Chronic Myelogenous Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Chronic Myelogenous Leukemia (CML)

Incidence and Mortality

Estimated new cases and deaths from CML in the United States in 2023:[1]

• New cases: 8,930.
• Deaths: 1,310.

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

• Polycythemia vera.
• Myelofibrosis.
• Essential thrombocythemia.

For more information, see Chronic Myeloproliferative Neoplasms Treatment.

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] The Ph1 results from a reciprocal translocation between the long arms of chromosomes 9 and 22 and is demonstrable in all hematopoietic precursors.[3] 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).[3] 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 for all newly diagnosed patients 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.[4]

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

Diagnosis

A small subset of patients have BCR/ABL rearrangement 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, which is a distinct clinical entity related to myelodysplastic syndrome.[6,8,9] Fluorescence in situ hybridization of the BCR/ABL translocation can be performed on the bone marrow aspirate or on the peripheral blood of patients with CML.[10]

When patients are diagnosed with CML, splenomegaly is the most common finding on physical examination.[10] 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.[11] 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.

References:

1. American Cancer Society: Cancer Facts and Figures 2023. American Cancer Society, 2023. Available online. Last accessed January 13, 2023.
2. Jabbour E, Kantarjian H: Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring. Am J Hematol 95 (6): 691-709, 2020.
3. Deininger MW, Goldman JM, Melo JV: The molecular biology of chronic myeloid leukemia. Blood 96 (10): 3343-56, 2000.
4. 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.
5. Onida F, Ball G, Kantarjian HM, et al.: Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia. Cancer 95 (8): 1673-84, 2002.
6. Martiat P, Michaux JL, Rodhain J: Philadelphia-negative (Ph-) chronic myeloid leukemia (CML): comparison with Ph+ CML and chronic myelomonocytic leukemia. The Groupe Français de Cytogénétique Hématologique. Blood 78 (1): 205-11, 1991.
7. Cortes JE, Talpaz M, Beran M, et al.: Philadelphia chromosome-negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Long-term follow-up results. Cancer 75 (2): 464-70, 1995.
8. Oscier DG: Atypical chronic myeloid leukaemia, a distinct clinical entity related to the myelodysplastic syndrome? Br J Haematol 92 (3): 582-6, 1996.
9. Kurzrock R, Bueso-Ramos CE, Kantarjian H, et al.: BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol 19 (11): 2915-26, 2001.
10. Jabbour E, Kantarjian H: Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol 87 (11): 1037-45, 2012.
11. Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic myelogenous leukemia: playing the odds. J Clin Oncol 16 (9): 2897-903, 1998.

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 transcription–polymerase chain reaction (RT–PCR) or fluorescence in situ hybridization (FISH) 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] Signs and symptoms commonly indicating such a change include the following:

• Progressive leukocytosis.
• Thrombocytosis or thrombocytopenia.
• Anemia. For more information, see Fatigue.
• Increasing and painful splenomegaly or hepatomegaly.
• Fever.
• Bone pain. For more information, see Cancer Pain.
• Development of destructive bone lesions.
• Thrombotic or bleeding complications.

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

Studies have suggested that certain presenting features have prognostic significance. The following are predictive of a shorter chronic phase after treatment with tyrosine kinase inhibitors:

• Older age.[3]
• Cytogenetic abnormalities in addition to the Ph1.[3,4]
• A higher proportion of marrow or peripheral blood blasts.[3]
• Anemia.[3]

Predictive models using multivariate analysis have been derived.[2,5,6]

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.[7]

Accelerated-phase CML

Accelerated-phase CML is characterized by 10% to 19% blasts in either the peripheral blood or bone marrow.[7]

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.[7]

Relapsing CML

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

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

Detection of the BCR/ABL translocation by RT–PCR during prolonged remissions does not constitute relapse on its own. However, exponential drops in quantitative RT–PCR measurements for 3 to 12 months correlates with the degree of cytogenetic response, just as exponential rises may be associated with quantitative RT–PCR measurements that are closely connected with clinical relapse.[8]

References:

1. Jabbour E, Kantarjian H: Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol 87 (11): 1037-45, 2012.
2. Sokal JE, Baccarani M, Russo D, et al.: Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 25 (1): 49-61, 1988.
3. Lauseker M, Bachl K, Turkina A, et al.: Prognosis of patients with chronic myeloid leukemia presenting in advanced phase is defined mainly by blast count, but also by age, chromosomal aberrations and hemoglobin. Am J Hematol 94 (11): 1236-1243, 2019.
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.
5. 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.
6. 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.
7. 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.
8. 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.

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 a median follow-up of 10.9 years, 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 B1] However, most of these continually responding patients still showed detectable evidence of the BCR/ABL translocation by the most-sensitive measurement of reverse transcription–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 (TKIs) 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 B3] 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] A phase II study of 122 patients who received nilotinib (400 mg twice daily) showed a 10-year event-free survival (EFS) rate of 85% and a 10-year OS rate of 88% after a median follow-up of 78 months.[7][Level of evidence C2]

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).[8][Level of evidence B3] 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).[8] A phase II study of 149 patients who received dasatinib (100 mg daily) showed a 10-year EFS rate of 86% and a 10-year OS rate of 89% after a median follow-up of 78 months.[9][Level of evidence C2]

In a randomized prospective study of 536 patients that compared bosutinib with imatinib, the MMR rate at 12 months was 47.2% in the bosutinib arm versus 36.9% in the imatinib arm (P = .0075).[10][Level of evidence B3] 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 studies showed statistically significant decreased rates of progression to accelerated or blastic phase, at 5 to 10 years of follow-up, patients who received nilotinib, dasatinib, and bosutinib had similar survival to those who received 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.[11]

Allogeneic bone marrow transplantation (BMT) or stem cell transplantation (alloSCT) has also been applied with curative intent.[12] 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 fluorescence 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.[12] In a prospective trial of 427 transplant-eligible, previously untreated patients, 166 patients were allocated to alloSCT, and 261 patients were allocated to drug treatment (mostly imatinib); there was no difference in 10-year OS.[13][Level of evidence C1] Similar outcomes were seen in patients who underwent alloSCT because of TKI intolerance or nonadherence.[14]

Long-term data are also available for patients treated with interferon alpha.[15,16,17] 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.[12] Maintenance of therapy with interferon is required, however, and some patients experience side effects that preclude continued treatment.

References:

1. Jabbour E, Kantarjian H: Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol 87 (11): 1037-45, 2012.
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.
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.
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.
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.
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.
7. Masarova L, Cortes JE, Patel KP, et al.: Long-term results of a phase 2 trial of nilotinib 400 mg twice daily in newly diagnosed patients with chronic-phase chronic myeloid leukemia. Cancer 126 (7): 1448-1459, 2020.
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.
9. Maiti A, Cortes JE, Patel KP, et al.: Long-term results of frontline dasatinib in chronic myeloid leukemia. Cancer 126 (7): 1502-1511, 2020.
10. 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.
11. Wei G, Rafiyath S, Liu D: First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J Hematol Oncol 3: 47, 2010.
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.
13. 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.
14. Wu J, Chen Y, Hageman L, et al.: Late mortality after bone marrow transplant for chronic myelogenous leukemia in the context of prior tyrosine kinase inhibitor exposure: A Blood or Marrow Transplant Survivor Study (BMTSS) report. Cancer 125 (22): 4033-4042, 2019.
15. 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.
16. 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.
17. 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.

Treatment of Chronic-Phase CML

Treatment Options for Chronic-Phase CML

1. Targeted therapy with tyrosine kinase inhibitors (TKIs).
2. High-dose therapy followed by allogeneic bone marrow transplant (BMT) or stem cell transplantation (alloSCT).
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 (TKIs)

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

Table 1. Response Rate Definitions

Abbreviation	Definition
a Previously 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 B1] 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 was 83.3%, with fewer than 50% of all deaths (4.5%) caused by CML.[1] More than 90% of completely responding patients still showed 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]

TKIs 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 B3] 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 imatinib-treated patients.[7] A phase II study of 122 patients who received nilotinib (400 mg twice daily) showed a 10-year event-free survival (EFS) rate of 85% and a 10-year OS rate of 88% after a median follow-up of 78 months.[8][Level of evidence C2]

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).[9][Level of evidence B3] 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).[9] A phase II study of 149 patients who received dasatinib (100 mg daily) showed a 10-year EFS rate of 86% and a 10-year OS rate of 89% after a median follow-up of 78 months.[10][Level of evidence C2]

In a randomized prospective study of 536 patients that compared bosutinib with imatinib, the MMR rate at 12 months was 47.2% in the bosutinib arm versus 36.9% in the imatinib arm (P = .0075).[11][Level of evidence B3] 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 studies showed statistically significant decreased rates of progression to accelerated- or blastic-phase CML, at 5 to 10 years of follow-up, patients who received nilotinib, dasatinib, and bosutinib had similar survival to those who received imatinib. In randomized prospective trials, nilotinib, dasatinib, and bosutinib showed higher rates of earlier MMR compared with imatinib; whether this will translate to improved long-term outcomes remains unclear.[11,12,13][Level of evidence B3] 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.[14]

A BCR/ABL transcript level of less than 10% in patients after 3 months of treatment with a specific TKI (deemed early molecular response [EMR]) is associated with the best prognosis in terms of failure-free survival, PFS, and OS.[12,13,15,16,17,18] 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.[19] 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.[20] 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%.[21]

Higher doses of imatinib mesylate, alternative TKIs (such as dasatinib, nilotinib, or bosutinib), and alloSCT are implemented for suboptimal response or progression and are under clinical evaluation as front-line approaches.[22,23,24,25,26,27,28] 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, nilotinib, or bosutinib.[23,24,27,28] 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.[29,30][Level of evidence C3] 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.[25,31]

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 rate of 96% and transformation-free survival of 95%, with a confirmed MMR rate of 73% at 24 months.[32][Level of evidence C3] 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:

• 3 months: BCR/ABL ≤ 10% (defined as EMR).
• 6 months: BCR/ABL ≤ 1%.
• 12 months: BCR/ABL ≤ 0.1% (defined as MMR).

Employing front-line imatinib is an alternative to the immediate use of more-potent TKIs, such as nilotinib, dasatinib, or bosutinib.

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 EFS, transformation-free, and OS rates compared with patients who have better early cytogenetic responses.[33]

Among the many unanswered questions are the following:

• Should the newer TKIs, dasatinib and nilotinib, replace imatinib as front-line therapy? Randomized trials have failed to confirm OS differences. Imatinib blood levels and timed molecular targets that informed the need for increased doses of imatinib may make any clinical differences between nilotinib, dasatinib, bosutinib, and imatinib more about side effects and costs than about efficacy.[32]
• Does time-to-response matter if a good response is obtained eventually?
• Does a good response in a high-risk patient overcome the adverse prognosis of the high-risk features?
• Should other active agents be added to therapy with TKIs?[34]

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 TKIs can be discontinued. Several nonrandomized reports can be summarized as follows:[35,36,37,38,39][Level of evidence C3]

1. Patients who have taken a TKI 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 TKI is discontinued.
3. Almost all patients who progress by BCR/ABL RT−PCR quantitative testing can be successfully reinduced with the previous TKI.

However, the duration of remissions after a successful reinduction with a previous TKI or the depth of subsequent responses with reinduction of a previous TKI is not known. At this time, there are insufficient data to recommend routinely stopping TKIs, 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 allogeneic BMT or alloSCT.[40,41,42] 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.[43,44] Most transplant series suggest improved survival when the procedure is performed within 1 year of diagnosis.[45,46,47][Level of evidence C1] 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.[48][Level of evidence A1]

About 20% of otherwise eligible CML patients lack a suitably matched sibling donor.[49] 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.[49] A retrospective review of 2,444 patients who received myeloablative alloSCT showed 15-year OS rates of 88% (95% confidence interval [CI], 86%–90%) for sibling-matched transplant and 87% (95% CI, 83%–90%) for unrelated donor transplant.[50] 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.[50]

Although the majority of relapses occur within 5 years of transplantation, relapses have occurred for as long as 15 years after a BMT.[51] 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.[52] The risk of relapse appears to be less in patients transplanted early in disease and in patients who develop chronic GVHD.[44,53]

With the advent of imatinib, dasatinib, and nilotinib, the timing and sequence of allogeneic BMT or alloSCT has been cast in doubt.[54] AlloSCT 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 T315I mutation resistant to ponatinib (an oral TKI), and for patients with complete intolerance to the pharmacologic options.[55] Similar outcomes were seen in patients who underwent alloSCT due to TKI intolerance or nonadherence.[56]

In a prospective trial of 354 patients aged younger than 60 years, 123 of 135 patients with a matched, related donor underwent early alloSCT while the others received interferon-based therapy and imatinib at relapse; some also underwent a matched, unrelated-donor transplant in remission.[57] 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.[57][Level of evidence B4] There are the following unanswered questions:

• Should younger eligible patients move quickly toward alloSCT after induction failure by several TKIs?
• Does the substantial toxicity and mortality of allogeneic transplantation render its early use obsolete?

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

TKI-resistant CML

For patients resistant to several TKIs, 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.[58][Level of evidence C3]

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.[59] 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.

References:

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.
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.
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.
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.
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.
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.
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.
8. Masarova L, Cortes JE, Patel KP, et al.: Long-term results of a phase 2 trial of nilotinib 400 mg twice daily in newly diagnosed patients with chronic-phase chronic myeloid leukemia. Cancer 126 (7): 1448-1459, 2020.
9. 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.
10. Maiti A, Cortes JE, Patel KP, et al.: Long-term results of frontline dasatinib in chronic myeloid leukemia. Cancer 126 (7): 1502-1511, 2020.
11. 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.
12. 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.
13. 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.
14. Wei G, Rafiyath S, Liu D: First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J Hematol Oncol 3: 47, 2010.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. Shanmuganathan N, Hughes TP: Molecular monitoring in CML: how deep? How often? How should it influence therapy? Blood 132 (20): 2125-2133, 2018.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. Hochhaus A, Gambacorti-Passerini C, Abboud C, et al.: Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study. Leukemia 34 (8): 2125-2137, 2020.
28. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al.: Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica 103 (8): 1298-1307, 2018.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. 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.
35. 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.
36. 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.
37. 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.
38. Chamoun K, Kantarjian H, Atallah R, et al.: Tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia: a single-institution experience. J Hematol Oncol 12 (1): 1, 2019.
39. Atallah E, Schiffer CA, Radich JP, et al.: Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial. JAMA Oncol 7 (1): 42-50, 2021.
40. 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.
41. 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.
42. 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.
43. 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.
44. 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.
45. 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.
46. Clift RA, Appelbaum FR, Thomas ED: Treatment of chronic myeloid leukemia by marrow transplantation. Blood 82 (7): 1954-6, 1993.
47. 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.
48. 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.
49. 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.
50. 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.
51. Maziarz R: Transplantation for CML: lifelong PCR monitoring? Blood 107 (10): 3820, 2006.
52. 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.
53. 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.
54. 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.
55. 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.
56. Wu J, Chen Y, Hageman L, et al.: Late mortality after bone marrow transplant for chronic myelogenous leukemia in the context of prior tyrosine kinase inhibitor exposure: A Blood or Marrow Transplant Survivor Study (BMTSS) report. Cancer 125 (22): 4033-4042, 2019.
57. 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.
58. 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.
59. 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.

Treatment of Accelerated-Phase CML

Treatment Options for Accelerated-Phase CML

1. Bosutinib. Bosutinib was given U.S. Food and Drug Administration clearance as a first-line treatment for patients with accelerated-phase chronic myelogenous leukemia (CML). These patients were included in the initial phase I/II trial that showed improved efficacy versus imatinib, on the basis of response rates and major molecular response at 5 years of follow-up.[1]
2. Allogeneic bone marrow transplantation or stem cell transplantation (alloSCT). In 132 patients with accelerated-phase CML, a cohort study compared imatinib as first-line therapy with alloSCT; with a median follow-up of 32 months, overall survival rate was improved using alloSCT for the Sokal high-risk patients (100% vs. 17.7%; P = .008).[2][Level of evidence C1] 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 alloSCT, when feasible, is a standard approach for patients with accelerated-phase CML.[2]
3. Imatinib mesylate. Among 176 patients with accelerated-phase CML, the complete hematologic response rate was 82%, and the complete cytogenetic response rate was 43%; with a median follow-up of 41 months, the estimated 4-year survival rate was 53%.[3] Other tyrosine kinase inhibitors need to be evaluated as first-line therapy in accelerated-phase CML.
4. Interferon alpha.[4] 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.[4,5] 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.[5][Level of evidence C1]
5. High-dose cytarabine.[6]
6. Hydroxyurea.
7. Busulfan.

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

• Increasing fatigue and malaise. For more information, see Fatigue.
• Progressive splenomegaly.
• Increasing leukocytosis and/or thrombocytosis.
• Worsening anemia.

Bone marrow examination shows increasing blast cell percentage (but ≤30%) and basophilia. Additional cytogenetic abnormalities occur during the accelerated phase (trisomy 8, trisomy 19, isochromosome 17Q, TP53 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.[7] 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.[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.

References:

1. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al.: Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica 103 (8): 1298-1307, 2018.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.

Treatment of Blastic-Phase CML

Treatment Options for Blastic-Phase CML

1. Imatinib mesylate, dasatinib, nilotinib, and bosutinib have demonstrated activity in patients with myeloid blast crisis and lymphoid blast crisis or Philadelphia chromosome–positive acute lymphoblastic leukemia.[1,2,3] 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%.[2,4,5][Level of evidence C1] Clinical trials will explore combining imatinib mesylate with other drugs to improve the prognosis of patients with blastic-phase CML.[6]
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.[7] The median overall survival was 12 months and the median failure-free survival was 5 months.[7][Level of evidence C3] 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.[8]

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.

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. 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.
3. Gambacorti-Passerini C, Cortes JE, Lipton JH, et al.: Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica 103 (8): 1298-1307, 2018.
4. 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.
5. 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.
6. 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.
7. 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.
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.

Treatment of 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 (TKIs) 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 (alloSCT) have been studied in this setting.[5,6,7,8,9,10,11,12,13,14,15,16,17]

Ponatinib

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 TKI.[18][Level of evidence C3] Ponatinib also has activity in heavily pretreated-resistant CML and in one-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 C3] 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 C3] 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 alloSCT but this could have been due to selection bias.[21][Level of evidence C3]

Asciminib

For heavily pretreated patients with resistance to or unacceptable side effects from standard TKIs, 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 C3]

Asciminib mimics myristate to function as an allosteric inhibitor with a different mechanism of action than other TKIs. Higher doses are required for efficacy in the presence of the T315I mutation in the tyrosine kinase domain. Grade 3 or 4 toxicities include hypertension, cytopenias, and pancreatitis. Asciminib has been approved by the U.S. Food and Drug Administration for patients who received two previous TKIs. A trial of 31 patients in Spain showed a 41% MMR rate by 12 months.[23][Level of evidence C3] Three of nine patients with disease that failed to respond to previous ponatinib responded to asciminib.

For patients resistant to several TKIs, 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.[24][Level of evidence C3]

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.[25,26] 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 alloSCT, some patients will also respond to interferon alpha.[27] Most patients will respond to imatinib mesylate with durable (>1 year) cytogenetic and molecular responses. (These patients had not previously received imatinib.)[28,29,30]

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.

References:

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
23. Garcia-Gutiérrez V, Luna A, Alonso-Dominguez JM, et al.: Safety and efficacy of asciminib treatment in chronic myeloid leukemia patients in real-life clinical practice. Blood Cancer J 11 (2): 16, 2021.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.

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.

• Hughes TP, Saglio G, Kantarjian HM, et al.: Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with front-line nilotinib or imatinib. Blood 123 (9): 1353-60, 2014. [PUBMED Abstract]

  Cited in:

  • Treatment of Chronic-Phase CML
• 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]

  Cited in:

  • Treatment of Chronic-Phase CML
• 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]

  Cited in:

  • Treatment of Chronic-Phase CML
• 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]

  Cited in:

  • Treatment Option Overview for CML
  • Treatment of Chronic-Phase CML

Changes to This Summary (01 / 20 / 2023)

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)

Updated statistics with estimated new cases and deaths for 2023 (cited American Cancer Society as reference 1).

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® Cancer Information for Health Professionals 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 in the care of their 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:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

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.

The lead reviewers for Chronic Myelogenous Leukemia Treatment are:

• Aaron Gerds, MD
• Eric J. Seifter, MD (Johns Hopkins University)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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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Last Revised: 2023-01-20