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医療専門家向け Chronic Myelogenous Leukemia Treatment (PDQ®)

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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic myelogenous leukemia. It 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.

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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General Information About Chronic Myelogenous Leukemia (CML)

Incidence and Mortality

Estimated new cases and deaths from CML in the United States in 2020:[ 1 ]

CML is one of a group of diseases called the myeloproliferative disorders. Other related entities include the following:

(Refer to the PDQ summary on Chronic Myeloproliferative Neoplasms Treatment for more information.)

Molecular Biology and Cytogenetics of CML

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 ABL oncogene on chromosome 9 to an area of chromosome 22 termed the breakpoint cluster region (within the BCR gene).[ 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. Molecular techniques are used to detect the presence of the 9;22 translocation using peripheral blood. The utility of bone marrow aspiration and biopsy has been questioned outside the context of a clinical trial in routine presentations of CML. Clinical signs indicative of accelerated phase or blast crisis (fever, enlarged spleen, or >20% blasts in the peripheral blood) suggest the clinical utility for bone marrow testing.[ 5 ]

Prognosis and Survival

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.[ 6 ] Ph1-negative patients who have BCR/ABL gene rearrangement detectable by Southern blot analysis, however, have prognoses equivalent to Ph1-positive patients.[ 7 ][ 8 ]

Diagnosis

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.[ 7 ][ 9 ][ 10 ] 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.[ 11 ]

At the time of diagnosis of patients with CML, splenomegaly is the most-common finding on physical examination.[ 11 ] 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.

The median age of patients with Ph1-positive CML is 67 years.[ 12 ] While the median survival used to be 4 to 6 years, with the advent of the new oral therapies, the median survival is expected to approach normal life expectancy for most patients, although it is still too soon to say this definitively.

参考文献
  1. American Cancer Society: Cancer Facts and Figures 2020. Atlanta, Ga: American Cancer Society, 2020. Available online. Last accessed May 12, 2020.[PUBMED Abstract]
  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. Hidalgo-Lόpez JE, Kanagal-Shamanna R, Quesada AE, et al.: Bone marrow core biopsy in 508 consecutive patients with chronic myeloid leukemia: Assessment of potential value. Cancer 124 (19): 3849-3855, 2018.[PUBMED Abstract]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. Jabbour E, Kantarjian H: Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol 87 (11): 1037-45, 2012.[PUBMED Abstract]
  12. 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]
Stage Information for CML

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 analyses on blood or marrow aspirates may be necessary to demonstrate the 9;22 translocation.

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 indicating such a change include the following:

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:

Predictive models using multivariate analysis have been derived.[ 2 ][ 3 ][ 5 ][ 6 ][ 7 ][ 8 ]

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.[ 9 ]

Accelerated-phase CML

Accelerated-phase CML is characterized by 10% to 19% blasts in either the peripheral blood or bone marrow.[ 9 ]

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.[ 9 ]

Relapsing CML

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

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.[ 10 ]

参考文献
  1. Jabbour E, Kantarjian H: Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol 87 (11): 1037-45, 2012.[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. Fabarius A, Leitner A, Hochhaus A, et al.: Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 118 (26): 6760-8, 2011.[PUBMED Abstract]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
Treatment Option Overview for CML

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 count, splenomegaly, thrombocytosis, and identification of the BCR/ABL translocation.[ 1 ] The optimal front-line 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 that compared imatinib mesylate with interferon plus cytarabine, at 10.9 years' median follow-up, imatinib mesylate induced complete cytogenetic responses in 83% 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 ][ 4 ][ 5 ] Although evidence-based survival advantages are unavailable because of crossover in randomized trials, the overall survival (OS) rate for all patients at 10 years is 83.3%, with fewer than 50% of all deaths (4.5%) caused by CML.[ 2 ]

Tyrosine kinase inhibitors with greater potency and selectivity than imatinib for BCR/ABL have been evaluated in newly diagnosed patients with CML. In a randomized, prospective study of 846 patients that compared nilotinib with imatinib, the rate of major molecular response (MMR) at 24 months was 71% and 67% for two-dose schedules of nilotinib and 44% for imatinib (P < .0001 for both comparisons).[ 6 ][Level of evidence: 1iiDiv] Progression to accelerated-phase CML or blast crisis occurred in 17 patients who received imatinib (14%), but this progression occurred in only two patients (<1%, P = .0003) and in five patients (<1.8%, P = .0089), respectively, who received two-dose schedules of nilotinib.[ 6 ]

In a randomized, prospective study of 519 patients that compared dasatinib with imatinib, the rate of MMR at 12 months was 46% for the dasatinib arm and 28% for the imatinib arm (P < .0001). The rate of MMR at 24 months was 64% for dasatinib and 46% for imatinib (P < .0001).[ 7 ][Level of evidence: 1iiDiv] At 5 years, there was no difference in progression-free survival or OS. Progression to accelerated-phase CML or blast crisis occurred in 7% of patients who received imatinib and in 5% of patients who received dasatinib (not statistically different).[ 7 ]

In a randomized prospective study of 536 patients that compared bosutinib with imatinib, the MMR at 12 months was 47.2% in the bosutinib arm versus 36.9% in the imatinib arm (P = .0075).[ 8 ][Level of evidence: 1iiDiv] Progression to accelerated phase/blast crisis occurred in four patients (1.6%) who received bosutinib and in six patients (2.5%) who received imatinib.

Although one of these three studies showed statistically significant decreased rates of progression to accelerated or blastic phase, the 5- to 10-year follow-up period with nilotinib and dasatinib demonstrated a survival for these agents, similar to that for imatinib. The preferred initial treatment for patients with newly diagnosed chronic-phase CML could be any of these specific inhibitors of the BCR/ABL tyrosine kinase.[ 9 ]

Allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT) has also been applied with curative intent.[ 10 ] 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). Some 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 5% to 10% treatment-related mortality can be expected, depending on whether a donor is related and on the presence of mismatched antigens.[ 10 ] In a prospective trial of 427 transplant-eligible, previously untreated patients, 166 patients were allocated to allogeneic SCT, and 261 patients were allocated to drug treatment (mostly imatinib); there was no difference in 10-year OS.[ 11 ][Level of evidence: 3iiiA]

Long-term data are also available for patients treated with interferon alpha.[ 12 ][ 13 ][ 14 ] 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.[ 10 ] Maintenance of therapy with interferon is required, however, and some patients experience side effects that preclude continued treatment.

参考文献
  1. Jabbour E, Kantarjian H: Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol 87 (11): 1037-45, 2012.[PUBMED Abstract]
  2. Hochhaus A, Larson RA, Guilhot F, et al.: Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med 376 (10): 917-927, 2017.[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, Hochhaus A, Saglio G, et al.: Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 12 (9): 841-51, 2011.[PUBMED Abstract]
  7. Cortes JE, Saglio G, Kantarjian HM, et al.: Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol 34 (20): 2333-40, 2016.[PUBMED Abstract]
  8. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al.: Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol 36 (3): 231-237, 2018.[PUBMED Abstract]
  9. Wei G, Rafiyath S, Liu D: First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J Hematol Oncol 3: 47, 2010.[PUBMED Abstract]
  10. 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]
  11. Gratwohl A, Pfirrmann M, Zander A, et al.: Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment. Leukemia 30 (3): 562-9, 2016.[PUBMED Abstract]
  12. 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]
  13. 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]
  14. 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]
Chronic-Phase CML

Treatment Options for Chronic-Phase CML

  1. Targeted therapy with tyrosine kinase inhibitors.
  2. High-dose therapy followed by allogeneic bone marrow transplant (BMT) or stem cell transplantation (SCT).
  3. Hydroxyurea.
  4. Splenectomy may be required and useful in patients having hematologic problems and physical discomfort from a massive spleen.

Targeted therapy with tyrosine kinase inhibitors

Abbreviations used in this section for response rate are defined in Table 1.

Table 1. Response Rate Definitions
Abbreviation Definition
aPreviously called CMR (complete molecular response).
DMRa Deep molecular response.
EMR Early molecular response.
MMR Major molecular response.

A trial randomly assigning 1,106 previously untreated patients to imatinib mesylate or to interferon plus cytarabine documented an 82.8% complete cytogenetic response rate with imatinib mesylate versus 14% for interferon plus cytarabine at a median follow-up of 10.9 years.[ 1 ][Level of evidence: 1iiDiii] At 18 months, 96.7% of the imatinib group had avoided progression to accelerated-phase chronic myelogenous leukemia (CML) 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. The overall survival (OS) rate for all patients at 10 years is 83.3%, with fewer than 50% of all deaths (4.5%) caused by CML.[ 1 ] More than 90% of completely responding patients still show detectable evidence of the BCR/ABL translocation, usually by reverse transcription-polymerase chain reaction (RT–PCR) or by fluorescence in situ hybridization of progenitor cell cultures.[ 2 ][ 3 ][ 4 ] Poor compliance is the predominant reason for inadequate molecular response to imatinib.[ 5 ]

Tyrosine kinase inhibitors with greater potency and selectivity for BCR/ABL than imatinib have been evaluated in newly diagnosed patients with CML. In a randomized, prospective study of 846 patients that compared nilotinib with imatinib, the rate of major molecular response (MMR) at 24 months was 71% and 67% for two-dose schedules of nilotinib and 44% for imatinib (P < .0001 for both comparisons).[ 6 ][Level of evidence: 1iiDiv] Progression to accelerated-phase CML or blast crisis occurred in 17 patients on imatinib (14%), but this progression only occurred in two patients (<1%, P = .0003) and in five patients (1.8%, P = .0089), respectively, for those patients on two-dose schedules of nilotinib.[ 6 ] Nilotinib-treated patients had a lower rate of treatment-emergent BCR/ABL mutations than did imatinib-treated patients.[ 7 ]

In a randomized, prospective study of 519 patients that compared dasatinib with imatinib, the rate of MMR at 12 months was 46% for dasatinib and 28% for imatinib (P < .0001). The rate of MMR at 24 months was 64% for dasatinib and 46% for imatinib (P < .0001).[ 8 ][Level of evidence: 1iiDiv] At 5 years, there was no difference in progression-free survival (PFS) or OS. Progression to accelerated-phase CML or blast crisis occurred in 13 patients (5%) who received imatinib and in 6 patients (2.3%) who received dasatinib (not statistically different).[ 8 ]

In a randomized prospective study of 536 patients that compared bosutinib with imatinib, the MMR at 12 months was 47.2% in the bosutinib arm versus 36.9% in the imatinib arm (P = .0075).[ 9 ][Level of evidence: 1iiDiv] Progression to accelerated phase/blast crisis occurred in four patients (1.6%) who received bosutinib and in six patients (2.5%) who received imatinib.

Although one of these three studies showed statistically significant decreased rates of progression to accelerated- or blastic-phase CML, the 5- to 10-year follow-up period with nilotinib and dasatinib demonstrated a similar survival for these agents, similar to that for imatinib. In randomized prospective trials, nilotinib and dasatinib showed higher rates of earlier molecular response compared with imatinib; whether this will translate to improved long-term outcomes remains unclear.[ 10 ][ 11 ][Level of evidence: 1iiDiv] The preferred initial treatment for patients with newly diagnosed chronic-phase CML could be any of these specific inhibitors of the BCR/ABL tyrosine kinase.[ 12 ]

A BCR/ABL transcript level of less than 10% in patients after 3 months of treatment with a specific tyrosine kinase inhibitor (deemed early molecular response [EMR]) is associated with the best prognosis in terms of failure-free survival, PFS, and OS.[ 10 ][ 11 ][ 13 ][ 14 ][ 15 ][ 16 ] However, in a retrospective analysis, even patients with a BCR/ABL transcript level greater than 10% after 3 months of therapy did well when the halving time was less than 76 days.[ 17 ] Mandating a change of therapy based on this 10% transcript level at 3 to 6 months is problematic because 75% of patients do well even with a suboptimal response.[ 18 ] After 1 year, the preferred response target is an MMR, which is defined as a BCR/ABL level of less than or equal to 0.1%. The optimal target is a deep molecular response (DMR), which is defined as under 4.5 logs (BCR/ABL <0.0032%) or undetectable, which is usually a BCR/ABL level of less than 0.001%.[ 19 ]

Higher doses of imatinib mesylate, alternative tyrosine kinase inhibitors (such as dasatinib or nilotinib), and allogeneic SCT are implemented for suboptimal response or progression and are under clinical evaluation as front-line approaches.[ 20 ][ 21 ][ 22 ][ 23 ][ 24 ] Dose escalation of imatinib can be considered for patients with suboptimal response, but clinical trials are required to establish the relative efficacy and sequencing of dose escalation versus the use of dasatinib or nilotinib.[ 21 ][ 22 ] Two studies looked at dose escalation of imatinib in almost 200 previously untreated patients, most of whom were of intermediate Sokal risk; 63% to 73% achieved an MMR by 18 to 24 months and only three patients showed progression to advanced phase in these preliminary phase II results.[ 25 ][ 26 ][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.[ 23 ][ 27 ]

A single-arm clinical trial using first-line imatinib with either selective imatinib intensification or selective switching to nilotinib resulted in a 3-year OS of 96% and transformation-free survival of 95%, with a confirmed MMR rate of 73% at 24 months.[ 28 ][Level of evidence: 3iiiDiv] All patients started treatment with imatinib and were given 600 mg daily. Imatinib plasma trough levels that were under 1,000 ng/mL on day 22 prompted an increase of imatinib to 800 mg daily (20% of patients). Molecular targets were set, and failure to reach these targets prompted an increase of imatinib to 800 mg daily (if not already performed) or a switch to nilotinib. The molecular targets were as follows:

This strategy of employing front-line imatinib is an alternative to the immediate use of more-potent tyrosine kinase inhibitors, such as nilotinib and dasatinib.

A single-center, retrospective analysis of 483 patients with chronic-phase CML who were treated with imatinib (400 mg or 800 mg every day), dasatinib, or nilotinib indicated that patients who have greater than 35% t(9;22)+ cells at 3 months of therapy have inferior event-free, transformation-free, and OS rates compared with patients who have better early cytogenetic responses.[ 29 ]

Among the many unanswered questions are the following:

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

For patients who obtain a DMR, the question is whether therapy with tyrosine kinase inhibitors can be discontinued. Several nonrandomized reports can be summarized as follows:[ 31 ][ 32 ][ 33 ][ 34 ][Level of evidence: 3iiiDiv]

  1. Patients who have taken a tyrosine kinase inhibitor for more than 3 to 5 years and attained a DMR (molecular remission, 4.5; BCR/ABL ≤ 0.0032%) are the best candidates to consider stopping therapy.
  2. In 50% of patients, a relapse with their disease will occur if the tyrosine kinase inhibitor is discontinued.
  3. Almost all patients who progress by BCR/ABL RT−PCR quantitative testing can be successfully reinduced with the previous tyrosine kinase inhibitor.

However, the duration of remissions after a successful reinduction with a previous tyrosine kinase inhibitor or the depth of subsequent responses with reinduction of a previous tyrosine kinase inhibitor is not known. At this time, there are insufficient data to recommend routinely stopping tyrosine kinase inhibitors, even in this select group of patients. Intensive follow-up (i.e., at least every 3 months, although the precise interval is not well-defined) is required after stopping therapy because relapses have been noted even after 1 year.

High-dose therapy followed by allogeneic BMT or SCT

The only consistently successful curative treatment of CML has been high-dose therapy followed by allogeneic BMT or SCT.[ 35 ] 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.[ 36 ][ 37 ] Most transplant series suggest improved survival when the procedure is performed within 1 year of diagnosis.[ 38 ][ 39 ][ 40 ][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 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 (GVHD) and fewer fevers, hospitalizations, and hospital days.[ 41 ][Level of evidence: 1iiA] Reduced-intensity conditioning allogeneic SCT is under evaluation in first or second remissions.[ 42 ] [ 43 ]

About 20% of otherwise eligible CML patients lack a suitably matched sibling donor.[ 44 ] 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.[ 44 ] A retrospective review of 2,444 patients who received myeloablative allogeneic SCT showed OS at 15 years of 88% (95% confidence interval [CI], 86%–90%) for sibling-matched transplant and of 87% (95% CI, 83%–90%) for unrelated donor transplant.[ 45 ] The cumulative incidences of relapse were 8% (95% CI, 7%–10%) for sibling-matched transplant and 2% (95% CI, 1%– 4%) for unrelated donor transplant.[ 45 ]

Although the majority of relapses occur within 5 years of transplantation, relapses have occurred for as long as 15 years after a BMT.[ 46 ] 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.[ 47 ] The risk of relapse appears to be less in patients transplanted early in disease and in patients who develop chronic GVHD.[ 37 ][ 48 ]

With the advent of imatinib, dasatinib, and nilotinib, the timing and sequence of allogeneic BMT or SCT has been cast in doubt.[ 49 ] Allogeneic SCT is the preferred choice for some patients presenting with accelerated-phase disease, for most patients with blast-phase disease, for almost all patients with a T3151 mutation resistant to ponatinib (an oral tyrosine kinase inhibitor), and for patients with complete intolerance to the pharmacologic options.[ 50 ]

In a prospective trial of 354 patients aged younger than 60 years, 123 of 135 patients with a matched, related donor underwent early allogeneic SCT while the others received interferon-based therapy and imatinib at relapse; some also underwent a matched, unrelated-donor transplant in remission.[ 51 ] With a 9-year median follow-up, survival still favored the drug treatment 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.[ 51 ][Level of evidence: 2A] Among the many unanswered questions are the following:

Clinical trials and long-term results from ongoing trials will be required before these controversies are resolved.

Tyrosine kinase inhibitor-resistant CML

For patients resistant to several tyrosine kinase inhibitors, omacetaxine mepesuccinate (a cephalotaxine, formerly known as homoharringtonine, with activity independent of BCR/ABL) has shown a hematologic response rate of 67% and a median PFS of 7 months in a small, phase II study of 46 patients.[ 52 ][Level of evidence: 3iiiDiv]

Hydroxyurea

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.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

参考文献
  1. Hochhaus A, Larson RA, Guilhot F, et al.: Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med 376 (10): 917-927, 2017.[PUBMED Abstract]
  2. 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]
  3. 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]
  4. 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]
  5. Marin D, Bazeos A, Mahon FX, et al.: Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 28 (14): 2381-8, 2010.[PUBMED Abstract]
  6. Kantarjian HM, Hochhaus A, Saglio G, et al.: Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 12 (9): 841-51, 2011.[PUBMED Abstract]
  7. Hochhaus A, Saglio G, Larson RA, et al.: Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 121 (18): 3703-8, 2013.[PUBMED Abstract]
  8. Cortes JE, Saglio G, Kantarjian HM, et al.: Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol 34 (20): 2333-40, 2016.[PUBMED Abstract]
  9. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al.: Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol 36 (3): 231-237, 2018.[PUBMED Abstract]
  10. Hughes TP, Saglio G, Kantarjian HM, et al.: Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood 123 (9): 1353-60, 2014.[PUBMED Abstract]
  11. Jabbour E, Kantarjian HM, Saglio G, et al.: Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 123 (4): 494-500, 2014.[PUBMED Abstract]
  12. Wei G, Rafiyath S, Liu D: First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J Hematol Oncol 3: 47, 2010.[PUBMED Abstract]
  13. Marin D, Ibrahim AR, Lucas C, et al.: Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol 30 (3): 232-8, 2012.[PUBMED Abstract]
  14. Branford S, Kim DW, Soverini S, et al.: Initial molecular response at 3 months may predict both response and event-free survival at 24 months in imatinib-resistant or -intolerant patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase treated with nilotinib. J Clin Oncol 30 (35): 4323-9, 2012.[PUBMED Abstract]
  15. Marin D, Hedgley C, Clark RE, et al.: Predictive value of early molecular response in patients with chronic myeloid leukemia treated with first-line dasatinib. Blood 120 (2): 291-4, 2012.[PUBMED Abstract]
  16. Neelakantan P, Gerrard G, Lucas C, et al.: Combining BCR-ABL1 transcript levels at 3 and 6 months in chronic myeloid leukemia: implications for early intervention strategies. Blood 121 (14): 2739-42, 2013.[PUBMED Abstract]
  17. Branford S, Yeung DT, Parker WT, et al.: Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood 124 (4): 511-8, 2014.[PUBMED Abstract]
  18. Baccarani M, Deininger MW, Rosti G, et al.: European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122 (6): 872-84, 2013.[PUBMED Abstract]
  19. Shanmuganathan N, Hughes TP: Molecular monitoring in CML: how deep? How often? How should it influence therapy? Blood 132 (20): 2125-2133, 2018.[PUBMED Abstract]
  20. Kantarjian HM, Larson RA, Guilhot F, et al.: Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 115 (3): 551-60, 2009.[PUBMED Abstract]
  21. Jabbour E, Cortes JE, Kantarjian HM: Suboptimal response to or failure of imatinib treatment for chronic myeloid leukemia: what is the optimal strategy? Mayo Clin Proc 84 (2): 161-9, 2009.[PUBMED Abstract]
  22. Jabbour E, Kantarjian HM, Jones D, et al.: Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 113 (10): 2154-60, 2009.[PUBMED Abstract]
  23. Cortes JE, Baccarani M, Guilhot F, et al.: Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol 28 (3): 424-30, 2010.[PUBMED Abstract]
  24. Hehlmann R, Müller MC, Lauseker M, et al.: Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol 32 (5): 415-23, 2014.[PUBMED Abstract]
  25. Castagnetti F, Palandri F, Amabile M, et al.: Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party. Blood 113 (15): 3428-34, 2009.[PUBMED Abstract]
  26. Cortes JE, Kantarjian HM, Goldberg SL, et al.: High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J Clin Oncol 27 (28): 4754-9, 2009.[PUBMED Abstract]
  27. Hehlmann R, Lauseker M, Jung-Munkwitz S, et al.: Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29 (12): 1634-42, 2011.[PUBMED Abstract]
  28. Yeung DT, Osborn MP, White DL, et al.: TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 125 (6): 915-23, 2015.[PUBMED Abstract]
  29. Jain P, Kantarjian H, Nazha A, et al.: Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities. Blood 121 (24): 4867-74, 2013.[PUBMED Abstract]
  30. Preudhomme C, Guilhot J, Nicolini FE, et al.: Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 363 (26): 2511-21, 2010.[PUBMED Abstract]
  31. Hughes TP, Ross DM: Moving treatment-free remission into mainstream clinical practice in CML. Blood 128 (1): 17-23, 2016.[PUBMED Abstract]
  32. Saussele S, Richter J, Guilhot J, et al.: Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol 19 (6): 747-757, 2018.[PUBMED Abstract]
  33. Mahon FX, Boquimpani C, Kim DW, et al.: Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Single-Group, Phase 2, Open-Label Study. Ann Intern Med 168 (7): 461-470, 2018.[PUBMED Abstract]
  34. Legros L, Nicolini FE, Etienne G, et al.: Second tyrosine kinase inhibitor discontinuation attempt in patients with chronic myeloid leukemia. Cancer 123 (22): 4403-4410, 2017.[PUBMED Abstract]
  35. 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]
  36. 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]
  37. 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]
  38. 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]
  39. Clift RA, Appelbaum FR, Thomas ED: Treatment of chronic myeloid leukemia by marrow transplantation. Blood 82 (7): 1954-6, 1993.[PUBMED Abstract]
  40. 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]
  41. 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]
  42. 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]
  43. Bacher U, Klyuchnikov E, Zabelina T, et al.: The changing scene of allogeneic stem cell transplantation for chronic myeloid leukemia--a report from the German Registry covering the period from 1998 to 2004. Ann Hematol 88 (12): 1237-47, 2009.[PUBMED Abstract]
  44. 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]
  45. Goldman JM, Majhail NS, Klein JP, et al.: Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase. J Clin Oncol 28 (11): 1888-95, 2010.[PUBMED Abstract]
  46. Maziarz R: Transplantation for CML: lifelong PCR monitoring? Blood 107 (10): 3820, 2006.[PUBMED Abstract]
  47. 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]
  48. 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]
  49. Saussele S, Lauseker M, Gratwohl A, et al.: Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood 115 (10): 1880-5, 2010.[PUBMED Abstract]
  50. O'Brien S, Berman E, Moore JO, et al.: NCCN Task Force report: tyrosine kinase inhibitor therapy selection in the management of patients with chronic myelogenous leukemia. J Natl Compr Canc Netw 9 (Suppl 2): S1-25, 2011.[PUBMED Abstract]
  51. 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]
  52. Cortes J, Digumarti R, Parikh PM, et al.: Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol 88 (5): 350-4, 2013.[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]
Accelerated-Phase CML

Treatment Options for Accelerated-Phase CML

  1. Allogeneic bone marrow transplantation or stem cell transplantation (SCT). In 132 patients with accelerated-phase chronic myelogenous leukemia (CML), a cohort study compared imatinib as first-line therapy with allogeneic SCT; with a median follow-up of 32 months, overall survival was improved using allogeneic SCT for the Sokal high-risk patients (100% vs. 17.7%; P = .008).[ 1 ][Level of evidence: 3iiiA] Sokal low- and intermediate-risk patients showed no survival differences starting with either approach. Induction of remission using a tyrosine kinase inhibitor followed by an allogeneic SCT, when feasible, is a standard approach for patients with accelerated-phase CML.[ 1 ]
  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%.[ 2 ] Other tyrosine kinase inhibitors need to be evaluated as first-line therapy in accelerated-phase CML.
  3. Interferon alpha.[ 3 ] 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.[ 3 ][ 4 ] 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.[ 4 ][Level of evidence: 3iiiA]
  4. High-dose cytarabine.[ 5 ]
  5. Hydroxyurea.
  6. Busulfan.
  7. Supportive transfusion therapy.

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

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.[ 6 ] 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.[ 6 ]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

参考文献
  1. Jiang Q, Xu LP, Liu DH, et al.: Imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in the accelerated phase. Blood 117 (11): 3032-40, 2011.[PUBMED Abstract]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
Blastic-Phase CML

Treatment Options for Blastic-Phase CML

  1. Imatinib mesylate, dasatinib, and nilotinib have demonstrated activity in patients with myeloid blast crisis and lymphoid blast crisis or Philadelphia chromosome–positive acute lymphoblastic leukemia.[ 1 ][ 2 ] Two trials of imatinib mesylate and one trial of dasatinib involving a total of 518 patients in blastic-phase chronic myelogenous leukemia (CML) confirm a hematologic response rate of 42% to 55% and a major cytogenetic response rate of 16% to 25%, but the estimated 2-year survival rate is under 28%.[ 2 ][ 3 ][ 4 ][Level of evidence: 3iiiA] Clinical trials will explore combining imatinib mesylate with other drugs to improve the prognosis of patients with blastic-phase CML.[ 5 ]
  2. A review of 477 patients in blastic phase CML treated between 1997 and 2016 at a single center showed that 72% had received previous tyrosine kinase inhibitor therapy in chronic phase before transformation.[ 6 ] The median overall survival was 12 months and the median failure-free survival was 5 months.[ 6 ][Level of evidence: 3iiiDiv] Patients who could complete an allogeneic stem cell transplant fared best, but this may have been due to selection bias.
  3. Allogeneic bone marrow transplantation (BMT) represents the only potentially curative approach in these patients. Allogeneic BMT is more effective in patients induced into a second chronic phase.
  4. Hydroxyurea as palliative therapy.
  5. High-dose cytarabine.[ 7 ]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

参考文献
  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. Saglio G, Hochhaus A, Goh YT, et al.: Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer 116 (16): 3852-61, 2010.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  5. 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]
  6. Jain P, Kantarjian HM, Ghorab A, et al.: Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients. Cancer 123 (22): 4391-4402, 2017.[PUBMED Abstract]
  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.[PUBMED Abstract]
Relapsed CML

Overt failure is defined as a loss of hematologic remission or progression to accelerated-phase or blast-crisis phase chronic myelogenous leukemia (CML) as previously defined. A consistently rising quantitative reverse–transcription polymerase chain reaction BCR/ABL level suggests relapsing disease.

In the setting of relapse or intolerance to imatinib, the use of dasatinib resulted in a 7-year major molecular response rate of 46% and an overall survival (OS) rate of 65%.[ 1 ] The incidence of drug-related pleural effusion was 28% with dasatinib in this report.

In case of treatment failure or suboptimal response, patients should undergo BCR/ABL kinase domain mutation analysis to help guide therapy with the newer tyrosine kinase inhibitors or with allogeneic transplantation.[ 2 ][ 3 ] Next-generation sequencing appears to be more sensitive than Sanger sequencing for identifying actionable mutations.[ 4 ] Mutations in the tyrosine kinase domain can confer resistance to imatinib mesylate; alternative inhibitors such as dasatinib, nilotinib, or bosutinib, higher doses of imatinib mesylate, and allogeneic stem cell transplantation (SCT) have been studied in this setting.[ 5 ][ 6 ][ 7 ][ 8 ][ 9 ][ 10 ][ 11 ][ 12 ][ 13 ][ 14 ][ 15 ][ 16 ][ 17 ] In particular, the T315I mutation marks resistance to imatinib, dasatinib, nilotinib, and bosutinib. In a phase II study with 449 patients, 60% of the 129 patients with the T315I mutation had a molecular response to ponatinib, an oral tyrosine kinase inhibitor.[ 18 ][Level of evidence: 3iiiDiv] Ponatinib also has activity in heavily pretreated-resistant CML and in a third of the patients with accelerated-phase or blast-crisis phase CML.[ 18 ][ 19 ]

In a retrospective review of 184 patients with recurrent chronic CML and the T315I mutation, patients treated with ponatinib had a higher 4-year OS rate than did patients treated with SCT (73% vs. 56%; hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.16−0.84; P = .017).[ 20 ][Level of evidence: 3iiiDiv] For patients with accelerated CML, survival was equivalent, while for patients with blast crisis, OS was worse for those who received ponatinib (HR, 2.29; 95% CI, 1.08−4.82; P = .030).[ 20 ][Level of evidence: 3iiiDiv] In a retrospective review, patients with a T315I mutation and CML that did not respond to ponatinib had a poor prognosis, with a median survival of 16 months; outcomes were best after allogeneic SCT but this could have been due to selection bias.[ 21 ][Level of evidence: 3iiiDiv]

For heavily pretreated patients with resistance to or unacceptable side effects from standard tyrosine kinase inhibitors, including those with a T315I mutation and those in whom ponatinib had failed, a major molecular response was achieved by 12 months in 48% of 141 patients in a phase I study using asciminib, an allosteric inhibitor of BCR/ABL with a unique mechanism of action.[ 22 ][Level of evidence: 3iiiDiv]

For patients resistant to several tyrosine kinase inhibitors, omacetaxine mepesuccinate (a cephalotaxine, formerly known as homoharringtonine, with activity independent of BCR/ABL) has shown a hematologic response rate of 67% and a median progression-free survival of 7 months in a small, phase II study of 46 patients.[ 23 ][Level of evidence: 3iiiDiv]

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.[ 24 ][ 25 ] 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.[ 26 ] Most patients will respond to imatinib mesylate with durable (>1 year) cytogenetic and molecular responses. (These patients had not previously received imatinib.)[ 27 ][ 28 ][ 29 ]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

参考文献
  1. Shah NP, Rousselot P, Schiffer C, et al.: Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol 91 (9): 869-74, 2016.[PUBMED Abstract]
  2. Soverini S, Hochhaus A, Nicolini FE, et al.: BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118 (5): 1208-15, 2011.[PUBMED Abstract]
  3. Parker WT, Lawrence RM, Ho M, et al.: Sensitive detection of BCR-ABL1 mutations in patients with chronic myeloid leukemia after imatinib resistance is predictive of outcome during subsequent therapy. J Clin Oncol 29 (32): 4250-9, 2011.[PUBMED Abstract]
  4. Soverini S, Bavaro L, De Benedittis C, et al.: Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study. Blood 135 (8): 534-541, 2020.[PUBMED Abstract]
  5. 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]
  6. le Coutre PD, Giles FJ, Hochhaus A, et al.: Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia 26 (6): 1189-94, 2012.[PUBMED Abstract]
  7. 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]
  8. 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]
  9. Kantarjian HM, Giles FJ, Bhalla KN, et al.: Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood 117 (4): 1141-5, 2011.[PUBMED Abstract]
  10. Kantarjian H, Cortes J, Kim DW, et al.: Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood 113 (25): 6322-9, 2009.[PUBMED Abstract]
  11. Jabbour E, Jones D, Kantarjian HM, et al.: Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations. Blood 114 (10): 2037-43, 2009.[PUBMED Abstract]
  12. Apperley JF, Cortes JE, Kim DW, et al.: Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol 27 (21): 3472-9, 2009.[PUBMED Abstract]
  13. Hughes T, Saglio G, Branford S, et al.: Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol 27 (25): 4204-10, 2009.[PUBMED Abstract]
  14. Kantarjian H, Pasquini R, Lévy V, et al.: Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer 115 (18): 4136-47, 2009.[PUBMED Abstract]
  15. Saglio G, Hochhaus A, Goh YT, et al.: Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer 116 (16): 3852-61, 2010.[PUBMED Abstract]
  16. Cortes JE, Kantarjian HM, Brümmendorf TH, et al.: Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 118 (17): 4567-76, 2011.[PUBMED Abstract]
  17. Khoury HJ, Cortes JE, Kantarjian HM, et al.: Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 119 (15): 3403-12, 2012.[PUBMED Abstract]
  18. Cortes JE, Kim DW, Pinilla-Ibarz J, et al.: A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 369 (19): 1783-96, 2013.[PUBMED Abstract]
  19. Shacham-Abulafia A, Raanani P, Lavie D, et al.: Real-life Experience With Ponatinib in Chronic Myeloid Leukemia: A Multicenter Observational Study. Clin Lymphoma Myeloma Leuk 18 (7): e295-e301, 2018.[PUBMED Abstract]
  20. Nicolini FE, Basak GW, Kim DW, et al.: Overall survival with ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome-positive leukemias with the T315I mutation. Cancer 123 (15): 2875-2880, 2017.[PUBMED Abstract]
  21. Boddu P, Shah AR, Borthakur G, et al.: Life after ponatinib failure: outcomes of chronic and accelerated phase CML patients who discontinued ponatinib in the salvage setting. Leuk Lymphoma 59 (6): 1312-1322, 2018.[PUBMED Abstract]
  22. Hughes TP, Mauro MJ, Cortes JE, et al.: Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med 381 (24): 2315-2326, 2019.[PUBMED Abstract]
  23. Cortes J, Digumarti R, Parikh PM, et al.: Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol 88 (5): 350-4, 2013.[PUBMED Abstract]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. 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]
Key References for CML

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of chronic myelogenous leukemia (CML) treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for CML. Listed after each reference are the sections within this summary where the reference is cited.

Changes to This Summary (06/24/2020)

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.

General Information About Chronic Myelogenous Leukemia (CML)

Revised text to state that clinical signs indicative of accelerated phase or blast crisis (fever, enlarged spleen, or >20% blasts in the peripheral blood) suggest the clinical utility for bone marrow testing.

Relapsed CML

Added text to state that next-generation sequencing appears to be more sensitive than Sanger sequencing for identifying actionable mutations (cited Soverini et al. as reference 4).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic myelogenous leukemia. It 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.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

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Levels of Evidence

Some of the reference citations in this 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.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Chronic Myelogenous Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/cml-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389354]

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