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NCI/PDQ^® Health professionals: Chronic Myelogenous Leukemia

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National Cancer Institute
Last Modified: July 15, 2003

TABLE OF CONTENTS

• General Information
• Stage Information
• Treatment Option Overview
• Chronic Phase Chronic Myelogenous Leukemia
• Accelerated Phase Chronic Myelogenous Leukemia
• Blastic Phase Chronic Myelogenous Leukemia
• Relapsing Chronic Myelogenous Leukemia
• Changes to This Summary (07/15/2003)
• Important

General Information

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). 1 The Ph1 results from a reciprocal translocation between the long arms of chromosomes 9 and 22 and is demonstrable in all hematopoietic precursors. 1 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). 1 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. However, Ph1-negative patients who have bcr-abl gene rearrangement detectable by Southern blot analysis have prognoses equivalent to Ph1-positive patients. 2 3 A small subset of patients have bcr-abl detectable only by reverse transcription-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, a distinct clinical entity related to myelodysplastic syndrome. 2 4 5 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. 6

The median age of patients with Ph1-positive CML is 67 years of age. 7 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. 6

References:

1. Deininger MW, Goldman JM, Melo JV: The molecular biology of chronic myeloid leukemia. Blood 96 (10): 3343-56, 2000.
2. Martiat P, Michaux JL, Rodhain J: Philadelphia-negative (Ph-) chronic myeloid leukemia (CML): comparison with Ph+ CML and chronic myelomonocytic leukemia. The Groupe Franais de Cytogénétique Hématologique. Blood 78 (1): 205-11, 1991.
3. 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.
4. Oscier DG: Atypical chronic myeloid leukaemia, a distinct clinical entity related to the myelodysplastic syndrome? Br J Haematol 92 (3): 582-6, 1996.
5. Kurzrock R, Bueso-Ramos CE, Kantarjian H, et al.: BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol 19 (11): 2915-26, 2001.
6. Sawyers CL: Chronic myeloid leukemia. N Engl J Med 340 (17): 1330-40, 1999.
7. 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.

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 transcription-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. 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, although they often show increasing morphologic abnormalities, and increasing anemia and thrombocytopenia and marrow fibrosis are apparent. 1 4 5

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 3 6 7 8 9

Chronic phase chronic myelogenous leukemia

Chronic phase chronic myelogenous leukemia is characterized by bone marrow and cytogenetic findings as described above with 5% or fewer blasts and promyelocytes in the peripheral blood and bone marrow.

Accelerated phase chronic myelogenous leukemia

Accelerated phase chronic myelogenous leukemia is characterized by greater than 5% blasts in either the peripheral blood or bone marrow but 30% or fewer blasts in both the peripheral blood and bone marrow.

Blastic phase chronic myelogenous leukemia

Blastic phase chronic myelogenous leukemia is characterized by greater than 30% blasts in the peripheral blood or bone marrow.

When greater than 30% blasts are present in the face of fever, malaise, and progressive splenomegaly, the patient has entered blast crisis, and survival is on the order of a few months. 4 5

Relapsing chronic myelogenous leukemia

Relapsed chronic myelogenous leukemia 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 when previously FISH-negative.

Detection of the bcr-abl translocation by RT-PCR during prolonged remissions does not constitute relapse on its own.

References:

1. Sawyers CL: Chronic myeloid leukemia. N Engl J Med 340 (17): 1330-40, 1999.
2. Sokal JE, Cox EB, Baccarani M, et al.: Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 63 (4): 789-99, 1984.
3. Sokal JE, Baccarani M, Russo D, et al.: Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 25 (1): 49-61, 1988.
4. Kantarjian HM, Keating MJ, Talpaz M, et al.: Chronic myelogenous leukemia in blast crisis. Analysis of 242 patients. Am J Med 83 (3): 445-54, 1987.
5. Cervantes F, Rozman M, Rosell J, et al.: A study of prognostic factors in blast crisis of Philadelphia chromosome-positive chronic myelogenous leukaemia. Br J Haematol 76 (1): 27-32, 1990.
6. 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.
7. 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.
8. 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.
9. 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.

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 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 translocation. 1 The optimal front-line treatment for chronic-phase CML is controversial and the subject of active investigation. The only consistently successful curative treatment of CML for more than half of eligible patients has been allogeneic bone marrow or stem cell transplantation. 2 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 (cytogenetics, reverse transcription-polymerase chain reaction [RT-PCR] or fluorescent in-situ hybridization [FISH]). However, many patients are not eligible for this approach because of age, comorbid conditions, or lack of a suitable donor. In addition, there is substantial morbidity and mortality from allogeneic bone marrow or stem cell transplantation; a 15% to 30% treatment-related mortality can be expected, depending on whether the donor is related and on the presence of mismatched antigens. 2

Long-term data are also available for patients treated with interferon alfa. 3 4 5 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. 2 Maintenance of therapy with interferon is required, however, and some patients experience side effects that preclude continued treatment. Imatinib mesylate (STI571), a specific inhibitor of the bcr-abl tyrosine kinase, produces a complete cytogenetic response in more than 60% of previously untreated patients with very few side effects. 6 No long-term data exist as yet in regards to the durability of this response, and there is no information about the efficacy of salvage strategies using interferon alfa or allogeneic stem cell transplantation after failure of imatinib mesylate. In addition, almost all completely responding patients still show detectable evidence of the bcr-abl translocation, usually by RT-PCR or by FISH of progenitor cell cultures. 7 The clinical implication of this finding is unknown.

Newly diagnosed patients with chronic-phase CML should be offered clinical trials. There are many unanswered questions. What is the best dose of imatinib mesylate and should it be combined with other agents (such as interferon alfa and/or cytarabine)? What is the role of allogeneic bone marrow or stem cell transplantation for younger, eligible patients? Should this be offered before or after initiation of imatinib mesylate? Will transplantation be more or equally efficacious before or after failure on imatinib mesylate? Will responses on imatinib mesylate be durable for many years or will responses be short-lived and the relapsing disease more difficult to control? Should imatinib mesylate be withheld for a window of opportunity trial for interferon to identify cytogenetic responders for whom long-term follow-up data are available? All of these issues have led to an active reappraisal of recommendations for optimal front-line therapy for chronic phase CML.

Newly diagnosed patients with very high levels of circulating leukocytes (WBC > 100,000/mm3) require rapid reduction using chemotherapeutic agents, usually hydroxyurea. 1 This will avoid cerebrovascular events or death from leukostasis. Leukophoresis and plateletpheresis are sometimes required for an even more emergent reduction of counts.

The designations in PDQ that treatments are standard or under clinical evaluation are not to be used as a basis for reimbursement determinations.

References:

1. Sawyers CL: Chronic myeloid leukemia. N Engl J Med 340 (17): 1330-40, 1999.
2. 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.
3. 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.
4. 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.
5. 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.
6. Drucker B: STI571 (Gleevec/Gilvac, Imatinib) versus interferon (IFN) + cytarabine as initial therapy for patients with CML: results of a randomized study. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1, 1a, 2002.
7. 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.

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. The only consistently successful curative treatment of chronic myelogenous leukemia (CML) has been high-dose therapy followed by allogeneic bone marrow or stem cell transplantation. 1 Patients younger than 60 years of age with an identical twin or with HLA-identical siblings can be considered for bone marrow transplantation (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, with the results better in younger patients (especially those younger than 20 years of age). The results of patients transplanted in the accelerated and blastic phases of the disease are progressively worse. 2 3 Most transplant series suggest improved survival when the procedure is performed within 1 year of diagnosis. 4 5 6 [Level of evidence: 3iiiA] However, the data supporting early transplant have never been confirmed in controlled trials. In a randomized clinical trial, disease-free and overall survival 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. 7 [Level of evidence: 1iiA]

   About 20% of otherwise eligible CML patients lack a suitably-matched sibling donor. 8 HLA-matched unrelated donors or donors mismatched at 1 HLA antigen HLA-matched unrelated donors or donors mismatched at 1 HLA antigen can be found for about 50% of eligible participants through the National Marrow can be found for about 50% of eligible participants through the National Marrow Donor Program.Donor Program. 8 However, there are still major obstacles in using unrelated However, there are still major obstacles in using unrelated donors, especially in older patients. Two retrospective series following donors, especially in older patients. Two retrospective series following allogeneic BMT from an HLA-matched unrelated donor showed a 5-year relapse rate allogeneic BMT from an HLA-matched unrelated donor showed a 5-year relapse rate of 3% to 10% and a 5-year overall survival rate of 31% to 57% (most deaths were of 3% to 10% and a 5-year overall survival rate of 31% to 57% (most deaths were treatment-related).treatment-related). 3 [Level of evidence: 3iiiA];[Level of evidence: 3iiiA]; 6 Patients with unrelated Patients with unrelated donor transplants were generally younger and had a longer interval from donor transplants were generally younger and had a longer interval from diagnosis to transplant. While the majority of relapses occur within 5 years diagnosis to transplant. While the majority of relapses occur within 5 years of transplantation, relapses have occurred as long as 9 years following BMT. of transplantation, relapses have occurred as long as 9 years following BMT. The risk of relapse appears to be less in patients transplanted early in The risk of relapse appears to be less in patients transplanted early in disease, and in patients who develop chronic graft-versus-host disease.disease, and in patients who develop chronic graft-versus-host disease. 3 9 BMT from an unrelated donor is associated with a higher risk of post-transplant BMT from an unrelated donor is associated with a higher risk of post-transplant graft failure and infection (viral and fungal). The incidence of relapse is graft failure and infection (viral and fungal). The incidence of relapse is lower with BMT from unrelated donors than it is from sibling donors. lower with BMT from unrelated donors than it is from sibling donors. Interferon alfa, hydroxyurea, or both, are standard treatments used to Interferon alfa, hydroxyurea, or both, are standard treatments used to stabilize patients prior to BMT. Early studies also suggested that prior stabilize patients prior to BMT. Early studies also suggested that prior interferon exposure had an adverse effect on outcome following subsequent interferon exposure had an adverse effect on outcome following subsequent allogeneic BMT;allogeneic BMT; 10 11 however, subsequent studies have not confirmed these however, subsequent studies have not confirmed these observations.observations. 12 13 Retrospective studies suggest that the potential negative Retrospective studies suggest that the potential negative impact of interferon on transplant outcome appears to be limited to patients impact of interferon on transplant outcome appears to be limited to patients receiving transplantation from a matched, unrelated donor, and may be receiving transplantation from a matched, unrelated donor, and may be ameliorated by withdrawal of interferon for at least 90 days prior to ameliorated by withdrawal of interferon for at least 90 days prior to transplantation.transplantation. 12 13 14

   With the advent of imatinib mesylate (STI571), the timing and sequence of allogeneic bone marrow or stem cell transplantation has been cast in doubt. Will responses to imatinib mesylate be sufficiently durable to warrant delaying transplantation in otherwise younger eligible patients, particularly in view of the differing toxicities of these approaches? Will the efficacy or even eligibility for transplantation be precluded by prior imatinib mesylate therapy? Should younger eligible patients still move toward allogeneic stem cell transplantation after induction by interferon alfa, saving imatinib mesylate for future use? Does the substantial toxicity and mortality of allogeneic transplantation render its early use obsolete? Clinical trials and longer-term results from ongoing trials will be required before these controversies are resolved.

2. Long-term data are available for initial treatment with interferon alfa. A meta-analysis of 7 trials that randomized 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<.00001). 15 [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=.00007). 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<.00001). Further analysis of the 2 trials, which included a 3-way randomization between interferon, hydroxyurea, and busulfan, showed hydroxyurea to be superior to busulfan, decreasing the proportional odds of death by 24% (P=.02). 15 About 20% of the chronic-phase patients treated with interferon alfa 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. 16 17 18 These data have only been published in the context of a review article, rather than a peer-reviewed research manuscript. 18

   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. 19 Seventy-four percent of patients with complete cytogenetic responses and 55% of Seventy-four percent of patients with complete cytogenetic responses and 55% of patients with major cytogenetic responses were alive and had shown no disease patients with major cytogenetic responses were alive and had shown no disease progression at date of publication (median follow-up time was not provided). progression at date of publication (median follow-up time was not provided). However, using molecular methods of analysis, small numbers of Ph1-positive cells can However, using molecular methods of analysis, small numbers of Ph1-positive cells can still be detected in the majority of patients having long-term cytogenetic still be detected in the majority of patients having long-term cytogenetic remissions, and longer follow-up will be required to ascertain whether the remissions, and longer follow-up will be required to ascertain whether the disease will recur. disease will recur.

   Patients older than 60 years of age 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. 20 Interferon alfa has significant toxic effects Interferon alfa has significant toxic effects that can result in dosage modification or discontinuation of therapy in many that can result in dosage modification or discontinuation of therapy in many cases. Common side effects include influenza-like syndrome, nausea, anorexia, cases. Common side effects include influenza-like syndrome, nausea, anorexia, weight loss, and neuropsychiatric symptoms, all of which are completely weight loss, and neuropsychiatric symptoms, all of which are completely reversible with cessation of therapy.reversible with cessation of therapy. 21 Immune-mediated complications, such Immune-mediated complications, such as hyperthyroidism, hemolysis, and connective tissue diseases may occur rarely as hyperthyroidism, hemolysis, and connective tissue diseases may occur rarely after long-term treatment.after long-term treatment. 22 Interferon alfa is quite costly, and daily Interferon alfa is quite costly, and daily subcutaneous injections can be troublesome. subcutaneous injections can be troublesome.

   Patients who achieve cytogenetic remission should continue therapy (3-5 million units/m22 daily) daily) for at least 2 to 3 years beyond remission, and perhaps indefinitely, as 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 bone marrow or stem cell transplantation (if eligible). suggested by some investigators. After 1 year, patients with only a partial cytogenetic response should consider alternative therapy with imatinib mesylate or allogeneic bone marrow or stem cell transplantation (if eligible). The French Chronic Myeloid Leukemia Study Group randomized 721 patients to The French Chronic Myeloid Leukemia Study Group randomized 721 patients to interferon and cytarabine versus interferon alone.interferon and cytarabine versus interferon alone. 23 [Level of evidence: 1iiA] [Level of evidence: 1iiA] Patients who received the combination had significantly more major cytogenetic Patients who received the combination had significantly more major cytogenetic responses (41% versus 24%, Presponses (41% versus 24%, P<<.001) and improved 3-year survival (86% versus .001) and improved 3-year survival (86% versus 80%). Another trial by the Italian Cooperative Study Group on CML did not show a survival benefit for interferon plus cytarabine versus interferon alone.80%). Another trial by the Italian Cooperative Study Group on CML did not show a survival benefit for interferon plus cytarabine versus interferon alone. 24 [Level of evidence: 1iiA] Both studies showed increased toxic effects for the combination versus interferon alone.[Level of evidence: 1iiA] Both studies showed increased toxic effects for the combination versus interferon alone. 23 24 Interferon alfa is also effective for patients who have relapsed Interferon alfa is also effective for patients who have relapsed after allogeneic bone marrow transplantation.after allogeneic bone marrow transplantation. 25 26

3. Since tyrosine kinase activity is required for the transforming function of the bcr-abl fusion protein, a specific inhibitor of the kinase could be an effective treatment for patients with CML. 27 28 Imatinib mesylate is a compound which inhibits the bcr-abl oncoprotein which is pathogenic in CML. In 454 patients with chronic phase CML who had previously not responded to interferon, imatinib mesylate induced major cytogenetic responses in 60% of patients and complete hematologic response in 95% of patients, with 89% of patients free of progression to accelerated phase or blastic phase with a median follow-up of 18 months. 29 [Level of evidence: 3iiiDiii] Responses were also seen in patients with myeloid and lymphoid blast crises, although the responses appear more durable for the myeloid blast phenotype. 30 [Level of evidence: 3iiiDiii] These preliminary results demonstrate activity which appears greater than that of any other agent used in treatment of CML.

   Preliminary results in abstract form from a trial randomizing 1106 previously untreated patients to imatinib mesylate or to interferon plus cytarabine documented a 63% major cytogenetic response rate with imatinib mesylate versus 10% for interferon plus cytarabine at 6 months. 31 [Level of evidence: 1iiDii] However, no long-term data exist as yet in regard to the durability of this response, and there is no information about the efficacy of salvage strategies using interferon alfa or allogeneic stem cell transplantation after failure of imatinib mesylate. In addition, almost all 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.[Level of evidence: 1iiDii] However, no long-term data exist as yet in regard to the durability of this response, and there is no information about the efficacy of salvage strategies using interferon alfa or allogeneic stem cell transplantation after failure of imatinib mesylate. In addition, almost all 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. 32 The clinical implication of this finding is unknown. The clinical implication of this finding is unknown.

   Newly diagnosed patients with chronic phase CML should be offered clinical trials. There are many unanswered questions. What is the best dose of imatinib mesylate and should it be combined with other agents (such as interferon alfa and/or cytarabine)? What is the role of allogeneic bone marrow or stem cell transplantation for younger, eligible patients? Should this be offered before or after initiation of imatinib mesylate? Will transplantation be more or equally efficacious before or after failure on imatinib mesylate? Will responses on imatinib mesylate be durable for many years or will responses be short-lived and the relapsing disease more difficult to control? All of these issues have led to an active reappraisal of recommendations for optimal front-line therapy for chronic phase CML.

   In patients with blast crisis who have relapsed following treatment with imatinib mesylate, imatinib resistance was associated with reactivation of bcr-abl signal transduction. In 6 of 9 patients studied, this was associated with a mutation in the abl kinase domain which forms a critical hydrogen bond with the drug. In 3 patients, resistance was associated with progressive gene amplification of bcr-abl. 33

4. Hydroxyurea is given daily by mouth (1-3 grams/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. 34 A dose of 40 milligrams/kilogram/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 millimeter3, 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.

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. Clift RA, Appelbaum FR, Thomas ED: Treatment of chronic myeloid leukemia by marrow transplantation. Blood 82 (7): 1954-6, 1993.
6. 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.
7. 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.
8. 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.
9. 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.
10. Beelen DW, Graeven U, Elmaagacli AH, et al.: Prolonged administration of interferon-alpha in patients with chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia before allogeneic bone marrow transplantation may adversely affect transplant outcome. Blood 85 (10): 2981-90, 1995.
11. Giralt SA, Kantarjian HM, Talpaz M, et al.: Effect of prior interferon alfa therapy on the outcome of allogeneic bone marrow transplantation for chronic myelogenous leukemia. J Clin Oncol 11 (6): 1055-61, 1993.
12. Giralt S, Szydlo R, Goldman JM, et al.: Effect of short-term interferon therapy on the outcome of subsequent HLA-identical sibling bone marrow transplantation for chronic myelogenous leukemia: an analysis from the international bone marrow transplant registry. Blood 95 (2): 410-5, 2000.
13. Hehlmann R, Hochhaus A, Kolb HJ, et al.: Interferon-alpha before allogeneic bone marrow transplantation in chronic myelogenous leukemia does not affect outcome adversely, provided it is discontinued at least 90 days before the procedure. Blood 94 (11): 3668-77, 1999.
14. Morton AJ, Gooley T, Hansen JA, et al.: Association between pretransplant interferon-alpha and outcome after unrelated donor marrow transplantation for chronic myelogenous leukemia in chronic phase. Blood 92 (2): 394-401, 1998.
15. 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.
16. 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.
17. 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.
18. Kantarjian HM, Deisseroth A, Kurzrock R, et al.: Chronic myelogenous leukemia: a concise update. Blood 82 (3): 691-703, 1993.
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.
20. 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.
21. 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.
22. 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.
23. 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.
24. Baccarani M, Rosti G, de Vivo A, et al.: Italian Cooperative Study Group on Myeloid Leukemia: A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia. Blood 99 (5): 1527-35, 2002.
25. 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.
26. 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.
27. Deininger MW, Goldman JM, Melo JV: The molecular biology of chronic myeloid leukemia. Blood 96 (10): 3343-56, 2000.
28. Druker BJ, Talpaz M, Resta DJ, et al.: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344 (14): 1031-7, 2001.
29. Kantarjian H, Sawyers C, Hochhaus A, et al.: The International STI571 CML Study Group: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346 (9): 645-52, 2002.
30. 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.
31. Drucker B: STI571 (Gleevec/Gilvac, Imatinib) versus interferon (IFN) + cytarabine as initial therapy for patients with CML: results of a randomized study. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1, 1a, 2002.
32. 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.
33. Gorre ME, Mohammed M, Ellwood K, et al.: Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293 (5531): 876-80, 2001.
34. 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.

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.)

Standard treatment options:

1. Bone marrow transplantation. Autologous marrow transplantation may return the patient to a chronic phase, which may be durable. Allogeneic marrow transplantation has the potential for cure, although results to date are poor. 1 2 3
2. Imatinib mesylate (STI571). Among 200 patients with accelerated phase chronic myelogenous leukemia, the complete hematologic response was 80% and the complete cytogenetic response was 24%; 82% of the cytogenetic responses were maintained at 18 months. 4
3. Interferon alfa. 5 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. 5 6 When cytarabine was added to interferon alfa, in comparison to historical controls of interferon alone, the response rate and 3-year survival appeared to be improved in late-stage patients. 6 [Level of evidence: 3iiiA]
4. High-dose cytarabine. 7
5. Hydroxyurea.
6. Busulfan.
7. Supportive transfusion therapy.

References:

1. 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.
2. 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.
3. 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.
4. Kantarjian HM, O'Brien S, Cortes JE, et al.: Treatment of philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res 8 (7): 2167-76, 2002.
5. 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.
6. 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.
7. 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.

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 (STI571) 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 had a decrease in blasts in the marrow to 15% or less. 1 Of the 20 patients in the lymphoid cohort, 4 had a complete hematologic response and 10 had a decrease in blasts in the marrow to 15% or less. Unfortunately, these 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.[Level of evidence: 3iiiA] Clinical trials will explore combining imatinib mesylate with other drugs to improve the prognosis of patients with blastic phase CML.

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

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.
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.
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.
4. 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.
5. 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.
6. 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.
7. 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.
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.

Relapsing 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.)

In 454 patients with chronic phase chronic myelogenous leukemia (CML) who had previously not responded to interferon, imatinib mesylate (STI571) induced major cytogenetic responses in 60% of patients and complete hematologic response in 95% of patients, with 89% free of progression to accelerated phase or blastic phase with a median follow-up of 18 months. 1 [Level of evidence: 3iiiDiii] Responses were also seen in patients with myeloid and lymphoid blast crises, although the responses appear more durable for the myeloid blast phenotype. 2 3 4 [Level of evidence: 3iiiDiii] Clinical trials will explore combining imatinib mesylate with other drugs to improve the prognosis of patients with relapsing CML. The results of salvage therapies, such as interferon alfa or allogeneic bone marrow or stem cell transplantation, after failure of front-line imatinib mesylate are unknown.

After relapse from allogeneic bone marrow transplantation, some patients will respond to interferon alfa. 5

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. The efficacy of this treatment is thought to be due to 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. 6 7 8 9 10

References:

1. Kantarjian H, Sawyers C, Hochhaus A, et al.: The International STI571 CML Study Group: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346 (9): 645-52, 2002.
2. 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.
3. 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.
4. 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.
5. 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 Franaise de Greffe de Moelle. Bone Marrow Transplant 15 (6): 819-24, 1995.
6. Mackinnon S, Papadopoulos EB, Carabasi MH, et al.: Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. Blood 86 (4): 1261-8, 1995.
7. Br BM, Schattenberg A, Mensink EJ, et al.: Donor leukocyte infusions for chronic myeloid leukemia relapsed after allogeneic bone marrow transplantation. J Clin Oncol 11 (3): 513-9, 1993.
8. Porter DL, Roth MS, McGarigle C, et al.: Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med 330 (2): 100-6, 1994.
9. Kolb HJ, Schattenberg A, Goldman JM, et al.: Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 86 (5): 2041-50, 1995.
10. van Rhee F, Savage D, Blackwell J, et al.: Adoptive immunotherapy for relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: equal efficacy of lymphocytes from sibling and matched unrelated donors. Bone Marrow Transplant 21 (10): 1055-61, 1998.

Changes to This Summary (07/15/2003)

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.

Stage Information

Added text to state that relapsed CML is characterized by any evidence of progression of disease from a stable remission, including increasing myeloid or blast cells in the peripheral blood or bone marrow, cytogenetic positivity when previously cytogenetic-negative, and FISH positivity when previously FISH-negative, and that detection of the bcr-abl translocation by RT-PCR can be seen during prolonged remissions and does not constitute relapse on its own.

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).