Purpose of This PDQ Summary
General Information
Stage Information
Treatment Option Overview
Chronic-Phase Chronic Myelogenous Leukemia

Current Clinical Trials

Accelerated-Phase Chronic Myelogenous Leukemia

Current Clinical Trials

Blastic-Phase Chronic Myelogenous Leukemia

Current Clinical Trials

Relapsing Chronic Myelogenous Leukemia

Current Clinical Trials

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Changes to This Summary (03/06/2009)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic myelogenous leukemia. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Molecular diagnostic factors.
• Cellular classification.
• Staging.
• Treatment options by cancer phase.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

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General Information

Note: Estimated new cases and deaths from chronic myelogenous leukemia in the United States in 2008:[1]

• New cases: 4,830.
• Deaths: 450

Chronic myelogenous leukemia (CML) is one of a group of diseases called the myeloproliferative disorders. Other related entities include polycythemia vera, myelofibrosis, and essential thrombocythemia. (Refer to the PDQ summary on Chronic Myeloproliferative Disorders Treatment for more information.)

CML is a clonal disorder that is usually easily diagnosed because the leukemic cells of more than 95% of patients have a distinctive cytogenetic abnormality, the Philadelphia chromosome (Ph1).[2,3] The Ph1 results from a reciprocal translocation between the long arms of chromosomes 9 and 22 and is demonstrable in all hematopoietic precursors.[4] This translocation results in the transfer of the Abelson (ABL) on chromosome 9 oncogene to an area of chromosome 22 termed the breakpoint cluster region (BCR).[4] This in turn results in a fused BCR/ABL gene and in the production of an abnormal tyrosine kinase protein that causes the disordered myelopoiesis found in CML. Furthermore, these molecular techniques can now be used to supplement cytogenetic studies to detect the presence of the 9;22 translocation in patients without a visible Ph1 (Ph1-negative).

Ph1-negative CML is a poorly defined entity that is less clearly distinguished from other myeloproliferative syndromes. Patients with Ph1-negative CML generally have a poorer response to treatment and shorter survival than Ph1-positive patients.[5] Ph1-negative patients who have BCR/ABL gene rearrangement detectable by Southern blot analysis, however, have prognoses equivalent to Ph1-positive patients.[6,7] A small subset of patients have BCR/ABL detectable only by reverse transcriptase–polymerase chain reaction (RT–PCR), which is the most sensitive technique currently available. Patients with RT–PCR evidence of the BCR/ABL fusion gene appear clinically and prognostically identical to patients with a classic Ph1; however, patients who are BCR/ABL-negative by RT–PCR have a clinical course more consistent with chronic myelomonocytic leukemia, which is a distinct clinical entity related to myelodysplastic syndrome.[6,8,9] Fluorescent in situ hybridization of the BCR/ABL translocation can be performed on the bone marrow aspirate or on the peripheral blood of patients with CML.[10]

The median age of patients with Ph1-positive CML is 67 years.[11] The median survival is 4 to 6 years, with a range of less than 1 year to more than 10 years. Survival after development of an accelerated phase is usually less than 1 year and after blastic transformation is only a few months.[10]

References

1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. Last accessed October 1, 2008. 
   
   
2. Kurzrock R, Kantarjian HM, Druker BJ, et al.: Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 138 (10): 819-30, 2003.  [PUBMED Abstract]
   
   
3. Goldman JM, Melo JV: Chronic myeloid leukemia--advances in biology and new approaches to treatment. N Engl J Med 349 (15): 1451-64, 2003.  [PUBMED Abstract]
   
   
4. Deininger MW, Goldman JM, Melo JV: The molecular biology of chronic myeloid leukemia. Blood 96 (10): 3343-56, 2000.  [PUBMED Abstract]
   
   
5. Onida F, Ball G, Kantarjian HM, et al.: Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia. Cancer 95 (8): 1673-84, 2002.  [PUBMED Abstract]
   
   
6. Martiat P, Michaux JL, Rodhain J: Philadelphia-negative (Ph-) chronic myeloid leukemia (CML): comparison with Ph+ CML and chronic myelomonocytic leukemia. The Groupe Français de Cytogénétique Hématologique. Blood 78 (1): 205-11, 1991.  [PUBMED Abstract]
   
   
7. Cortes JE, Talpaz M, Beran M, et al.: Philadelphia chromosome-negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Long-term follow-up results. Cancer 75 (2): 464-70, 1995.  [PUBMED Abstract]
   
   
8. Oscier DG: Atypical chronic myeloid leukaemia, a distinct clinical entity related to the myelodysplastic syndrome? Br J Haematol 92 (3): 582-6, 1996.  [PUBMED Abstract]
   
   
9. Kurzrock R, Bueso-Ramos CE, Kantarjian H, et al.: BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol 19 (11): 2915-26, 2001.  [PUBMED Abstract]
   
   
10. Sawyers CL: Chronic myeloid leukemia. N Engl J Med 340 (17): 1330-40, 1999.  [PUBMED Abstract]
    
    
11. Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic myelogenous leukemia: playing the odds. J Clin Oncol 16 (9): 2897-903, 1998.  [PUBMED Abstract]
    
    

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Stage Information

Bone marrow sampling is done to assess cellularity, fibrosis, and cytogenetics. The Philadelphia chromosome (Ph1) is usually more readily apparent in marrow metaphases than in peripheral blood metaphases; in some cases, it may be mashed and reverse transcriptase–polymerase chain reaction (RT–PCR) or fluorescent in situ hybridization (FISH) analyses on blood or marrow aspirates may be necessary to demonstrate the 9;22 translocation.

The most common finding on physical examination at diagnosis is splenomegaly.[1] The spleen may be enormous, filling most of the abdomen and presenting a significant clinical problem, or the spleen may be only minimally enlarged. In about 10% of patients, the spleen is neither palpable nor enlarged on splenic scan.

Histopathologic examination of bone marrow aspirate demonstrates a shift in the myeloid series to immature forms that increase in number as patients progress to the blastic phase of the disease. The marrow is hypercellular, and differential counts of both marrow and blood show a spectrum of mature and immature granulocytes similar to that found in normal marrow. Increased numbers of eosinophils or basophils are often present, and sometimes monocytosis is seen. Increased megakaryocytes are often found in the marrow, and sometimes fragments of megakaryocytic nuclei are present in the blood, especially when the platelet count is very high. The percentage of lymphocytes is reduced in both the marrow and blood in comparison with normal subjects, and the myeloid/erythroid ratio in the marrow is usually greatly elevated. The leukocyte alkaline phosphatase enzyme is either absent or markedly reduced in the neutrophils of patients with chronic myelogenous leukemia (CML).[1]

Transition from the chronic phase to the accelerated phase and later the blastic phase may occur gradually over a period of 1 year or more, or it may appear abruptly (blast crisis). The annual rate of progression from chronic phase to blast crisis is 5% to 10% in the first 2 years and 20% in subsequent years.[2,3] Signs and symptoms commonly heralding such a change include the following:

• Progressive leukocytosis.
• Thrombocytosis or thrombocytopenia.
• Anemia.
• Increasing and painful splenomegaly or hepatomegaly.
• Fever.
• Bone pain.
• Development of destructive bone lesions.
• Thrombotic or bleeding complications.

In the accelerated phase, differentiated cells persist, though they often show increasing morphologic abnormalities, and increasing anemia and thrombocytopenia and marrow fibrosis are apparent.[1]

Studies have suggested that certain presenting features have prognostic significance. The following are predictive of a shorter chronic phase:

• Increased splenomegaly.
• Older age.
• Male gender.
• Elevated serum lactate dehydrogenase.
• Cytogenetic abnormalities in addition to the Ph1.
• A higher proportion of marrow or peripheral blood blasts.
• Basophilia.
• Eosinophilia.
• Thrombocytosis.
• Anemia.

Predictive models using multivariate analysis have been derived.[2-7]

Chronic-phase CML

Chronic-phase CML is characterized by bone marrow and cytogenetic findings as described above with less than 10% blasts and promyelocytes in the peripheral blood and bone marrow.[8]

Accelerated-phase CML

Accelerated-phase CML is characterized by 10% to 19% blasts in either the peripheral blood or bone marrow.[8]

Blastic-phase CML

Blastic-phase CML is characterized by 20% or more blasts in the peripheral blood or bone marrow.

When 20% or more blasts are present in the face of fever, malaise, and progressive splenomegaly, the patient has entered blast crisis.[8]

Relapsing CML

Relapsed CML is characterized by any evidence of progression of disease from a stable remission. This may include the following:

• Increasing myeloid or blast cells in the peripheral blood or bone marrow.
• Cytogenetic positivity when previously cytogenetic-negative.
• FISH positivity for BCR/ABL (breakpoint cluster region/Abelson) translocation when previously FISH-negative.

Detection of the BCR/ABL translocation by RT–PCR during prolonged remissions does not constitute relapse on its own. However, exponential drops in quantitative RT–PCR measurements for 3 to 12 months correlates with the degree of cytogenetic response, just as exponential rises may be associated with quantitative RT–PCR measurements that are closely connected with clinical relapse.[9]

References

1. Sawyers CL: Chronic myeloid leukemia. N Engl J Med 340 (17): 1330-40, 1999.  [PUBMED Abstract]
   
   
2. Sokal JE, Cox EB, Baccarani M, et al.: Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 63 (4): 789-99, 1984.  [PUBMED Abstract]
   
   
3. Sokal JE, Baccarani M, Russo D, et al.: Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 25 (1): 49-61, 1988.  [PUBMED Abstract]
   
   
4. Kantarjian HM, Smith TL, McCredie KB, et al.: Chronic myelogenous leukemia: a multivariate analysis of the associations of patient characteristics and therapy with survival. Blood 66 (6): 1326-35, 1985.  [PUBMED Abstract]
   
   
5. Sacchi S, Kantarjian HM, Smith TL, et al.: Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia. J Clin Oncol 16 (3): 882-9, 1998.  [PUBMED Abstract]
   
   
6. Hasford J, Pfirrmann M, Hehlmann R, et al.: A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 90 (11): 850-8, 1998.  [PUBMED Abstract]
   
   
7. Kvasnicka HM, Thiele J, Schmitt-Graeff A, et al.: Bone marrow features improve prognostic efficiency in multivariate risk classification of chronic-phase Ph(1+) chronic myelogenous leukemia: a multicenter trial. J Clin Oncol 19 (12): 2994-3009, 2001.  [PUBMED Abstract]
   
   
8. Cortes JE, Talpaz M, O'Brien S, et al.: Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer 106 (6): 1306-15, 2006.  [PUBMED Abstract]
   
   
9. Martinelli G, Iacobucci I, Rosti G, et al.: Prediction of response to imatinib by prospective quantitation of BCR-ABL transcript in late chronic phase chronic myeloid leukemia patients. Ann Oncol 17 (3): 495-502, 2006.  [PUBMED Abstract]
   
   

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Treatment Option Overview

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 of patients with chronic myelogenous leukemia (CML) is usually initiated when the diagnosis is established, which is done by the presence of an elevated white blood cell (WBC) count, splenomegaly, thrombocytosis, and identification of the BCR/ABL (breakpoint cluster region/Abelson) translocation.[1] The optimal frontline treatment for patients with chronic-phase CML is the subject of active clinical evaluation but involves specific inhibitors of the BCR/ABL tyrosine kinase. In a randomized trial comparing imatinib mesylate with interferon plus cytarabine, with 5 years' median follow-up, imatinib mesylate induced complete cytogenetic responses in more than 80% of newly diagnosed patients; in addition, the annual rate of progression to accelerated phase or blast crisis dropped from 2% to less than 1% in the fourth year on the imatinib arm.[2][Level of evidence: 1iiDiii] However, most of these continually responding patients still showed detectable evidence of the BCR/ABL translocation by the most sensitive measurement of reverse transcriptase–polymerase chain reaction (RT–PCR).[3-5] 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.[6,7] In addition, the overall survival rate for all patients at 5 years is 89%, with fewer than 50% of all deaths (4.5%) caused by CML. Higher doses of imatinib, alternative tyrosine kinase inhibitors such as dasatinib or nilotinib, and allogeneic stem cell transplantation (SCT) are implemented for suboptimal response or progression and are under clinical evaluation as frontline approaches.[8-15]

The only consistently successful curative treatment of CML beyond 10 years' follow-up has been allogeneic bone marrow transplantation (BMT) or SCT.[16] Long-term data beyond 10 years of therapy are available, and most long-term survivors show no evidence of the BCR/ABL translocation by any available test (e.g., cytogenetics, RT–PCR, or fluorescent in situ hybridization [FISH]). Many patients, however, are not eligible for this approach because of age, comorbid conditions, or lack of a suitable donor. In addition, substantial morbidity and mortality result from allogeneic BMT or SCT; a 15% to 30% treatment-related mortality can be expected, depending on whether a donor is related and on the presence of mismatched antigens.[16]

Long-term data are also available for patients treated with interferon-alpha.[17-19] Approximately 10% to 20% of these patients have a complete cytogenetic response with no evidence of BCR/ABL translocation by any available test, and the majority of these patients are disease-free beyond 10 years.[16] Maintenance of therapy with interferon is required, however, and some patients experience side effects that preclude continued treatment.

Newly diagnosed patients with very high levels of circulating leukocytes (WBC >100,000/mm³) require immediate therapy with imatinib mesylate to avoid cerebrovascular events or death from leukostasis. Leukophoresis and plateletpheresis are sometimes required for an even more emergent reduction of counts.

References

1. Sawyers CL: Chronic myeloid leukemia. N Engl J Med 340 (17): 1330-40, 1999.  [PUBMED Abstract]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   
6. Kantarjian HM, Talpaz M, O'Brien S, et al.: Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 108 (6): 1835-40, 2006.  [PUBMED Abstract]
   
   
7. Baccarani M, Saglio G, Goldman J, et al.: Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108 (6): 1809-20, 2006.  [PUBMED Abstract]
   
   
8. 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]
   
   
9. le Coutre P, Ottmann OG, Giles F, et al.: Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 111 (4): 1834-9, 2008.  [PUBMED Abstract]
   
   
10. Talpaz M, Shah NP, Kantarjian H, et al.: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354 (24): 2531-41, 2006.  [PUBMED Abstract]
    
    
11. Hochhaus A, Kantarjian HM, Baccarani M, et al.: Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109 (6): 2303-9, 2007.  [PUBMED Abstract]
    
    
12. Quintas-Cardama A, Kantarjian H, Jones D, et al.: Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood 109 (2): 497-9, 2007.  [PUBMED Abstract]
    
    
13. Cortes J, Rousselot P, Kim DW, et al.: Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 109 (8): 3207-13, 2007.  [PUBMED Abstract]
    
    
14. Kantarjian H, Pasquini R, Hamerschlak N, et al.: Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood 109 (12): 5143-50, 2007.  [PUBMED Abstract]
    
    
15. Guilhot F, Apperley J, Kim DW, et al.: Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 109 (10): 4143-50, 2007.  [PUBMED Abstract]
    
    
16. Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic myelogenous leukemia: playing the odds. J Clin Oncol 16 (9): 2897-903, 1998.  [PUBMED Abstract]
    
    
17. Ozer H, George SL, Schiffer CA, et al.: Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study 8583. Blood 82 (10): 2975-84, 1993.  [PUBMED Abstract]
    
    
18. Kantarjian HM, Smith TL, O'Brien S, et al.: Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med 122 (4): 254-61, 1995.  [PUBMED Abstract]
    
    
19. Long-term follow-up of the Italian trial of interferon-alpha versus conventional chemotherapy in chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Blood 92 (5): 1541-8, 1998.  [PUBMED Abstract]
    
    

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Chronic-Phase Chronic Myelogenous Leukemia

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 failed interferon, imatinib mesylate induced major cytogenetic responses in 67% of patients and complete hematologic response in 96% of patients, with 61% of patients free of progression to accelerated-phase or blastic-phase with a median follow-up of 5.5 years.[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.[14-19] 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.[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.

   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)?[21]
   • 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?[22]
   • 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.[23][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.[24]

   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.[25]




2. The only consistently successful curative treatment of CML has been high-dose therapy followed by allogeneic BMT or SCT.[26] 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.[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 (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.[32][Level of evidence: 1iiA] Reduced-intensity conditioning allogeneic SCT is under evaluation in first or second remissions.[33]

   About 20% of otherwise eligible CML patients lack a suitably matched sibling donor.[34] 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.[34] 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.[28][Level of evidence: 3iiiA][31] 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.[35] 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.[36] The risk of relapse appears to be less in patients transplanted early in disease and in patients who develop chronic graft-versus-host disease.[28,37] 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.[38] 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.[38][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).[39][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).[39] 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.[40-42] These data have only been published in the context of a review article, rather than a peer-reviewed research manuscript.[42]

   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.[43] 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.[44] 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.[45][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.[46] Immune-mediated complications, such as hyperthyroidism, hemolysis, and connective tissue diseases may occur rarely after long-term treatment.[47] 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.[48][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.[49][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.[50][Level of evidence: 1iiA] Both studies showed increased toxic effects for the combination versus interferon alone.[49,50] Interferon-alpha is also effective for patients who have relapsed after allogeneic BMT.[51,52]




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.[53] 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

1. Kurzrock R, Kantarjian HM, Druker BJ, et al.: Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 138 (10): 819-30, 2003.  [PUBMED Abstract]
   
   
2. Goldman JM, Melo JV: Chronic myeloid leukemia--advances in biology and new approaches to treatment. N Engl J Med 349 (15): 1451-64, 2003.  [PUBMED Abstract]
   
   
3. Hochhaus A, Druker B, Sawyers C, et al.: Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood 111 (3): 1039-43, 2008.  [PUBMED Abstract]
   
   
4. Kantarjian HM, Cortes JE, O'Brien S, et al.: Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood 104 (7): 1979-88, 2004.  [PUBMED Abstract]
   
   
5. Iacobucci I, Rosti G, Amabile M, et al.: Comparison between patients with Philadelphia-positive chronic phase chronic myeloid leukemia who obtained a complete cytogenetic response within 1 year of imatinib therapy and those who achieved such a response after 12 months of treatment. J Clin Oncol 24 (3): 454-9, 2006.  [PUBMED Abstract]
   
   
6. Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344 (14): 1038-42, 2001.  [PUBMED Abstract]
   
   
7. O'Brien SG, Guilhot F, Larson RA, et al.: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348 (11): 994-1004, 2003.  [PUBMED Abstract]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. Kantarjian HM, Talpaz M, O'Brien S, et al.: Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 108 (6): 1835-40, 2006.  [PUBMED Abstract]
    
    
13. Baccarani M, Saglio G, Goldman J, et al.: Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108 (6): 1809-20, 2006.  [PUBMED Abstract]
    
    
14. 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]
    
    
15. le Coutre P, Ottmann OG, Giles F, et al.: Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 111 (4): 1834-9, 2008.  [PUBMED Abstract]
    
    
16. Talpaz M, Shah NP, Kantarjian H, et al.: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354 (24): 2531-41, 2006.  [PUBMED Abstract]
    
    
17. Hochhaus A, Kantarjian HM, Baccarani M, et al.: Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109 (6): 2303-9, 2007.  [PUBMED Abstract]
    
    
18. Quintas-Cardama A, Kantarjian H, Jones D, et al.: Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood 109 (2): 497-9, 2007.  [PUBMED Abstract]
    
    
19. Shah NP, Kantarjian HM, Kim DW, et al.: Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 26 (19): 3204-12, 2008.  [PUBMED Abstract]
    
    
20. 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. Blood 103 (8): 2873-8, 2004.  [PUBMED Abstract]
    
    
21. Deenik W, van der Holt B, Verhoef GE, et al.: Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia. Blood 111 (5): 2581-8, 2008.  [PUBMED Abstract]
    
    
22. Peggs K, Mackinnon S: Imatinib mesylate--the new gold standard for treatment of chronic myeloid leukemia. N Engl J Med 348 (11): 1048-50, 2003.  [PUBMED Abstract]
    
    
23. Rousselot P, Huguet F, Rea D, et al.: Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 109 (1): 58-60, 2007.  [PUBMED Abstract]
    
    
24. Cortes JE: Imatinib therapy for chronic myeloid leukemia: where do we go now? J Clin Oncol 26 (20): 3308-9, 2008.  [PUBMED Abstract]
    
    
25. Branford S, Rudzki Z, Walsh S, et al.: Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 102 (1): 276-83, 2003.  [PUBMED Abstract]
    
    
26. Gratwohl A, Hermans J: Allogeneic bone marrow transplantation for chronic myeloid leukemia. Working Party Chronic Leukemia of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 17 (Suppl 3): S7-9, 1996.  [PUBMED Abstract]
    
    
27. Wagner JE, Zahurak M, Piantadosi S, et al.: Bone marrow transplantation of chronic myelogenous leukemia in chronic phase: evaluation of risks and benefits. J Clin Oncol 10 (5): 779-89, 1992.  [PUBMED Abstract]
    
    
28. Enright H, Davies SM, DeFor T, et al.: Relapse after non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: early transplantation, use of an unrelated donor, and chronic graft-versus-host disease are protective. Blood 88 (2): 714-20, 1996.  [PUBMED Abstract]
    
    
29. Goldman JM, Szydlo R, Horowitz MM, et al.: Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase. Blood 82 (7): 2235-8, 1993.  [PUBMED Abstract]
    
    
30. Clift RA, Appelbaum FR, Thomas ED: Treatment of chronic myeloid leukemia by marrow transplantation. Blood 82 (7): 1954-6, 1993.  [PUBMED Abstract]
    
    
31. Hansen JA, Gooley TA, Martin PJ, et al.: Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 338 (14): 962-8, 1998.  [PUBMED Abstract]
    
    
32. Clift RA, Buckner CD, Thomas ED, et al.: Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood 84 (6): 2036-43, 1994.  [PUBMED Abstract]
    
    
33. Crawley C, Szydlo R, Lalancette M, et al.: Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 106 (9): 2969-76, 2005.  [PUBMED Abstract]
    
    
34. Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic myelogenous leukemia: playing the odds. J Clin Oncol 16 (9): 2897-903, 1998.  [PUBMED Abstract]
    
    
35. Maziarz R: Transplantation for CML: lifelong PCR monitoring? Blood 107 (10): 3820, 2006. 
    
    
36. Kaeda J, O'Shea D, Szydlo RM, et al.: Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. Blood 107 (10): 4171-6, 2006.  [PUBMED Abstract]
    
    
37. Pichert G, Roy DC, Gonin R, et al.: Distinct patterns of minimal residual disease associated with graft-versus-host disease after allogeneic bone marrow transplantation for chronic myelogenous leukemia. J Clin Oncol 13 (7): 1704-13, 1995.  [PUBMED Abstract]
    
    
38. Hehlmann R, Berger U, Pfirrmann M, et al.: Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood 109 (11): 4686-92, 2007.  [PUBMED Abstract]
    
    
39. Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials: Chronic Myeloid Leukemia Trialists' Collaborative Group. J Natl Cancer Inst 89 (21): 1616-20, 1997.  [PUBMED Abstract]
    
    
40. Ozer H, George SL, Schiffer CA, et al.: Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study 8583. Blood 82 (10): 2975-84, 1993.  [PUBMED Abstract]
    
    
41. Kantarjian HM, Smith TL, O'Brien S, et al.: Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med 122 (4): 254-61, 1995.  [PUBMED Abstract]
    
    
42. Kantarjian HM, Deisseroth A, Kurzrock R, et al.: Chronic myelogenous leukemia: a concise update. Blood 82 (3): 691-703, 1993.  [PUBMED Abstract]
    
    
43. Long-term follow-up of the Italian trial of interferon-alpha versus conventional chemotherapy in chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Blood 92 (5): 1541-8, 1998.  [PUBMED Abstract]
    
    
44. Cortes J, Kantarjian H, O'Brien S, et al.: Result of interferon-alpha therapy in patients with chronic myelogenous leukemia 60 years of age and older. Am J Med 100 (4): 452-5, 1996.  [PUBMED Abstract]
    
    
45. Kluin-Nelemans HC, Buck G, le Cessie S, et al.: Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups. Blood 103 (12): 4408-15, 2004.  [PUBMED Abstract]
    
    
46. Hensley ML, Peterson B, Silver RT, et al.: Risk factors for severe neuropsychiatric toxicity in patients receiving interferon alfa-2b and low-dose cytarabine for chronic myelogenous leukemia: analysis of Cancer and Leukemia Group B 9013. J Clin Oncol 18 (6): 1301-8, 2000.  [PUBMED Abstract]
    
    
47. Sacchi S, Kantarjian H, O'Brien S, et al.: Immune-mediated and unusual complications during interferon alfa therapy in chronic myelogenous leukemia. J Clin Oncol 13 (9): 2401-7, 1995.  [PUBMED Abstract]
    
    
48. Michallet M, Maloisel F, Delain M, et al.: Pegylated recombinant interferon alpha-2b vs recombinant interferon alpha-2b for the initial treatment of chronic-phase chronic myelogenous leukemia: a phase III study. Leukemia 18 (2): 309-15, 2004.  [PUBMED Abstract]
    
    
49. Guilhot F, Chastang C, Michallet M, et al.: Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med 337 (4): 223-9, 1997.  [PUBMED Abstract]
    
    
50. Baccarani M, Rosti G, de Vivo A, et al.: A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia. Blood 99 (5): 1527-35, 2002.  [PUBMED Abstract]
    
    
51. Higano CS, Raskind WH, Singer JW: Use of alpha interferon for the treatment of relapse of chronic myelogenous leukemia in chronic phase after allogeneic bone marrow transplantation. Blood 80 (6): 1437-42, 1992.  [PUBMED Abstract]
    
    
52. Arcese W, Goldman JM, D'Arcangelo E, et al.: Outcome for patients who relapse after allogeneic bone marrow transplantation for chronic myeloid leukemia. Chronic Leukemia Working Party. European Bone Marrow Transplantation Group. Blood 82 (10): 3211-9, 1993.  [PUBMED Abstract]
    
    
53. Hehlmann R, Heimpel H, Hasford J, et al.: Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. The German CML Study Group. Blood 82 (2): 398-407, 1993.  [PUBMED Abstract]
    
    

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Accelerated-Phase Chronic Myelogenous Leukemia

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.)

Patients with accelerated-phase chronic myelogenous leukemia (CML) show signs of progression without meeting the criteria for blast crisis (acute leukemia). Symptoms and findings include:

• Increasing fatigue and malaise.
• Progressive splenomegaly.
• Increasing leukocytosis and/or thrombocytosis.
• Worsening anemia.

Bone marrow examination shows increasing blast cell percentage (but ≤30%) and basophilia. Additional cytogenetic abnormalities occur during the accelerated phase (trisomy 8, trisomy 19, isochromosome 17Q, p53 mutations or deletions), and the combination of hematologic progression plus additional cytogenetic abnormalities predicts for lower response rates and a shorter time to treatment failure on imatinib mesylate.[1] At 1 year after the start of imatinib, the failure rate is 68% for patients with both hematologic progression and cytogenetic abnormalities, 31% for patients with only hematologic progression, and 0% for patients with cytogenetic abnormalities only. Before the availability of imatinib, the median survival time of accelerated-phase CML patients was less than 1 year.[1]

Standard treatment options:

1. Bone marrow transplantation (BMT). Autologous BMT may return the patient to a chronic phase, which may be durable. Allogeneic BMT has the potential for cure, though results to date are poor.[2-4] Induction of remission with imatinib mesylate followed by allogeneic stem cell transplantation is under clinical evaluation.
2. Imatinib mesylate. Among 176 patients with accelerated-phase CML, the complete hematologic response was 82%, and the complete cytogenetic response was 43%; with a median follow-up of 41 months, the estimated 4-year survival was 53%.[5]
3. Interferon-alpha.[6] Although the response rate is lower for accelerated-phase disease than it is for chronic phase disease, durable responses and suppression of cytogenetic clonal evolution have been reported.[6,7] When cytarabine was added to interferon-alpha, in comparison to historical controls of interferon alone, the response rate and 3-year survival appeared to be improved in late-stage patients.[7][Level of evidence: 3iiiA]
4. High-dose cytarabine.[8]
5. Hydroxyurea.
6. Busulfan.
7. Supportive transfusion therapy.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with accelerated 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

1. O'Dwyer ME, Mauro MJ, Kurilik G, et al.: The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 100 (5): 1628-33, 2002.  [PUBMED Abstract]
   
   
2. Martin PJ, Clift RA, Fisher LD, et al.: HLA-identical marrow transplantation during accelerated-phase chronic myelogenous leukemia: analysis of survival and remission duration. Blood 72 (6): 1978-84, 1988.  [PUBMED Abstract]
   
   
3. Copelan EA, Grever MR, Kapoor N, et al.: Marrow transplantation following busulfan and cyclophosphamide for chronic myelogenous leukaemia in accelerated or blastic phase. Br J Haematol 71 (4): 487-91, 1989.  [PUBMED Abstract]
   
   
4. Reiffers J, Trouette R, Marit G, et al.: Autologous blood stem cell transplantation for chronic granulocytic leukaemia in transformation: a report of 47 cases. Br J Haematol 77 (3): 339-45, 1991.  [PUBMED Abstract]
   
   
5. 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 103 (10): 2099-108, 2005.  [PUBMED Abstract]
   
   
6. Cortes J, Talpaz M, O'Brien S, et al.: Suppression of cytogenetic clonal evolution with interferon alfa therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. J Clin Oncol 16 (10): 3279-85, 1998.  [PUBMED Abstract]
   
   
7. Kantarjian HM, Keating MJ, Estey EH, et al.: Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine. J Clin Oncol 10 (5): 772-8, 1992.  [PUBMED Abstract]
   
   
8. Kantarjian HM, Talpaz M, Kontoyiannis D, et al.: Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte-macrophage colony-stimulating factor. J Clin Oncol 10 (3): 398-405, 1992.  [PUBMED Abstract]
   
   

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Blastic-Phase Chronic Myelogenous Leukemia

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.)

Standard treatment options:

1. Imatinib mesylate has demonstrated marked activity in patients with myeloid blast crisis and in patients with lymphoid blast crisis or Philadelphia chromosome-positive acute lymphoblastic leukemia. In a phase I trial, 4 of 38 patients with myeloid blast crisis had a complete hematologic remission, and 17 patients had a decrease in blasts in the marrow to 15% or less.[1] Of the 20 patients in the lymphoid cohort, 4 patients had a complete hematologic response, and 10 patients had a decrease in blasts in the marrow to 15% or less. These kinds of responses have not been durable. Of 21 responding patients with myeloid blast crisis, 9 relapsed between 42 and 194 days; of the 14 responding patients with lymphoid disease, 12 relapsed with a median duration of time to relapse of 58 days. Seven of the 21 responding patients with myeloid blast crisis continue in remission with longest follow-up of 349 days. These response data are the highest single agent responses in this disease.[1]

   Two larger trials involving a total of 304 patients in blastic-phase chronic myelogenous leukemia (CML) confirm a hematologic response rate of 52% to 55% and a major cytogenetic response rate of 16%, but the estimated 1-year survival is under 35%.[2,3][Level of evidence: 3iiiA] Clinical trials will explore combining imatinib mesylate with other drugs to improve the prognosis of patients with blastic-phase CML.[4]

2. Vincristine and prednisone with or without an anthracycline (for the approximately 25% of patients with terminal deoxynucleotidyl transferase-positive cells and lymphoblastic transformation).[5,6]
3. Allogeneic bone marrow transplantation (BMT) is successful in less than 10% of patients because of complications of transplantation and recurrent leukemia.[7] If available, this represents the only potentially curative approach in such patients. Allogeneic BMT is more effective in patients induced into a second chronic phase, with long-term disease-free survival approximating 20%.[8]
4. Hydroxyurea as palliative therapy.
5. High-dose cytarabine.[9]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with blastic 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

1. Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344 (14): 1038-42, 2001.  [PUBMED Abstract]
   
   
2. Kantarjian HM, Cortes J, O'Brien S, et al.: Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 99 (10): 3547-53, 2002.  [PUBMED Abstract]
   
   
3. Sawyers CL, Hochhaus A, Feldman E, et al.: Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99 (10): 3530-9, 2002.  [PUBMED Abstract]
   
   
4. Fruehauf S, Topaly J, Buss EC, et al.: Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer 109 (8): 1543-9, 2007.  [PUBMED Abstract]
   
   
5. Preti HA, O'Brien S, Giralt S, et al.: Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med 97 (1): 60-5, 1994.  [PUBMED Abstract]
   
   
6. Walters RS, Kantarjian HM, Keating MJ, et al.: Therapy of lymphoid and undifferentiated chronic myelogenous leukemia in blast crisis with continuous vincristine and adriamycin infusions plus high-dose decadron. Cancer 60 (8): 1708-12, 1987.  [PUBMED Abstract]
   
   
7. Copelan EA, Grever MR, Kapoor N, et al.: Marrow transplantation following busulfan and cyclophosphamide for chronic myelogenous leukaemia in accelerated or blastic phase. Br J Haematol 71 (4): 487-91, 1989.  [PUBMED Abstract]
   
   
8. Gratwohl A, Hermans J, Niederwieser D, et al.: Bone marrow transplantation for chronic myeloid leukemia: long-term results. Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation. Bone Marrow Transplant 12 (5): 509-16, 1993.  [PUBMED Abstract]
   
   
9. Kantarjian HM, Talpaz M, Kontoyiannis D, et al.: Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte-macrophage colony-stimulating factor. J Clin Oncol 10 (3): 398-405, 1992.  [PUBMED Abstract]
   
   

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Relapsing Chronic Myelogenous Leukemia

Overt failure is defined as a loss of hematologic remission or progression to accelerated phase or blast crisis phase as previously defined. Although presumed to represent relapsing disease, a rising quantitative reverse transcriptase–polymerase chain reaction signal is a controversial finding. Prospective studies comparing resumption of therapy versus continued observation have not been performed. Similarly, there has been no prospective validation for failure to achieve certain benchmarks during initial therapy. For initial use of imatinib mesylate, the designation of relative failure has been proposed for lack of complete hematologic remission by 3 months, no cytogenetic response by 6 months, or no major cytogenetic response by 12 months.[1]

Mutations in the tyrosine kinase domain can confer resistance to imatinib mesylate; alternative inhibitors such as dasatinib or nilotinib, higher doses of imatinib mesylate, and allogeneic stem cell transplantation (SCT) are being studied, as evidenced in the UCLA-0501047-01 trial, for example, in this setting.[2-11] Clinical trial participation should help establish the optimal sequence of these options.

Infusions of buffy coat leukocytes or isolated T cells obtained by pheresis from the bone marrow transplant donor have induced long-term remissions in more than 50% of patients who relapse following allogeneic transplant.[12,13] The efficacy of this treatment is thought to be the result of an immunologic graft-versus-leukemia effect. This treatment is most effective for patients whose relapse is detectable only by cytogenetics or molecular studies and is associated with significant graft-versus-host disease. After relapse from allogeneic SCT, some patients will also respond to interferon-alpha.[14] Most patients will respond to imatinib mesylate with durable (>1 year) cytogenetic and molecular responses. (These patients had not previously received imatinib.)[15-17]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with relapsing 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

1. Baccarani M, Saglio G, Goldman J, et al.: Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108 (6): 1809-20, 2006.  [PUBMED Abstract]
   
   
2. 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]
   
   
3. le Coutre P, Ottmann OG, Giles F, et al.: Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 111 (4): 1834-9, 2008.  [PUBMED Abstract]
   
   
4. Talpaz M, Shah NP, Kantarjian H, et al.: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354 (24): 2531-41, 2006.  [PUBMED Abstract]
   
   
5. Hochhaus A, Baccarani M, Deininger M, et al.: Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22 (6): 1200-6, 2008.  [PUBMED Abstract]
   
   
6. Quintas-Cardama A, Kantarjian H, Jones D, et al.: Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood 109 (2): 497-9, 2007.  [PUBMED Abstract]
   
   
7. Cortes J, Rousselot P, Kim DW, et al.: Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 109 (8): 3207-13, 2007.  [PUBMED Abstract]
   
   
8. Kantarjian H, Pasquini R, Hamerschlak N, et al.: Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood 109 (12): 5143-50, 2007.  [PUBMED Abstract]
   
   
9. Guilhot F, Apperley J, Kim DW, et al.: Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 109 (10): 4143-50, 2007.  [PUBMED Abstract]
   
   
10. Kantarjian HM, Giles F, Gattermann N, 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 110 (10): 3540-6, 2007.  [PUBMED Abstract]
    
    
11. Shah NP, Kantarjian HM, Kim DW, et al.: Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 26 (19): 3204-12, 2008.  [PUBMED Abstract]
    
    
12. Kaeda J, O'Shea D, Szydlo RM, et al.: Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. Blood 107 (10): 4171-6, 2006.  [PUBMED Abstract]
    
    
13. Dazzi F, Szydlo RM, Craddock C, et al.: Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 95 (1): 67-71, 2000.  [PUBMED Abstract]
    
    
14. Pigneux A, Devergie A, Pochitaloff M, et al.: Recombinant alpha-interferon as treatment for chronic myelogenous leukemia in relapse after allogeneic bone marrow transplantation: a report from the Société Française de Greffe de Moelle. Bone Marrow Transplant 15 (6): 819-24, 1995.  [PUBMED Abstract]
    
    
15. Olavarria E, Ottmann OG, Deininger M, et al.: Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia 17 (9): 1707-12, 2003.  [PUBMED Abstract]
    
    
16. Kantarjian HM, O'Brien S, Cortes JE, et al.: Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 100 (5): 1590-5, 2002.  [PUBMED Abstract]
    
    
17. Hess G, Bunjes D, Siegert W, et al.: Sustained complete molecular remissions after treatment with imatinib-mesylate in patients with failure after allogeneic stem cell transplantation for chronic myelogenous leukemia: results of a prospective phase II open-label multicenter study. J Clin Oncol 23 (30): 7583-93, 2005.  [PUBMED Abstract]
    
    

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Changes to This Summary (03/06/2009)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment Option Overview

Added le Coutre et al. as reference 9.

Chronic-Phase Chronic Myelogenous Leukemia

Added text to update long-term follow-up statistics for response, survival, and safety with imatinib mesylate therapy after failure of interferon-alpha (cited Hochhaus et al. as reference 3).

Cited le Coutre et al. as reference 15; added Shah et al. as reference 19.

Added Deenik et al. as reference 21.

Relapsing Chronic Myelogenous Leukemia

Cited le Coutre et al. as reference 3.

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More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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