National Cancer Institute


Expert-reviewed information summary about the treatment of chronic myelogenous leukemia.

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).

CML Treatment

Chronic Myelogenous Leukemia Treatment

General Information About Chronic Myelogenous Leukemia (CML)

Incidence and Mortality

Estimated new cases and deaths from CML in the United States in 2017:

  • New cases: 8,950.
  • Deaths: 1,080.

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

  • Polycythemia vera.
  • Myelofibrosis.
  • Essential thrombocythemia.

(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). The Ph1 results from a reciprocal translocation between the long arms of chromosomes 9 and 22 and is demonstrable in all hematopoietic precursors. This translocation results in the transfer of the Abelson (ABL) on chromosome 9 oncogene to an area of chromosome 22 termed the breakpoint cluster region (). This, in turn, results in a fused gene and in the production of an abnormal tyrosine kinase protein that causes the disordered myelopoiesis found in CML. Furthermore, these molecular techniques can now be used to supplement cytogenetic studies to detect the presence of the 9;22 translocation in patients without a visible Ph1 (Ph1-negative).

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. Ph1-negative patients who have gene rearrangement detectable by Southern blot analysis, however, have prognoses equivalent to Ph1-positive patients.

Diagnosis

A small subset of patients have 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 fusion gene appear clinically and prognostically identical to patients with a classic Ph1; however, patients who are -negative by RT–PCR have a clinical course more consistent with chronic myelomonocytic leukemia, which is a distinct clinical entity related to myelodysplastic syndrome. Fluorescent hybridization of the translocation can be performed on the bone marrow aspirate or on the peripheral blood of patients with CML.

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

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 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).

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. Signs and symptoms commonly indicating such a change include the following:

  • Progressive leukocytosis.
  • Thrombocytosis or thrombocytopenia.
  • Anemia. (Refer to the PDQ summary on Fatigue for more information on anemia.)
  • Increasing and painful splenomegaly or hepatomegaly.
  • Fever.
  • Bone pain. (Refer to the PDQ summary on Cancer Pain for more information.)
  • 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.

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

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

Predictive models using multivariate analysis have been derived.

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.

Accelerated-phase CML

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

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.

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 (breakpoint cluster region/Abelson) translocation when previously FISH-negative.

Detection of the 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.

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 (WBC) count, splenomegaly, thrombocytosis, and identification of the (breakpoint cluster region/Abelson) translocation. The optimal front-line treatment for patients with chronic-phase CML is the subject of active clinical evaluation but involves specific inhibitors of the tyrosine kinase.

In a randomized trial comparing imatinib mesylate with interferon plus cytarabine, with 5 years' median follow-up, imatinib mesylate induced complete cytogenetic responses in more than 80% of newly diagnosed patients; in addition, the annual rate of progression to accelerated phase or blast crisis dropped from 2% to less than 1% in the fourth year on the imatinib arm.[] However, most of these continually responding patients still showed detectable evidence of the translocation by the most-sensitive measurement of reverse transcriptase–polymerase chain reaction (RT–PCR). Although evidence-based survival advantages are unavailable because of crossover in randomized trials, the overall survival (OS) rate for all patients at 5 years is 89%, with fewer than 50% of all deaths (4.5%) caused by CML.

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

Similarly, in a randomized, prospective study of 519 patients comparing dasatinib with imatinib, the rate of major molecular response at 12 months was 46% for dasatinib and 28% for imatinib ( < .0001). The rate of major molecular response at 24 months was 64% for dasatinib and 46% for imatinib ( < .0001).[] 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 on imatinib and in 5% of patients on dasatinib (not statistically different).

Although one of these two 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 newly diagnosed patients with chronic-phase CML could be any of these specific inhibitors of the tyrosine kinase.

Allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT) has also been applied with curative intent. Long-term data beyond 10 years of therapy are available, and most long-term survivors show no evidence of the translocation by any available test (e.g., cytogenetics, RT–PCR, or fluorescent hybridization [FISH]). 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. 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.[]

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

Imatinib mesylate and the newer tyrosine kinase inhibitors, along with allogeneic SCT, have contributed to a life expectancy for a newly diagnosed patient in 2013 that is only 3 life-years fewer than that of the general population.

Chronic-Phase CML

Treatment Options for Chronic-Phase CML

Targeted therapy with tyrosine kinase inhibitors

A trial randomly assigning 1,106 previously untreated patients to imatinib mesylate or to interferon plus cytarabine documented a 76% complete cytogenetic response rate with imatinib mesylate versus 14% for interferon plus cytarabine at a median follow-up of 19 months.[] 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 ( < .001). Because 90% of the combination group had switched to imatinib by 18 months (mostly because of intolerance of side effects), a survival difference may never be observed. By the 5-year median follow-up of this trial, imatinib mesylate induced complete cytogenetic response in more than 80% of the participants, with the annual rate of progression to accelerated-phase CML or blast crisis dropping from 2% in the first year to less than 1% in the fourth year. In addition, the overall survival (OS) rate for all patients at 5 years is 89%, with fewer than 50% of all deaths (4.5%) caused by CML. More than 90% of completely responding patients still show detectable evidence of the translocation, usually by reverse transcription-polymerase chain reaction (RT–PCR) or by fluorescence hybridization of progenitor cell cultures. Poor compliance is the predominant reason for inadequate molecular response to imatinib.

Tyrosine kinase inhibitors with greater potency and selectivity for 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 at 24 months was 71% and 67% for two-dose schedules of nilotinib and 44% for imatinib ( < .0001 for both comparisons).[] Progression to accelerated-phase CML or blast crisis occurred in 17 patients on imatinib (14%), but this progression only occurred in two patients (<1%, = .0003) and in five patients (1.8%, = .0089), respectively, for those patients on two-dose schedules of nilotinib. Nilotinib-treated patients had a lower rate of treatment-emergent mutations than did imatinib-treated patients.

Similarly, in a randomized, prospective study of 519 patients that compared dasatinib with imatinib, the rate of major molecular response at 12 months was 46% for dasatinib and 28% for imatinib ( < .0001). The rate of major molecular response at 24 months was 64% for dasatinib and 46% for imatinib ( < .0001).[] 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%) on imatinib and in 6 patients (2.3%) on dasatinib (not statistically different).

Although one of these two 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 show higher rates of earlier molecular response compared with imatinib; whether this will translate to improved long-term outcomes remains unclear.[] The preferred initial treatment for newly diagnosed patients with chronic-phase CML could be any of these specific inhibitors of the tyrosine kinase.

A transcript level of less than 10% in patients after 3 months of treatment with a specific tyrosine kinase inhibitor is associated with the best prognosis in terms of failure-free survival, PFS, and OS. However, in a retrospective analysis, even patients with a transcript level greater than 10% after 3 months of therapy did well when the halving time was less than 76 days. 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.

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. 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. 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 a major molecular response by 18 to 24 months and only three patients showed progression to advanced phase in these preliminary phase II results.[] 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.

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 major molecular response rate of 73% at 24 months.[] 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: ≤ 10%.
  • 6 months: ≤ 1%.
  • 12 months: ≤ 0.1%.

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 qd), dasatinib, or nilotinib indicated that patients who have better 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.

Among the many unanswered questions are the following:

  • Should the newer tyrosine kinase inhibitors 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, and imatinib more about side effects than about efficacy.
  • 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 tyrosine kinase inhibitors?

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 complete molecular remission, the question is whether therapy with tyrosine kinase inhibitors can be discontinued. A review of several retrospective reports can be summarized as follows:[]

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.

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. Patients younger than 60 years with an identical twin or with 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. Most transplant series suggest improved survival when the procedure is performed within 1 year of diagnosis.[] 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 and fewer fevers, hospitalizations, and hospital days.[] Reduced-intensity conditioning allogeneic SCT is under evaluation in first or second remissions.

About 20% of otherwise eligible CML patients lack a suitably matched sibling donor. 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. 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. 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.

Although the majority of relapses occur within 5 years of transplantation, relapses have occurred for as long as 15 years after a BMT. In a molecular analysis of 243 patients who underwent allogeneic BMT over a 20-year interval, only 15% had no detectable transcript by polymerase chain reaction (PCR) analysis. The risk of relapse appears to be less in patients transplanted early in disease and in patients who develop chronic graft-versus-host disease.

With the advent of imatinib, dasatinib, and nilotinib, the timing and sequence of allogeneic BMT or SCT has been cast in doubt. Allogeneic SCT is the preferred choice for patients presenting with accelerated-phase or blast-phase disease, for patients with a mutation (resistant to currently available tyrosine kinase inhibitors), and for patients with complete intolerance to the pharmacologic options.

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. With a 9-year median follow-up, survival still favored the drug treatment arm ( = .049), but most of the benefit was early as a result of transplant-related mortality, with the survival curves converging by 8 years.[] Among the many unanswered questions are the following:

  • Should younger eligible patients move quickly toward allogeneic SCT after induction failure by imatinib mesylate?
  • 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.

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 ) has shown a hematologic response rate of 67% and a median PFS of 7 months in a small, phase II study of 46 patients.[]

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. 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 mm, 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

Check the list of NCI-supported cancer clinical trials that are now accepting patients with chronic phase chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Accelerated-Phase CML

Treatment Options for Accelerated-Phase CML

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. (Refer to the PDQ summary on Fatigue for more information.)
  • Progressive splenomegaly.
  • Increasing leukocytosis and/or thrombocytosis.
  • Worsening anemia.

Bone marrow examination shows increasing blast cell percentage (but ≤30%) and basophilia. Additional cytogenetic abnormalities occur during the accelerated phase (trisomy 8, trisomy 19, isochromosome 17Q, p53 mutations or deletions), and the combination of hematologic progression plus additional cytogenetic abnormalities predicts for lower response rates and a shorter time-to-treatment failure on imatinib mesylate. 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.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with accelerated phase chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Blastic-Phase CML

Treatment Options for Blastic-Phase CML

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with blastic phase chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Relapsing 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 level suggests relapsing disease. For initial use of imatinib mesylate, the designation of relative failure or suboptimal response has been proposed for lack of complete hematologic remission by 3 months, no cytogenetic response by 6 months, or no major cytogenetic response by 12 months. Nilotinib and dasatinib induce such high rates of complete cytogenetic responses and major molecular responses within several months that new benchmarks are required for responsiveness. These investigators propose that a complete cytogenetic response by 3 months should define an optimal response.

In case of treatment failure or suboptimal response, patients should undergo kinase domain mutation analysis to help guide therapy with the newer tyrosine kinase inhibitors or with allogeneic transplantation. 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. In particular, the mutation marks resistance to imatinib, dasatinib, nilotinib, and bosutinib. In a phase II study with 449 patients, 60% of the 129 patients with the mutation had a molecular response to ponatinib, an oral tyrosine kinase inhibitor.[] Ponatinib also has activity in heavily pretreated-resistant CML and in a third of the patients with accelerated-phase or blast-crisis phase CML.

For patients resistant to several tyrosine kinase inhibitors, omacetaxine mepesuccinate (a cephalotaxine, formerly known as homoharringtonine, with activity independent of ) 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.[]

Infusions of buffy-coat leukocytes or isolated T cells obtained by pheresis from the bone marrow transplant donor have induced long-term remissions in more than 50% of patients who relapse following allogeneic transplant. The efficacy of this treatment is thought to be 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. Most patients will respond to imatinib mesylate with durable (>1 year) cytogenetic and molecular responses. (These patients had not previously received imatinib.)

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with relapsing chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

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.

  • Druker BJ, Guilhot F, O'Brien SG, et al.: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355 (23): 2408-17, 2006.[PUBMED Abstract]

    Cited in:

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

    • 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:

    • 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:

    • 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
    • Chronic-Phase CML
  • Kantarjian HM, Shah NP, Cortes JE, et al.: Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 119 (5): 1123-9, 2012.[PUBMED Abstract]

    Cited in:

    • Treatment Option Overview for CML
    • Chronic-Phase CML
  • Mahon FX, Réa D, Guilhot J, et al.: Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11 (11): 1029-35, 2010.[PUBMED Abstract]

    Cited in:

    • Chronic-Phase CML
  • Rousselot P, Charbonnier A, Cony-Makhoul P, et al.: Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol 32 (5): 424-30, 2014.[PUBMED Abstract]

    Cited in:

    • Chronic-Phase CML

Changes to This Summary (07/14/2017)

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

Treatment Option Overview for Chronic Myelogenous Leukemia (CML)

Revised text to state that at 5 years, there was no difference in progression-free survival (PFS) or overall survival (OS). Added that progression to accelerated-phase CML or blast crisis occurred in 7% of patients on imatinib and in 5% of patients on dasatinib (cited Cortes et al. as reference 8).

Revised text to state that although one of these two 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.

Revised text to state that allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT) has also been applied with curative intent. Added that long-term data beyond 10 years of therapy are available, and most long-term survivors show no evidence of the translocation by any available test; however, some patients 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. Also added that 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; there was no difference in 10-year OS (cited Gratwohl et al. as reference 11 and level of evidence 3iiiA).

Added text to state that imatinib mesylate and the newer tyrosine kinase inhibitors, along with allogeneic SCT, have contributed to a life expectancy for a newly diagnosed patient in 2013 that is only 3 life-years fewer than that of the general population (cited Bower et al. as reference 15).

Chronic-Phase CML

Added text to state that at 5 years, there was no difference in PFS or OS. Revised text about the progression to accelerated-phase CML or blast crisis that occurred in 13 patients on imatinib and in 6 patients on dasatinib (cited Cortes et al. as reference 9).

Revised text to state that although one of these two 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 survival for these agents similar to that for imatinib.

Added text to state that 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 major molecular response rate of 73% at 24 months (cited Yeung et al. as reference 27 and level of evidence 3iiiDiv). Also added that 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. Molecular targets were set, and failure to reach these targets prompted an increase of imatinib to 800 mg daily or a switch to nilotinib. The molecular target rates for at 3, 6, or 12 months were given.

Added text to state that 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.

Added text to answer the question of whether the newer tyrosine kinase inhibitors, dasatinib and nilotinib, should replace imatinib as front-line therapy by stating that randomized trials have failed to confirm OS differences. Also added that imatinib blood levels and timed molecular targets that informed of the need for increased doses of imatinib may make any clinical differences between nilotinib, dasatinib, and imatinib more about side effects than about efficacy.

Added text that reviewed several retrospective reports to answer the question of whether patients who obtain a complete molecular remission can discontinue therapy with tyrosine kinase inhibitors; provided three summarizations of the data (cited Hughes et al. as reference 30 and level of evidence 3iiiDiv).

Added text to state that 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.

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:

  • 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:

  • Keith W. Pratz, MD (Johns Hopkins University)
  • Eric J. Seifter, MD (Johns Hopkins University)
  • Mikkael A. Sekeres, MD, MS (Cleveland Clinic Taussig Cancer Institute)

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.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

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

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.


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