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Home > Living Well > Health Library > Chronic Myelogenous Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Incidence and Mortality
Estimated new cases and deaths from CML in the United States in 2022:
CML is one of a group of diseases called the myeloproliferative disorders. Other related entities include the following:
(Refer to the PDQ summary on Chronic Myeloproliferative Neoplasms Treatment for more information.)
Molecular Biology and Cytogenetics of CML
CML is a clonal disorder that is usually easily diagnosed because the leukemic cells of more than 95% of patients have a distinctive cytogenetic abnormality, the Philadelphia chromosome (Ph1). 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 ABL oncogene on chromosome 9 to an area of chromosome 22 termed the breakpoint cluster region (within the BCR gene). 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.
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 BCR/ABL gene rearrangement detectable by Southern blot analysis, however, have prognoses equivalent to Ph1-positive patients.[6,7]
A small subset of patients have BCR/ABL 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.
When patients are diagnosed 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.
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).
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:
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 after treatment with tyrosine kinase inhibitors:
Predictive models using multivariate analysis have been derived.[2,5,6]
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 is characterized by 10% to 19% blasts in either the peripheral blood or bone marrow.
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.
Relapsed CML is characterized by any evidence of progression of disease from a stable remission. This may include the following:
Detection of the BCR/ABL translocation by RT–PCR during prolonged remissions does not constitute relapse on its own. However, exponential drops in quantitative RT–PCR measurements for 3 to 12 months correlates with the degree of cytogenetic response, just as exponential rises may be associated with quantitative RT–PCR measurements that are closely connected with clinical relapse.
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. 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.[Level of evidence: 1iiDiii] However, most of these continually responding patients still showed detectable evidence of the BCR/ABL translocation by the most-sensitive measurement of reverse 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.
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).[Level of evidence: 1iiDiv] Progression to accelerated-phase CML or blast crisis occurred in 17 patients who received imatinib (14%), but this progression occurred in only two patients (<1%, P = .0003) and in five patients (<1.8%, P = .0089), respectively, who received two-dose schedules of nilotinib. 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.[Level of evidence: 3iiiD]
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).[Level of evidence: 1iiDiv] At 5 years, there was no difference in progression-free survival or OS. Progression to accelerated-phase CML or blast crisis occurred in 7% of patients who received imatinib and in 5% of patients who received dasatinib (not statistically different). 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.[Level of evidence: 3iiiD]
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).[Level of evidence: 1iiDiv] Progression to accelerated phase/blast crisis occurred in four patients (1.6%) who received bosutinib and in six patients (2.5%) who received imatinib.
Although one of these 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.
Allogeneic bone marrow transplantation (BMT) or stem cell transplantation (alloSCT) 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 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. 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.[Level of evidence: 3iiiA] Similar outcomes were seen in patients who underwent alloSCT because of TKI intolerance or nonadherence.
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. Maintenance of therapy with interferon is required, however, and some patients experience side effects that preclude continued treatment.
Treatment Options for Chronic-Phase CML
Targeted therapy with tyrosine kinase inhibitors (TKIs)
Abbreviations used in this section for response rate are defined in Table 1.
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.[Level of evidence: 1iiDiii] At 18 months, 96.7% of the imatinib group had avoided progression to accelerated-phase chronic myelogenous leukemia (CML) or blast crisis compared with 91.5% of the interferon plus cytarabine group (P < .001). Because 90% of the combination group had switched to imatinib by 18 months (mostly because of intolerance of side effects), a survival difference may never be observed. The overall survival (OS) rate for all patients at 10 years was 83.3%, with fewer than 50% of all deaths (4.5%) caused by CML. 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.
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).[Level of evidence: 1iiDiv] Progression to accelerated-phase CML or blast crisis occurred in 17 patients on imatinib (14%), but this progression only occurred in two patients (<1%, P = .0003) and in five patients (1.8%, P = .0089), respectively, for those patients on two-dose schedules of nilotinib. Nilotinib-treated patients had a lower rate of treatment-emergent BCR/ABL mutations than imatinib-treated patients. 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.[Level of evidence: 3iiiD]
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).[Level of evidence: 1iiDiv] At 5 years, there was no difference in progression-free survival (PFS) or OS. Progression to accelerated-phase CML or blast crisis occurred in 13 patients (5%) who received imatinib and in 6 patients (2.3%) who received dasatinib (not statistically different). 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.[Level of evidence: 3iiiD]
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).[Level of evidence: 1iiDiv] Progression to accelerated phase/blast crisis occurred in four patients (1.6%) who received bosutinib and in six patients (2.5%) who received imatinib.
Although one of these 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: 1iiDiv] The preferred initial treatment for patients with newly diagnosed chronic-phase CML could be any of these specific inhibitors of the BCR/ABL tyrosine kinase.
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. 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. 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%.
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: 3iiiDiv] Until randomized studies are performed, it is unclear whether the increased response with increased dosage will translate into longer durations of response or survival advantages.[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.[Level of evidence: 3iiiDiv] All patients started treatment with imatinib and were given 600 mg daily. Imatinib plasma trough levels that were under 1,000 ng/mL on day 22 prompted an increase of imatinib to 800 mg daily (20% of patients). Molecular targets were set, and failure to reach these targets prompted an increase of imatinib to 800 mg daily (if not already performed) or a switch to nilotinib. The molecular targets were as follows:
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.
Among the many unanswered questions are the following:
All of these issues have led to an active reappraisal of recommendations for optimal front-line therapy for chronic-phase CML.
For patients who obtain a DMR, the question is whether therapy with TKIs can be discontinued. Several nonrandomized reports can be summarized as follows:[35,36,37,38,39][Level of evidence: 3iiiDiv]
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: 3iiiA] The data supporting early transplant, however, have never been confirmed in controlled trials. In a randomized clinical trial, disease-free survival and OS were comparable when allogeneic transplantation followed preparative therapy with cyclophosphamide and total-body irradiation (TBI) or busulfan and cyclophosphamide without TBI. The latter regimen was associated with less graft-versus-host disease (GVHD) and fewer fevers, hospitalizations, and hospital days.[Level of evidence: 1iiA]
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 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. 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 BCR/ABL transcript by PCR analysis. 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. 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. Similar outcomes were seen in patients who underwent alloSCT due to TKI intolerance or nonadherence.
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. 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.[Level of evidence: 2A] There are the following unanswered questions:
Clinical trials and long-term results from ongoing trials will be required before these controversies are resolved.
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.[Level of evidence: 3iiiDiv]
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 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.
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:
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. 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.
Treatment Options for Blastic-Phase 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%. 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. 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]
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.[Level of evidence: 3iiiDiv] 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).[Level of evidence: 3iiiDiv] For patients with accelerated CML, survival was equivalent, while for patients with blast crisis, OS was worse for those who received ponatinib (HR, 2.29; 95% CI, 1.08−4.82; P = .030).[Level of evidence: 3iiiDiv] In a retrospective review, patients with a T315I mutation and CML that did not respond to ponatinib had a poor prognosis, with a median survival of 16 months; outcomes were best after alloSCT but this could have been due to selection bias.[Level of evidence: 3iiiDiv]
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.[Level of evidence: 3iiiDiv]
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.[Level of evidence: 3iiiDiv] 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.[Level of evidence: 3iiiDiv]
Infusions of buffy-coat leukocytes or isolated T cells obtained by pheresis from the bone marrow transplant donor have induced long-term remissions in more than 50% of patients who relapse following allogeneic transplant.[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. 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]
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.
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 2022 (cited American Cancer Society as reference 1).
Treatment Option Overview for CML
Revised text to state that at 5 to 10 years of follow-up, patients who received nilotinib, dasatinib, and bosutinib had similar survival to those who received imatinib.
Treatment of Chronic-Phase CML
Revised text to state that 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 major molecular response compared with imatinib; whether this will translate to improved long-term outcomes remains unclear.
Revised text to state that 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 (cited Hochhaus et al. and Gambacorti-Passerini et al. as references 27 and 28, respectively).
Revised text to state employing front-line imatinib is an alternative to the immediate use of more-potent tyrosine kinase inhibitors (TKIs), such as nilotinib, dasatinib, or bosutinib.
Revised text to state that 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.
Treatment of Accelerated-Phase CML
Added text to state that bosutinib is a treatment option for accelerated-phase CML. Bosutinib was given U.S. Food and Drug Administration clearance as a first-line treatment for patients with accelerated-phase CML on the basis of initial phase I/II trial results that showed improved efficacy versus imatinib (cited Gambacorti-Passerini et al. as reference 1).
Treatment of Blastic-Phase CML
Revised text to state that 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 (cited Gambacorti-Passerini et al. as reference 3).
Treatment of Relapsed CML
Added text about the mechanism of action, required doses, toxicities, and patient outcomes of asciminib. 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 (cited Garcia-Gutiérrez et al. as reference 23 and level of evidence 3iiiDiv).
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.
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:
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:
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 <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/cml-treatment-pdq. Accessed <MM/DD/YYYY>. [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.
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.
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.
Last Revised: 2022-01-21
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