit® (epoetin alfa) or Aranesp® (darbepoetin alfa) can be used to prevent or correct anemia.1819 For more information, go to Managing Side Effects.
1 Silver RT, Talpaz M, Sawyers CL, et al. Four years of follow-up of 1027 patients with late chronic phase (L-CP), accelerated phase (AP), or blast crisis (BC) chronic myeloid leukemia (CML) treated with imatinib in three large phase II trials. Proceedings of the American Society of Hematology. Blood. 2004;104:11a, abstract number 23.
2 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.
3 Aoki E, Kantarjian H, O’Brien S, et al. High-dose (HD) imatinib provides better responses in patients with untreated early chronic phase (CP) CML. Blood 2006;608a, abstract 2143.
4 Kantarjian H, Talpaz M, O’Brien S, et al. Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia—comparison with historic experience. Cancer 2005;103:2099-2108.
5 Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New England Journal of Medicine. 2006;354:2531-2541.
6 Cortes J, Kim DW, Guilhot F, et al. Dasatinib (Sprycel®) in patients (pts) with chronic myelogenous leukemia in accelerated phase (AP-CML) that is imatinib-resistant (im-r) or –intolerant (im-i): Updated results of the CA180-005 ‘START-A’ phase II study. Blood 2006;108:613a, abstract 2160.
7 Giles F, Ottmann O, Bhalla K, et al. Update on AMN107 in Leukemia. Proceedings from the 23rd annual Chemotherapy Symposium. New York, NY. November 2005. Abstract #19
8 Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.The New England Journal of Medicine. 2006;354:2542-2551.
9 Jabbour E, Kantarjian H, Giles F, et al. Treatment with nilotinib for patients with chronic myeloid leukemia (CML) who failed prior therapy with imatinib and dasatinib. Blood 2006;108:616a, abstract 2171.
10 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.
11 Smith B, Kasamon Y, Miller C, et al. K562/GM-CSF Vaccination Reduces Tumor Burden, Including Achieving Molecular Remissions, in Chronic Myeloid Leukemia (CML) in Patients (Pts) with Residual Disease on Imatinib Mesylate (IM). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2006. Abstract # 6509.
12 Pinilla-Ibarz J, Cathcart K, Korontsvit T, et al. Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses. Blood 2000;95:1781-1787.
13 Qazilbash MH, Wieder E, Rios R et al. Vaccination with the PRI leukemia-associated antigen can induce complete remission in patients with myeloid leukemia. Blood 2004;104:77a, abstract 259.
14 Bocchia M, Gentili S, Abruzzese E, et al. Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial. The Lancet 2005;365:657-662.
15 Rojas JM, Knight K, Wang L-H, et al. Clinical BCR-ABL peptide vaccination in chronic myeloid leukaemia: Results of the EPIC study. 2005. Blood 2006;108:623a, abstract 2197.
16 Quintas-Cardana, Kantarjian H, Garcia-Manero G, et al. Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. Cancer 2007;109:248-255.
17 Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Granulocyte-Colony Stimulating Factor (Filgrastim) May Overcome Imatinib-Induced Neutropenia in Patients with Chronic-Phase Chronic Myelogenous Leukemia. Cancer 2004;100:2592-2597.
18 Cortes J, O’Brien S, Quintas A, et al. Erythropoietin is Effective in Improving the Anemia Induced by Imatinib Mesylate Therapy in Patients with Chronic Myeloid Leukemia in Chronic Phase. Cancer 2004;100:2396-2402.
19 Cortes J, O’Brien S, Quintas A, et al. Erythropoietin is Effective in Improving the Anemia Induced by Imatinib Mesylate Therapy in Patients with Chronic Myeloid Leukemia in Chronic Phase. Cancer 2004;100:2396-2402.
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