Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells. CML accounts for 20% of all leukemias affecting adults. See the image below.
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Chronic myelogenous leukemia. Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. C....
See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, to help detect chronic leukemias and determine the specific type present.
Signs and symptoms
The clinical manifestations of CML are insidious, changing somewhat as the disease progresses through its 3 phases (chronic, accelerated, and blast). Patients in the chronic phase may be asymptomatic or may display any of the following signs and symptoms:
Fatigue, weight loss, loss of energy, decreased exercise tolerance
Low-grade fever and excessive sweating from hypermetabolism
Elevated white blood cell (WBC) count or splenomegaly on routine assessment
Early satiety and decreased food intake from encroachment on stomach by enlarged spleen
Left upper quadrant abdominal pain from spleen infarction
Hepatomegaly
The following are signs and symptoms of progressive disease:
Bleeding, petechiae, and ecchymoses during the accelerated phase
Bone pain and fever in the blast phase
Increasing anemia, thrombocytopenia, basophilia, and a rapidly enlarging spleen in blast crisis
See Presentation for more detail.
Diagnosis
The diagnosis of CML is based on the following:
Histopathologic findings in the peripheral blood
Philadelphia chromosome (Ph1) in bone marrow cells
The workup for CML consists of the following:
CBC with differential
Peripheral blood smear
Bone marrow analysis
Blood count and peripheral smear findings
Total WBC count 20,000-60,000 cells/μL, with mildly increased basophils and eosinophils
Mild to moderate anemia, usually normochromic and normocytic
Platelet counts low, normal, or increased
Leukocyte alkaline phosphatase stains very low to absent in most cells
Leukoerythroblastosis, with circulating immature cells from the bone marrow
Early myeloid cells (eg, myeloblasts, myelocytes, metamyelocytes, nucleated red blood cells)
Bone marrow findings
Ph1 (a reciprocal translocation of chromosomal material between chromosomes 9 and 22)
BCR-ABL mutation
Hypercellularity, with expansion of the myeloid cell line (eg, neutrophils, eosinophils, basophils) and its progenitor cells
Megakaryocytes are prominent and may be increased
Mild fibrosis in the reticulin stain
See Workup for more detail.
Management
Goals of treatment of CML include the following:
Hematologic remission (normal CBC and physical examination [ie, no organomegaly])
Cytogenetic remission (normal chromosome returns with 0% Ph1-positive cells)
Molecular remission (negative polymerase chain reaction [PCR] result for BCR-ABL mRNA
Tyrosine kinase inhibitors (TKIs) for CML
Imatinib (Gleevec): For Ph+ chronic, accelerated, and blastic phases
Dasatinib (Sprycel): For newly diagnosed chronic phase, and chronic, accelerated, or myeloid or lymphoid blast phase with resistance or intolerance to prior therapy including imatinib
Nilotinib (Tasigna): For newly diagnosed chronic phase, and chronic or accelerated phase with resistance to or intolerance of prior therapy that included imatinib
Bosutinib (Bosulif): For newly diagnosed chronic phase, and chronic, accelerated, or blast phase with resistance to or intolerance of prior therapy that included imatinib
Ponatinib (Iclusig): For chronic phase patients with resistance or intolerance to at least 2 prior kinase inhibitors, for accelerated or blast phase patients in whom no other TKI therapy is tolerated or indicated, and for BCR-ABL T315I–positive chronic, acclerated, or blast phase CML
Asciminib (Scemblix): For chronic phase cases that are BCR-ABL T315I positive or that were previously treated with 2 or more TKIs
Other medications for CML
Interferon-alfa: Former first-line agent; now combined with newer drugs for refractory cases
Hydroxyurea (Hydrea): Myelosuppressive agent for inducing hematologic remission
Busulfan: Myelosuppressive agent for inducing hematologic remission
Omacetaxine (Synribo): Protein translation inhibitor indicated for chronic- or accelerated-phase CML with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors
Allogeneic bone marrow transplantation (BMT) or stem cell transplantation
Only proven cure for CML
Ideally performed in the chronic phase
Candidate patients should be offered the procedure if they have a matched or single–antigen-mismatched related donor available
Overall survival for allogeneic BMT with matched unrelated donors ranges from 31% to 43% for patients younger than 30 years and from 14% to 27% for older patients
Currently relegated to patients who do not achieve molecular remissions or show resistance to imatinib and failure of second-generation tyrosine kinase inhibitors (eg, dasatinib)
Patients with minimal residual disease after transplantation require interferon maintenance therapy or donor lymphocyte infusion
Supportive treatment
Leukapheresis for white blood cell counts greater than 300,000 cells/µL
CML is one of the few cancers known to be caused by a single, specific genetic mutation. More than 90% of cases result from a cytogenetic aberration known as the Philadelphia chromosome (see Pathophysiology).
CML progresses through three phases: chronic, accelerated, and blast. In the chronic phase of disease, mature cells proliferate; in the accelerated phase, additional cytogenetic abnormalities occur; in the blast phase, immature cells rapidly proliferate.[1, 2] Approximately 85% of patients are diagnosed in the chronic phase and then progress to the accelerated and blast phases after 3-5 years. The diagnosis of CML is based on the histopathologic findings in the peripheral blood and the Philadelphia chromosome in bone marrow cells (see Workup).
CML accounts for 20% of all leukemias affecting adults. It typically affects middle-aged individuals. Uncommonly, the disease occurs in younger individuals. Younger patients may present with a more aggressive form of CML, such as in accelerated phase or blast crisis. Uncommonly, CML may appear as a disease of new onset in elderly individuals.
The goals of treatment are to achieve hematologic, cytogenetic, and molecular remission. Although a variety of medications have been used in CML, including myelosuppressive agents and interferon alfa, tyrosine kinase inhibitors (TKIs), starting with the first-generation TKI imatinib, have become the agents of choice in CML. They are playing increasingly important roles in inducing complete remission, which can allow cessation of therapy and excellent response if disease returns. TKIs are slowly replacing allogeneic hematopoietic stem cell transplantation as a proven cure for CML. (See Treatment.)
CML is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9 [t(9;22)]. The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph1) chromosome after the city of discovery. (See the image below.)
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The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chr....
This translocation relocates an oncogene called ABL from the long arm of chromosome 9 to a specific breakpoint cluster region (BCR) in the long arm of chromosome 22. The ABL oncogene encodes a tyrosine protein kinase. The resulting BCR-ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The expression of this protein leads to the development of the CML phenotype, through processes that are not yet fully understood.[3, 4, 5, 6, 7, 8, 9, 10, 2]
The presence of BCR-ABL rearrangement is the hallmark of CML, although this rearrangement has also been described in other diseases. It is considered diagnostic when present in a patient with clinical manifestations of CML.
The initiating factor of CML is still unknown, but exposure to ionizing radiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki. Other agents, such as benzene, are possible causes.
The American Cancer Society (ACS) estimates that 8930 new cases of CML will be diagnosed in 2023, 5190 in males and 3740 in females. The ACS estimates that 1220 deaths from CML will occur in 2022, 670 in males and 550 in females.[11]
Incidence and mortality rates for CML did not change significantly over 2009–2019; based on 2016–2020 data, the age-adjusted rate of new cases was 1.9 per 100,000 population per year, and the death rate was 0.3 per 100,000 population per year.[12]
Historically, the median survival of patients with CML was 3-5 years from the time of diagnosis. Currently, patients with CML have a median survival of 5 or more years. The 5-year survival rate has more than doubled, from 31% in the early 1990s to 70.6% for patients diagnosed from 2013 to 2019.[11, 12] The improvement has resulted from earlier diagnosis, therapy with targeted drugs and hematopoietic stem cell transplantation (HSCT), and better supportive care.
The outlook is even more favorable for patients with CML in the chronic phase who receive TKI therapy, because these agents often prevent progression to accelerated and blast crisis. For example, in the IRIS trial of the first TKI, imatinib, the estimated overall survival of patients who received imatinib as initial therapy was 89% at five years; only an estimated 7% of patients progressed to accelerated-phase CML or blast crisis.[13] The second-generation TKIs dasatinib, nilotinib, and bosutinib have proved significantly more effective than imatinib,[14, 15, 16] and the third-generation TKIs ponatinib and asciminib provide a second-line option for cases resistant to other therapies.[17, 18]
In the accelerated phase, survival rates vary widely according to treatment. If the patient responds well to TKIs, rates are nearly as good as for those in the chronic phase. Overall, survival rates for those in the blast crisis phase hover below 20%.[12] The best chance for survival involves using drugs to get the disease back into the chronic phase and then try HSCT. A retrospective review reported five-year overall survival (OS) of 34% in patients treated with combination therapy that included a TKI and intensive chemotherapy or a hypomethylating agent; five 5-year OS in patients who proceeded to transplantation was 58%.{ref73
Patients who develop blast crisis, which has manifestations similar to those of acute leukemia, have a very poor prognosis. Treatment results are unsatisfactory, and most of these patients succumb to the disease. Survival is 3-6 months.
Risk stratification
As treatment of CML has improved, the need to stage patients according to their prognoses became necessary to justify procedures with high morbidity and mortality, such as HSCT. Staging of patients is based on several analyses using multiple variate analysis between the association of pretreatment host and leukemic cell characteristics and corresponding survival rates. The findings from these studies classify patients into the following groups:
Good risk (average survival of 5-6 years)
Intermediate risk (average survival of 3-4 years)
Poor risk (average survival of 2 years)
One widely used prognostic index, the Sokal score, is calculated for patients aged 5-84 years by the following equation:
The three categories of the Sokal score are as follows:
Low risk: score < 0.8
Intermediate risk: score 0.8-1.2
High risk: score > 1.2
The Sokal score correlates with the likelihood of achieving complete cytogenetic response, as follows:
Low-risk patients: 91%
Intermediate-risk patients: 84%
High-risk patients: 69%
Since the advent of the Sokal score, other CML prognostic scores have been developed: the Hasford score in the 1990s and the EUTOS (European Treatment and Outcome Study) score in the 2000s. Like the Sokal score, the Hasford formula categorizes patients into low-, intermediate- and high-risk groups; the EUTOS score differentiates only between high-risk and low-risk groups. The Hasford score, which also incorporates peripheral blood eosinophils and basophils as a percentage of total leukocytes, may be more accurate at discriminating between low-risk and intermediate-risk CML, and so may be useful in predicting molecular response to initial TKI treatment of chronic-phase CML.[19]
Online calculators of these scores are available. See the Sokal Score for CML, Calculation of Relative Risk of CML Patients, and EUTOS Score for Chronic Myelogenous Leukemia (CML).
Currently, most patients with CML die from causes other than leukemia while still in remission. For that reason, another risk score, the EUTOS Long Term Survival (ELTS) score has been developed to predict the probability of dying from CML. The ELTS score, based on TKI-treated patients and validated for patients older than 18 years, uses the same criteria as the Sokal score but assigns different values, particularly for age. The score is calculated using the following formula[20] :
An online calculator is available. See The EUTOS long-term survival (ELTS) score.
Additional chromosomal abnormalities
A study by Wang et al addressed the prognostic impact of specific additional chromosomal abnormalities (ACAs) in CML.[21] In patients with a single chromosomal change, the following three ACAs were associated with a relatively good prognosis when they emerged during the chronic phase or at the time of CML diagnosis:
Trisomy 8
-Y
An extra copy of Philadelphia chromosome (+Ph)
However, if trisomy 8 was accompanied by one or more of those other ACAs, patients had a poorer prognosis.
The following three ACAs were associated with a relatively poor prognosis, regardless of the disease phase at the time of emergence:
i(17)(q10)
-7/7q (-7/del7q)
3q26.2 rearrangements
A study by Hehlmann et al of ACAs in patients in chronic phase CML concluded that although the prognosis with trisomy 8 alone was clearly better than with trisomy 8 accompanied by further abnormalities, it was still worse than with low-risk ACA.[22] In addition, these authors identified the following ACAs as conferring high risk:
Current patient education information on CML is available on the American Cancer Society and National Cancer Institute Web sites. For additional patient education information, see Leukemia.
The clinical manifestations of chronic myelogenous leukemia (CML) are insidious. The disease is often discovered incidentally in the chronic phase, when an elevated white blood cell (WBC) count is revealed by a routine blood count or when an enlarged spleen is found on a general physical examination.
Nonspecific symptoms of fatigue and weight loss may occur long after the onset of the disease. Loss of energy and decreased exercise tolerance may occur during the chronic phase after several months.
Patients often have symptoms related to enlargement of the spleen, liver, or both. The large spleen may encroach on the stomach and cause early satiety and decreased food intake. Left upper quadrant abdominal pain described as "gripping" may occur from spleen infarction. The enlarged spleen may also be associated with a hypermetabolic state, fever, weight loss, and chronic fatigue. The enlarged liver may contribute to the patient's weight loss.
Some patients with CML have low-grade fever and excessive sweating related to hypermetabolism.
In some patients who present in the accelerated, or acute, leukemia phase of the disease (skipping the chronic phase), bleeding, petechiae, and ecchymoses may be the prominent symptoms. In these situations, fever is usually associated with infections. Bone pain and fever, as well as an increase in bone marrow fibrosis, are harbingers of the blast phase.
Splenomegaly is the most common physical finding in patients with CML. In more than 50% of the patients with CML, the spleen extends more than 5 cm below the left costal margin at time of discovery.
The size of the spleen correlates with the peripheral blood granulocyte counts, with the largest spleens being observed in patients with high WBC counts. A very large spleen is usually a harbinger of the transformation into an acute blast crisis form of the disease.
Hepatomegaly also occurs, although less commonly than splenomegaly. Hepatomegaly is usually part of the extramedullary hematopoiesis occurring in the spleen.
Physical findings of leukostasis and hyperviscosity can occur in some patients, with extraordinary elevation of their WBC counts, exceeding 300,000-600,000 cells/μL. Upon funduscopy, the retina may show papilledema, venous obstruction, and hemorrhages.
The blast crisis is marked by an increase in the bone marrow or peripheral blood blast count or by the development of soft-tissue or skin leukemic infiltrates. Typical symptoms are due to increasing anemia, thrombocytopenia, basophilia, a rapidly enlarging spleen, and failure of the usual medications to control leukocytosis and splenomegaly.
The workup for chronic myelogenous leukemia (CML) consists of a complete blood count with differential, peripheral blood smear, and bone marrow analysis. Although typical hepatomegaly and splenomegaly may be imaged by using a liver/spleen scan, these abnormalities are often so obvious clinically that radiologic imaging is not necessary.
The diagnosis of CML is based on the histopathologic findings in the peripheral blood and the Philadelphia (Ph1) chromosome in bone marrow cells. Findings from the workup—in particular, the percentage of blasts in peripheral blood or bone marrow—are used to determine the phase of CML: chronic, accelerated, or blast. For more information, see Chronic Myelogenous Leukemia Staging.
Other laboratory abnormalities include hyperuricemia, which is a reflection of high bone marrow cellular turnover, and markedly elevated serum vitamin B12–binding protein (TC-I). The latter is synthesized by the granulocytes and reflects the degree of leukocytosis.
In CML, the increase in mature granulocytes and normal lymphocyte counts (low percentage due to dilution in the differential count) typically results in a total WBC count of 20,000-60,000 cells/μL. A mild increase in basophils and eosinophils is present and becomes more prominent during the transition to acute leukemia.
These mature neutrophils, or granulocytes, have decreased apoptosis (programmed cell death), resulting in accumulation of long-lived cells with low or absent enzymes, such as alkaline phosphatase (ALP). Consequently, the leukocyte alkaline phosphatase stains very low to absent in most cells, resulting in a low score.
The peripheral blood smear in patients with CML shows a typical leukoerythroblastic blood picture, with circulating immature cells from the bone marrow (see the image below).
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Chronic myelogenous leukemia. Blood film at 400X magnification demonstrates leukocytosis with the presence of precursor cells of the myeloid lineage. ....
The transitional or accelerated phase of CML is characterized by poor control of blood counts with myelosuppressive medication, the appearance of peripheral blast cells (≥15%), promyelocytes (≥30%), basophils (≥20%), and reduction in platelet counts to less than 100,000 cells/μL unrelated to therapy. Promyelocytes and basophils are shown in the images below.
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Chronic myelogenous leukemia. Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils. Courtesy of U. Woermann, MD, Div....
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Chronic myelogenous leukemia. Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. C....
Signs of transformation or accelerated phase in patients with CML are as follows:
Poor control of blood counts with therapy
Increasing blast cells in peripheral blood with basophilia and thrombocytopenia not related to therapy
New cytogenetic abnormalities
Increasing splenomegaly and myelofibrosis
In approximately two thirds of cases, the blasts are myeloid. However, in the remaining one third of patients, the blasts exhibit a lymphoid phenotype, further evidence of the stem cell nature of the original disease. Additional chromosomal abnormalities are usually found at the time of blast crisis, including additional Ph1 chromosomes or other translocations.
Early myeloid cells such as myeloblasts, myelocytes, metamyelocytes, and nucleated red blood cells are commonly present in the blood smear, mimicking the findings in the bone marrow. The presence of the different midstage progenitor cells differentiates CML from the acute myelogenous leukemias, in which a leukemic gap (maturation arrest) or hiatus exists that shows absence of these cells.
A mild to moderate anemia is very common at diagnosis and is usually normochromic and normocytic. The platelet counts at diagnosis can be low, normal, or even increased in some patients (>1 million in some).
The bone marrow is characteristically hypercellular, with expansion of the myeloid cell line (eg, neutrophils, eosinophils, basophils) and its progenitor cells. Megakaryocytes (see the image below) are prominent and may be increased. Mild fibrosis is often seen in the reticulin stain.
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Chronic myelogenous leukemia. Bone marrow film at 400X magnification demonstrates clear dominance of granulopoiesis. The number of eosinophils and meg....
Cytogenetic studies of the bone marrow cells, and even peripheral blood, should reveal the typical Ph1 chromosome, which is a reciprocal translocation of chromosomal material between chromosomes 9 and 22 (see the image below). This is the hallmark of CML, found in almost all patients with the disease and present throughout the entire clinical course of CML.
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The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chr....
In addition, the chimeric BCR-ABL messenger RNA (mRNA) that characterizes CML can be detected by polymerase chain reaction (PCR). This is a sensitive test that requires just a few cells and is useful in monitoring minimal residual disease (MRD) to determine the effectiveness of therapy. BCR-ABL mRNA transcripts can also be measured in peripheral blood
Karyotypic analysis of bone marrow cells requires the presence of a dividing cell without loss of viability because the material requires that the cells go into mitosis to obtain individual chromosomes for identification after banding. This is a slow, labor-intensive process.
Fluorescence in situ hybridization (FISH) uses labeled probes that are hybridized to either metaphase chromosomes or interphase nuclei, and the hybridized probe is detected with fluorochromes. This technique is a rapid and sensitive means of detecting recurring numerical and structural abnormalities. (See the image below.) European LeukemiaNet guidelines recommend FISH for use in cases that are Ph1 negative.[20]
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Chronic myelogenous leukemia. Fluorescence in situ hybridization using unique-sequence, double-fusion DNA probes for bcr (22q11.2) in red and c-abl (9....
Two forms of the BCR-ABL mutation have been identified. These vary according to the location of their joining regions on bcr 3' domain. Approximately 70% of patients who have the 5' DNA breakpoint have a b2a2 RNA message, and 30% of patients have a 3' DNA breakpoint and a b3a2 RNA message. The latter is associated with a shorter chronic phase, shorter survival, and thrombocytosis.
CML should be differentiated from Ph1-negative diseases with negative PCR results for BCR-ABL mRNA. These diseases include other myeloproliferative disorders and chronic myelomonocytic leukemia, which is now classified with the myelodysplastic syndromes.
Additional chromosomal abnormalities, such as an additional or double Ph1-positive chromosome or trisomy 8, 9, 19, or 21; isochromosome 17; or deletion of the Y chromosome, have been described as the patient enters a transitional form or accelerated phase of the blast crisis as the Ph chromosome persists.
Patients with conditions other than CML, such as newly diagnosed acute lymphocytic leukemia (ALL) or nonlymphocytic leukemia, may also be positive for the Ph1 chromosome. Some authors consider this the blastic phase of CML without a chronic phase. The chromosome is rarely found in patients with other myeloproliferative disorders, such as polycythemia vera or essential thrombocythemia, but these cases are probably misdiagnosed CML. It is rarely observed in myelodysplastic syndrome.
The goals of treatment of chronic myelogenous leukemia (CML) are threefold and have changed markedly since the advent of tyrosine kinase inhibitor (TKI) therapy. They are as follows:
Hematologic remission (normal complete blood cell count [CBC] and physical examination (ie, no organomegaly)
Cytogenetic remission (normal chromosome returns with 0% Philadelphia chromosome–positive (Ph+) cells)
Molecular remission (negative polymerase chain reaction [PCR] result for the mutational BCR-ABL mRNA), which represents an attempt for cure and prolongation of patient survival
Typically, CML has three clinical phases: an initial chronic phase, during which the disease process is easily controlled; then a transitional and unstable course (accelerated phase); and, finally, a more aggressive course (blast crisis), which is usually fatal. In all three phases, supportive therapy to control symptoms and complications resulting from anemia and thrombocytopenia (eg, with transfusions of red blood cells or platelets) may be used to relieve symptoms and improve quality of life.
In Western countries, 90% of patients with CML are diagnosed in the chronic phase. These patients’ white blood cell (WBC) count is usually controlled with medication (hematologic remission). For most patients with chronic-phase CML who are treated with TKIs, median survival is expected to approach normal life expectancy.[1, 23]
The standard treatment of choice for chronic phase CML is a TKI: either the first-generation TKI imatinib, which is a specific small-molecule inhibitor of BCR-ABL in all phases of CML, or a second-generation TKI—nilotinib (Tasigna), dasatinib (Sprycel), or bosutinib (Bosulif). Although the second-generation TKIs produce a higher rate of deep molecular response and provide better early control of disease than imatinib, the benefits and risks of these newer agents compared with imatinib, as well as their comparative long-term safety profiles, have not been fully established,[24, 25] and the second-generation TKIs have not been tested against each other.[20] Current National Comprehensive Cancer Network guidelines list imatinib as a preferred agent for low-risk CML and recommend second-generation TKIs as preferred agents for intermediate- and high-risk chronic phase CML.[26]
In patients with a durable deep molecular response to TKI therapy, treatment discontinuation may be considered (see Long-Term Monitoring, below). However, only about 20% of patients wich chronic-phase CML achieve treatment-free remission; most patients with CML require lifelong TKI therapy.[20]
Some patients with CML progress to a transitional or accelerated phase, which may last for several months. The survival of patients diagnosed in this phase is 1-1.5 years. This phase is characterized by poor control of blood counts with therapy and the appearance of peripheral blast cells (≥15%), promyelocytes (≥30%), basophils (≥20%), and platelet counts less than 100,000 cells/μL unrelated to therapy.
Many of the treatment decisions in CML, including possible hematopoietic stem cell transplantation[27] and investigative options for younger patients, are extremely complex and in constant flux. Individualized decisions should be made in conjunction with consultation with physicians familiar with the recent literature. New agents that are currently under study may prolong the survival of patients with CML and offer the possibility of eventual cure. Physicians should refer their patients to tertiary care centers for clinical trials involving these therapies.
For more information, see Chronic Myelogenous Leukemia Treatment Protocols.
Cost concerns
TKIs are expensive and require prolonged use, making drug cost an important issue in CML treatment. Many patients with CML require lifelong TKI therapy—and the life expectancy of patients with CML treated with imatinib, for example, now approaches that of the general population.[23, 28]
From 2001, when imatinib was first approved for use in CML, to 2016, when it went off patent, the list price of imatinib in the United States rose from $26,400 per year to $142,000 per year. Second-generation TKIs have demonstrated similar price increases.[29] Once a generic version of imatinib became available, costs fell only modestly at first, suggesting that generic price competition alone may be insufficient to reduce the price of cancer drugs in the US.[29, 28] As of December 2018, the average price of generic imatinib in the United States was $35,000/year, while prices of second-generation TKIs were $150,000+/year. Prices in other countries were substantially lower.[30]
Prices of brand name and generic imatinib and next-generation TKIs have continued to increase, averaging 10% to 20% annually, which contributes to financial hardship and possibly poor compliance with effective therapy.[31] Another potential driver is delays in some pharmacies passing on lower acquisition prices.
Comparison studies have demonstrated that generic formulations of imatinib have efficacy and toxicity comparable to that of original imatinib.[32] Nevertheless, despite a National Average Drug Acquisition Cost price for generic imatinib as low as $20 per 400-mg tablet in 2018, the average TKI costs per day for patients with CML exceeded $350, largely driven by the decision to treat these patients with more costly second-line TKIs.[28]
Imatinib is a tyrosine kinase inhibitor (TKI) that inhibits the abnormal bcr-abl tyrosine kinase created by the Philadelphia (Ph1) chromosome translocation abnormality. Imatinib inhibits proliferation and induces apoptosis in cells positive for BCR-ABL.[3, 4, 7, 33, 34]
For patients with chronic-phase CML, imatinib at 400 mg/day is the recommended dosage for primary therapy, because it induces a complete hematologic response in almost all patients and causes a high cytogenetic response rate. With imatinib at 400 mg/day orally in patients with newly diagnosed Ph1-positive CML in the chronic phase, the complete cytogenetic response rate is 70% and the estimated 3-year survival rate is 94%.
In patients unable to tolerate 400 mg/day of imatinib, the dosage may be reduced to 300 mg/day if the response is optimal.[26, 20] However, dosages of less than 300 mg/day have been associated with inferior response and survival rates.[26]
With higher doses of 800 mg/day, the complete cytogenetic response rate increases to 98%, the major molecular response rate is 70%, and the complete molecular response rate is 40-50%. Despite those improved early responses, however, randomized phase III studies suggested that higher-dose imatinib was not associated with lower rates of disease progression than imatinib at 400 mg, but was associated with higher rates of dose interruption, reduction, or discontinuation due to grade 3 or 4 adverse events.[26]
A study of imatinib in patients with newly diagnosed chronic phase CML found that imatinib maintained efficacy over median follow-up of 10.9 years, without unacceptable cumulative or late toxic effects. The IRIS (Randomized Study of Interferon vs STI571) trial was an open-label crossover trial that randomly assigned patients to receive either imatinib or interferon alfa plus cytarabine. Of patients assigned to imatinib, 48.3% completed study treatment with it, and 82.8% had a complete cytogenetic response. The estimated 10-year survival rate was 83.5%.[24]
Santos et al reported that the use of erythropoietic-stimulating growth factors with imatinib did not impact response rates or survival but increased risk for thrombosis. The presence of severe anemia in these patients was associated with worse survival and response.[35]
Kantarjian et al reported that in patients in the chronic phase who had failure or intolerance of interferon treatment, treatment with imatinib resulted in a complete hematologic response in 430 of 454 patients (95%), with a major cytogenetic response (ie, 0-35% of cells in metaphase positive for the Ph1 chromosome) in 60% of patients; 41% had a total response.[4] Among the study patients with features of accelerated-phase CML (n=17), rates of cytogenetic and hematologic responses were 59% and 88%, respectively and among those with features of blastic-phase CML (n=12), rates were 75% and 92%, respectively.
Talpaz et al reported that among 235 patients with accelerated-phase CML, treatment with imatinib yielded a hematologic response in 82% of patients (sustained in 69% and complete in 34%) and major cytogenetic response in 24% (complete in 17%).[6]
Sawyers et al found that among patients in myeloid blast crisis (260 patients), treatment with imatinib resulted in sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. Major cytogenetic responses occurred in 16% of patients, with 7% of the responses being complete.[36]
A study in 1106 patients with newly diagnosed, chronic-phase CML concluded that in terms of hematologic and cytogenetic responses, tolerability, and the likelihood of progression to accelerated-phase or blast-crisis CML, imatinib is superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed, chronic-phase CML.[37] The estimated rates of complete cytogenetic response were 76.2% for the imatinib group and 14.5% in the interferon alfa group.[37]
The estimated rate of a major cytogenetic response at 18 months was 87.1% in the imatinib group, compared with 34.7% in the group given interferon alfa plus cytarabine. At 18 months, the estimated rate of freedom from progression to accelerated-phase or blast-crisis CML was 96.7% in the imatinib group and 91.5% in the combination-therapy group. Imatinib was better tolerated than combination therapy.[37]
Molecular remission is the goal as measured by PCR. Continuation of the drug is important because approximately 20% of patients lose complete cytogenic response, at a rate of 1.4 per 100 person-years. This is due to poor adherence or poor tolerance of the drug in patients who had an adherence rate of less than 85% as the main reason for complete cytogenic response loss.[38]
Treatment of patients with CML in the accelerated phase or in blast crisis has yielded dismal results. Although imatinib can induce a hematologic response in 52-82% of patients, the response is sustained for at least 4 weeks in only 31-64% of patients. The complete response rate is lower, at 7-34% of patients. Karyotypic response occurs in 16-24%, and complete cytogenetic response is observed in only 17%.[36] Higher doses (ie, 600 mg/d) result in improved response rates, cytogenetic response, and disease-free and overall survival.
Resistance of CML cells to imatinib occurs through multiple mechanisms such as overexpression of BCR-ABL and mutations of the abl gene.[8, 9, 39] Kinase-domain mutations in BCR-ABL represent the most common mechanism of secondary or acquired resistance to imatinib, accounting for 50-90% of cases; 40 different mutations have currently been described. Because imatinib binds to the ABL kinase domain in the inactive, or closed, conformation to induce conformational changes, resistance occurs when the mutation prevents the kinase domain from adopting the specific conformation upon binding.
Patients whose CML demonstrates resistance to imatinib should be switched to a different TKI and considered for hematopoietic stem cell transplantation.[26, 40]
Kidney damage is an important adverse effect of imatinib. A study by Marcolino et al found that imatinib therapy in non–clinical trial patients with CML was associated with potentially irreversible acute kidney injury, and that long-term treatment may cause a clinically relevant decrease in the estimated glomerular filtration rate (eGFR).[41]
Currently, three second-generation tyrosine kinase inhibitors (TKIs) and two third-generation TKIs are available for treatment of CML. These agents are orally administered, generally well-tolerated, and highly effective.
The second-generation TKIs dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif) are more potent inhibitors of BCR/ABL than imatinib. Moreover, they exhibit significant activity against all resistant mutations except BCR/ABL1 T315I, which responds to the third-generation TKIs posatinib and asciminib.
All three second-generation TKIs have been approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with newly diagnosed Philadelphia chromosome–positive (Ph1+) chronic-phase CML, as well as for those with chronic-phase CML that is resistant to or who are intolerant of prior therapy that included imatinib.[42, 43, 44] Dasatinib and bosutinib are also FDA-approved for accelerated- and blast-phase Ph1+ CML in patients resistant to or intolerant of other therapies, and nilotinib is approved for resistant/intolerant accelerated-phase CML.
Compared with these second-generation agents, imatinib has relatively low potency and inhibits its target at micromolecular rather than nanomolar concentrations. In addition, imatinib has increased susceptibility to resistance through a number of mutations in the BCR-ABL target.[45]
That said, these new TKIs are not without their drawbacks and adverse events. Dasatinib has been associated with pleural effusions and pulmonary arterial hypertension,[46] while nilotinib has been linked to biochemical changes in liver function and QT-interval prolongation. Development of resistance may also occur with these agents.
Moreover, imatinib is still very effective; it remains a preferred first-line treatment for low-risk chronic phase CML.[26] It is also less expensive than the new TKIs, especially since it has gone out of patent and is available in generic form. Consequently, it may survive the challenge posed by newer agents because of a favorable balance of cost and efficacy.[47] Using risk factor scoring (see Overview/Prognosis) may help in identifying patients who require the more expensive second-generation agents for first-line use.[48]
A study by Verma et al found that second malignancies occur in a small percentage of patients receiving TKI treatment for hematologic malignancies, mostly CML. No evidence suggests, however, that exposure to these inhibitors increases the risk of developing second malignancies.[49]
How should these agents be used for an individual patient to ensure the best possible duration and quality of life, to avoid treatment-related complications, and potentially to achieve a cure at an affordable cost? Because CML patients may need to continue TKI therapy indefinitely, the long-term safety of each treatment option must be considered. Evidence-based care requires an understanding of the optimal use of these drugs, their specific early and late toxicities, the prognostic significance of achieving treatment milestones, and the critical importance of molecular monitoring.
Equally important determinants for which drug to use for an individual patient include tolerance (because it influences treatment adherence as well as quality-of-life), comorbidities and thus potential late complications, calculated risk status at diagnosis, and the achievement of molecular response.
Although efficacy is important, treatment choice does not depend only on efficacy. Choosing among various treatment options is informed by understanding the distinct benefits and risks of each agent, along with careful consideration of patient-specific factors, such as risk status, age, and comorbidities. Finally, given the high cost of these agents and the need for prolonged—often, lifelong—treatment, financial issues must also be considered.
Tthe choice of initial is likely to be driven by two considerations: one clinical (because survivals with different agents appear equivalent despite differences in efficacy), and the other financial (the price of generic imatinib is likely to fall to 20%-30% of the cost of the branded drug and the second-generation TKIs). Equally important determinants for which drug to use for an individual patient include the following:
Tolerance (because it influences treatment adherence as well as quality of life)
Comorbidities (and thus potential late complications)
Calculated risk status at diagnosis
Achievement of early molecular response (EMR)
Eventually, gene expression profiling may provide a better way to identify which patients require a second-generation TKI from the outset. The BCR-ABL T315I mutation confers complete resistance to imatinib,dasatinib, nilotinib, and bosutinib; the presence of this mutation is an indication for the use of a third-generation TKI, posatinib or asciminib. For now, appropriate monitoring and the use of guidelines regarding when to switch is the key to optimizing outcomes.
Dasatinib
Dasatinib, an inhibitor of multiple tyrosine kinases, received accelerated approval in 2006 for second-line treatment of all phases of CML, and received approval for first-line treatment of chronic-phase CML in 2013. Dasatinib has been shown to be more effective in inducing molecular remission than imatinib. In a comparison of dasatinib with imatinib in 519 patients with newly diagnosed chronic-phase CML, the rate of confirmed complete cytogenetic response after a minimum follow-up of 12 months was 77% with dasatinib versus 66% with imatinib.[50]
A study by Cortes et al that compared dasatinib 100 mg daily or 50 mg twice daily for at least 3 months as initial therapy for early chronic-phase CML found no difference in outcome between the 2 dosages.[51] Of the 50 patients in the study, 49 (98%) achieved a complete cytogenetic response and 41 (82%) achieved a major molecular response (MMR). The projected event-free survival rate at 24 months was 88%, and all patients were alive after a median follow-up time of 24 months.[51]
The efficacy and safety of dasatinib in patients with newly diagnosed Ph1+ CML that is in the chronic phase were demonstrated in the DASISION (Dasatinib vs Imatinib Study in Treatment-Naïve CML Patients) study, an ongoing open-label randomized phase III trial.[15] The confirmed cytogenetic response rate (CCyR) was higher in patients treated with dasatinib than with imatinib at 12 months (77% vs 66%, respectively) and at 36 months (83% vs 77%). The rate of MMR was also higher for dasatinib at both 12 and 36 months.
In CA180‐034, an open-label phase III study of dasatinib in 670 patients with imatinib‐resistant or ‐intolerant CML, 7-year analysis showed MMR of 46%, progression-free survival (PFS) of 42%, and overall survival (OS) of 65% in which transformation from chronic phase to accelerated or blast-phase CML occurred in fewer than 5% of dasatinib patients by 5 years.[52]
Nilotinib
Nilotinib received approval for second-line treatment of CML in 2007, and received approval for first-line treatment of chronic-phase CML in 2010. Nilotinib has been found superior to imatinib in patients with newly diagnosed chronic-phase Ph+ CML.[14] In addition, Kantarjian et al reported that nilotinib maintained better efficacy during a minimum follow-up of 24 months. Compared with imatinib, significantly more patients receiving nilotinib achieved MMR, or a complete molecular response at any time, and fewer progressed to accelerated or blast phase.[53]
The FDA has also approved nilotinib for first- and second-line treatment of pediatric patients aged 1 year and older with chronic-phase Ph+ CML. Approval was based on a cohort of 69 pediatric patients with chronic-phase Ph+ CML-CP who were either newly diagnosed or had resistance to or intolerance of TKI treatment. The MMR in newly diagnosed patients was 60% at 12 cycles, with 15 patients achieving MMR. The cumulative MMR in this group was 64% by cycle 12, and the median time to first MMR was 5.6 months. In the resistant/intolerant group, the MMR rate was 40.9% at 12 cycles, with 18 patients in MMR; the cumulative MMR rate was 47.7% by cycle 12, and the median time to first MMR was 2.8 months.[54]
Bosutinib
After granting accelerated approval in 2017, in 2021 the FDA issued standard approval of bosutinib for newly diagnosed chronic-phase Ph+ CML in adult patients. Approval was based on the BFORE study, a multinational, phase III study enrolling 536 patients with newly diagnosed chronic-phase CML. Cumulative MMR by 60 months in the modified intent-to-treat (mITT) population was 74% (95% CI: 69-80%) in the bosutinib arm and 66% (95% CI: 60-72%) in the imatinib arm. After 60 months of follow-up, the median time to MMR in responders was 9 months for bosutinib and 11.9 months for imatinib.[55, 16]
In September 2023, the FDA extended the approval of bosutinib to include pediatric patients 1 year of age and older with chronic-phase Ph+ CML that is newly diagnosed or resistant or intolerant to prior therapy. Approval was based on data from the single-arm, open-label phase I/II BCHILD trial, in which pediatric patients with newly diagnosed Ph+ CML (n=21) showed major (MCyR) and complete (CCyR) cytogenetic responses of 76.2% and 71.4%, respectively, and MMR of 28.6% on median follow-up of 14.2 months.[56]
In the BHCHILD patients (n=28) who had received at least 1 prior TKI therapy, MCyR was 82.1% and CCyR was 78.6%. The MMR was 50%, although 2 of the 14 responders lost MMR after 13.6 and 24.7 months of treatment. The complete molecular response (a 4.5-log reduction in transcript level to a BCR-ABL/ABL ratio ≤ 0.0032% [MR4.5]) was 17.9%. Median duration of follow-up for overall survival was 23.2 months.[56]
Ponatinib
The third-generation TKI ponatinib (Iclusig) was approved by the FDA in 2012 for use in patients with CML that had relapsed or become refractory to other therapies. Many of these patients will have developed a BCR-ABL T315I mutation, which confers resistance to imatinib and second-generation TKIs.[57, 17, 58]
In the phase II PACE (Ponatinib PH+ ALL [acute lymphoblastic leukemia] and CML Evaluation) trial, the drug successfully treated patients with chronic-phase CML (major cytogenetic response in 55% of cases, including 70% of patients with the T315I mutation, within 12 months), with accelerated-phase CML (major hematologic response in 57% of cases within 6 months), or with blast-phase CML/Ph1-positive ALL (major hematologic response in 34% of cases within 6 months).[57, 17, 58]
In October 2013, at the FDA’s request, ponatinib was temporarily removed from the market because of safety concerns. The FDA cited an increased risk for life-threatening blood clots and severe narrowing of blood vessels.[59] In December 2013, the FDA allowed resumption of marketing, since the benefits of response to ponatinib far outweigh the risk of complications from the drug. However, the FDA required the addition of a black box warning regarding arterial and venous thrombosis and occlusions, which occurred in at least 27% of patients in early trials, typically within 2 weeks of starting ponatinib. In addition, the FDA limited the indications for use of ponatinib to the following[60] :
Adult patients with T315I-positive CML in chronic, accelerated, or blast phase (or T315I-positive, Ph1-positive ALL)
Adult patients with chronic, accelerated, or blast phase CML for whom no other TKI therapy is indicated
The FDA also revised the dosing recommendations to state that the optimal dose of ponatinib had not been identified. The recommended starting dose remains 45 mg once daily, but additional information is included regarding dose decreases and discontinuations.
Subsequently, the prospective phase II OPTIC (Optimizing Ponatinib Treatment in CP-CML) trial assessed the benefit/risk ratio across 3 starting doses of ponatinib: 45, 30, and 15 mg. The study found that optimal benefit/risk outcomes occurred with the 45-mg starting dose, followed by a reduction to 15 mg upon achievement of ≤1% BCR-ABL1.[61] A 3-year update of the OPTIC trial supported the initial findings.[62]
A German expert consensus panel has published recommendations on management of cardiovascular risk in patients receiving ponatinib.[63]
Asciminib
In 2021, the FDA granted asciminib (Scemblix) accelerated approval for Ph+ CML in chronic phase in adults previously treated with 2 or more TKIs. Asciminib is also fully approved for the treatment of Ph+ CML in chronic phase in adults with the BCR-ABL T315I mutation. Asciminib is an ABL/BCR-ABL1 TKI that binds to ABL myristoyl pockets, which inhibits the ABL1 kinase activity of the BCR-ABL1 fusion protein.
Accelerated approval was granted on the basis of the phase III ASCEMBL trial, in which MMR was nearly twice as high in patients receiving asciminib than in those receiving bosutinib (25% vs 13%). Fewer patients in the asciminib arm discontinued treatment due to adverse reactions compared with those in the bosutinib arm (7% vs. 25%). On longer-term follow-up of ASCEMBL, the MMR rate at week 96 was 37.6% with asciminib vs 15.8% with bosutinib.[18]
Full approval of asciminib for treatment of chronic-phase Ph+-CML with BCR-ABL T315I mutation was based on the open-label CABL001X2101 study, in which achievement of MMR occurred in 42% of patients by week 24 (19 of 45 patients; 95% CI: 28% to 58%) and in 49% of patients by week 96 (22/45, 95% CI: 34% to 64%).[64]
Pemigatinib is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3). It inhibits FGFR 1/2/3 phosphorylation and signaling, and decreases cell viability in cancer cell lines that have activating FGFR amplifications and fusions. It is indicated for relapsed or refractory myeloid/lymphoid neoplasms (MLNs) in adults with FGFR1 rearrangement.
Approval was based on the phase II FIGHT-203 clinical trial. Study participants included patients with documented myeloid/lymphoid neoplasms with an 8p11 translocation on conventional cytogenetics and/or an FGFR1 rearrangement on break-apart fluorescence in situ hybridization (FISH) testing.
In patients with chronic phase in the marrow, with or without extramedullary disease (EMD) (n = 18), the complete response (CR) rate was 78%. The median time to CR was 104 days (range, 44 to 435 days), and the median duration of CR was not reached. In patients with blast phase in the marrow, with or without EMD, 2 of the 4 patients achieved a CR. For all patients (n = 28, including 3 patients without evidence of morphologic disease) the complete cytogenetic response rate was 79% (95% confidence interval: 59-92%).[65]
The protein translation inhibitor omacetaxine (Synribo) is approved for treatment of chronic- or accelerated-phase CML in patients with resistance to and/or intolerance of 2 or more tyrosine kinase inhibitors (TKIs) (eg, dasatinib, nilotinib, imatinib). Approval was based on combined data from 2 phase II open-label multicenter studies. Pooled data included patients (n=111) who had received two or more TKIs and showed evidence of resistance or intolerance. In patients with chronic-phase CML taking omacetaxine, 18% attained a major cytogenetic response (MCyR) (mean time to MCyR onset, 3.5 mo). The median duration of MCyR was 12.5 months. Of patients with accelerated-phase CML who received omacetaxine, 14% attained a major hematologic response (MaHR); mean time to MaHR was 2.3 mo and mean duration of MaHR was 4.7 months.[66]
Myelosuppressive therapy was formerly the mainstay of treatment to convert a patient with CML from an uncontrolled initial presentation to one with hematologic remission and normalization of the physical examination and laboratory findings. However, it has fallen out of favor as TKIs have proved to be more effective, with fewer adverse events and longer survival.
Hydroxyurea
Hydroxyurea (Hydrea), an inhibitor of deoxynucleotide synthesis, was the most common myelosuppressive agent used to achieve hematologic remission. The initial blood cell count is monitored every 2-4 weeks, and the dose is adjusted depending on the WBC and platelet counts. Most patients achieve hematologic remission within 1-2 months.
This medication causes only a short duration of myelosuppression; thus, even if the counts go lower than intended, stopping treatment or decreasing the dose usually restores the blood counts. Maintenance with hydroxyurea rarely results in cytogenetic or molecular remissions.
European Society for Medical Oncology (ESMO) guidelines suggest that hydroxyurea (40 mg/kg daily) may be used as initial therapy, before confirmation of the BCR-ABL1 fusion in patients with immediate need for therapy because of high leukocyte counts or clinical symptoms. TKI therapy should be started immediately after confirmation of BCR–ABL1 positivity, and the hydroxyurea dose tapered before discontinuation.[40]
Busulfan
Busulfan (Myleran) is an alkylating agent that has traditionally been used to keep leukocyte counts below 15,000 cells/µL. However, the myelosuppressive effects may occur much later and persist longer, which makes maintaining the counts within normal limits more difficult. Long-term use can cause pulmonary fibrosis, hyperpigmentation, and prolonged marrow suppression lasting for months.
Leukapheresis using a cell separator can lower WBC counts rapidly and safely in patients with WBC counts greater than 300,000 cells/µL, and it can alleviate acute symptoms of leukostasis, hyperviscosity, and tissue infiltration.
Leukapheresis usually reduces the WBC count only temporarily. Thus, it is often combined with cytoreductive chemotherapy for more lasting effects.
In the past, interferon alfa was the treatment of choice for most patients with CML who were too old for bone marrow transplantation or who did not have a matched bone marrow donor. With the advent of TKIs, interferon alfa is no longer considered first-line therapy for CML. However, it may be used in pregnant patients, as fetal harm has been reported with TKI therapy.[26, 20]
Interferon alfa may also be used in combination with TKIs for treatment of refractory cases. A study by Simonsson et al found that the addition of even relatively short periods of treatment with pegylated interferon alfa2b to imatinib increased the major molecular response rate at 12 months of therapy. The authors suggested that lower doses of pegylated interferon alfa2b may enhance tolerability while retaining efficacy and could be considered in future studies.[67]
Although a minority of CML patients who have a major molecular response to TKI therapy can discontinue TKIs and maintain treatment-free remission, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only proven cure for CML. Current guidelines recommend consideration of transplantation in patients who have a suboptimal response to two or more TKIs.[20] Ideally, HSCT should be performed in the chronic phase of the disease rather than in the transformation phase or in blast crisis. Candidate patients should be offered the procedure if they have a matched or single-antigen–mismatched related donor available. In general, younger patients fare better than older patients.
HSCT should be considered early in young patients (< 55 y) who have a matched sibling donor.[68, 69] All siblings should be typed for human leukocyte antigen (HLA)-A, HLA-B, and HLA-DR. If no match is available, the HLA type can be entered into a bone marrow registry for a completely matched unrelated donor.
Allogeneic HSCT with matched unrelated donors has yielded very encouraging results in this disease. The procedure does have a higher rate of early and late graft failures (16%), grade III-IV acute graft versus host disease (50%), and extensive chronic graft versus host disease (55%). The overall survival rate ranges from 31% to 43% for patients younger than 30 years and from 14% to 27% for older patients. Benefits and risks should be assessed carefully with each patient.
The mortality rate associated with HSCT is 10-20% or less with a matched sibling and 30-40% with an unrelated donor. The approximate cure rate for patients with CML is 50%.
Transplantation has been relegated to patients who do not achieve molecular remissions or show resistance to imatinib and failure of later-generation TKIs. Previous exposure to imatinib before transplantation does not adversely affect posttransplant outcomes such as overall survival and progression-free survival.
A retrospective analysis that included 70 patients with CML (44% in accelerated phase or blast crisis) who had received imatinib before stem cell transplantation showed 90% engraftment and estimated transplant-related mortality of 44% and estimated relapse mortality of 24% at 24 months. Graft versus host disease rates were 42% for acute and 17% for chronic.[70]
Most data are from allogeneic HSCT from HLA-matched sibling donors and a few syngeneic transplantations from an identical twin. Data show that allogeneic transplantations have better results than syngeneic transplantations because of some graft versus leukemia effects.
With patients in blast crisis who are imatinib naive, the drug is used in combination with induction regimens similar to those used in acute myelogenous or lymphoblastic leukemia. However, because a high percentage of imatinib-resistant mutations exist in these patients, relapses occur more frequently and at an earlier time from induction. Thus, all efforts are made to perform HSCT as soon as possible.
In patients who attain a complete cytogenetic response (CCyR) after transplantation, National Comprehensive Cancer Network (NCCN) guidelines recommend monitoring with quantitative polymerase chain reaction (qPCR) of peripheral blood every 3 months for 2 years, then every 3–6 months thereafter. In patients who had been in accelerated or blast phase CML, the NCCN recommends considering TKI therapy for at least a year. For patients with positive qPCR results, and those who fail to achieve CCyR, the NCCN recommends consultation with the transplant team; treatment options in these cases include a TKI with or without a reinfusion of T cells collected from the donor (ie, donor lymphocyte infusion). The selection of a TKI is based on prior therapy, BCR-ABL1 mutation profile, and post-transplant morbidities.[26]
Splenectomy and splenic irradiation have been used in patients with large and painful spleens, usually in the late phase of CML. This is rarely needed in patients whose disease is well controlled.
Some authors believe that splenectomy accelerates the onset of myeloid metaplasia in the liver. In addition, splenectomy is associated with high perioperative morbidity and mortality rates because of bleeding or thrombotic complications.
Molecular monitoring in CML is a powerful tool to document treatment responses and predict relapse. Nonetheless, the proliferation of clinical trials and guidelines using the molecular endpoints of CML has outpaced practice norms, commercial laboratory application, and reimbursement practices, leaving some clinicians feeling anxiety (if not confusion and despair) about molecular monitoring in the day-to-day treatment of CML.
Given the power of molecular monitoring in the transplantation setting, which has now been largely displaced by effective TKIs, molecular monitoring was used in the TKI trials as a measure of disease response. Such monitoring is now advocated for the routine clinical care of CML. The cytogenetic response is monitored every 3-6 months. Methods include karyotyping and fluorescence in situ hybridization (FISH) to count the percentage of bone marrow cells that are Ph1 positive.[71]
The most sensitive method for detecting CML is quantitative reverse transcriptase PCR (RT-PCR) for BCR-ABL messenger RNA (mRNA), which can detect one CML cell in approximately 100, 000 to 1 million cells. The assay has well-documented pitfalls, mostly revolving around its complexity and the lack of standardization across laboratories. On an extremely positive note, peripheral blood can be used instead of bone marrow for monitoring, because a good correlation exists between BCR/ABL mRNA in bone marrow and peripheral blood.
Molecular responses are defined by the magnitude of reduction in BCR-ABL transcripts from a standardized value (rather than an individual patient's original level). A major molecular response (MMR) is defined as a more than 3-log reduction in BCR-ABL/control gene ratio. The criteria for monitoring patients receiving TKIs are summarized in the European LeukemiaNet and National Comprehensive Cancer Network (NCCN) guidelines.[72]
The goal is 100% normal cells after 1-2 years of therapy. Patients who remain BCR-ABL positive (ie, those with minimal residual disease [MRD]) should be kept on maintenance therapy as long as they continue to have MRD.
Early monitoring after starting TKI therapy may also be useful in predicting response. The rate of BCR-ABL decline in the initial 2 to 3 months of imatinib therapy is a strong predictor of subsequent response, as patients with less than 1-log reduction after 3 months had a 13% probability of ever achieving an MMR after 2.5 years of follow-up, compared with more than 70% in patients with more than 1-log response.[73]
Cortes et al found that patients with chronic phase CML who have a less than 1-log reduction after 3 months of imatinib therapy had a 55% chance of ever achieving a MMR at 2 years, compared with those with a more than 1-log or 2-log reduction, in whom an MMR was achieved in 84% and 95%, respectively.[74]
More than 80% of newly diagnosed patients with CML in the chronic phase will achieve a complete cytogenetic response with the standard dose of 400 mg/day of imatinib. The probability of progression-free survival is strongly correlated with the level of response, approaching 100% in those patients who achieve molecular remission (a reduction of BCR-ABL mRNA by at least 3-log at 12 mo).
High Sokal risk predicts poorer outcome, but responses during treatment generally override pretherapeutic prognostic variables. When less-sensitive tests become negative, more-sensitive tests are done; thus, monitoring should be tailored to the level of response attained by a given patient.
The standard therapeutic milestones to be achieved are as follows:
At 3 months: complete hematologic response (normal complete blood count and no evidence of extramedullary disease)
At 6 months: minor cytogenetic response (36% to 65% of cells Ph1+)
At 12 months: major cytogenetic response (0% to 35% Ph1+)
At 18 months: complete cytogenetic response (0% Ph1+)
Failure to achieve these milestones should trigger a reassessment of the therapeutic strategy. Most patients with complete cytogenetic response continue to have positive RT-PCR findings, indicating the presence of MRD. Discontinuation of the drug in these patients is usually followed by relapse, suggesting that imatinib fails to eradicate leukemic stem cells in these patients.
Transcript increases after complete cytogenetic response
The BCR-ABL PCR result may rise in a patient for a number of reasons. One possibility is decreased compliance, especially in the context of an expensive drug and a patient who has had a good molecular response (a situation where the temptation to enjoy a “drug holiday” is strong). Second, variability in the test itself may result in some increase or decrease, especially when the tumor burden is very low. In most laboratories, however, a 5- to 10-fold change in the PCR result is probably “real.”
However, it is possible that BCR-ABL levels may vary naturally over time in patients on TKI therapy. CML is known to have cyclic oscillations, with peaks and troughs occurring at even 1- to 2-month intervals, and this has not been studied in cases with residual disease. Several lines of evidence suggest that a truly rising BCR-ABL deserves concern. First, several studies have shown that a rising BCR-ABL is associated with a greater increase of the acquisition of an Abl point mutation and resistance.[75] In addition, loss of MMR is associated with an increased risk of relapse and lower disease-free survival.[76]
Nonetheless, not all patients with a rise in BCR-ABL, or a detectable mutation, inevitably relapse. A reasonable first action is to repeat the test (eg, in a month). If the result is still increased (or is increasing), then mutation testing should be undertaken. The next response depends on how high the BCR-ABL level has risen. A rise from the lowest levels of detection (0.0001%) to a value even 50 times higher would still be well with the range of a MMR. However, a patient who begins at the MMR and rises above that level is certainly heading toward cytogenetic relapse, and here a bone marrow aspirate looking for cytogenetic recurrence would be warranted.
Abl mutations
Patients should be screened for mutations of the BCR-ABL kinase domain whenever there is an indication of loss of response to imatinib at any level. Primary hematologic resistance to imatinib occurs in approximately 5% of patients who fail to achieve complete histologic remission, and 15% show primary cytogenetic resistance in the chronic phase. Secondary or acquired resistance (loss of previous response) is 16% at 42 months and increases to 26% in those previously treated with interferon, and is 73-95% in the accelerated or blast phase.
Quantitative PCR is uniquely sensitive because it amplifies a chimeric mRNA not found in normal cells. The detection of a single point mutation in the tyrosine kinase domain of BCR-ABL against a background of wild type BCR-ABL is obviously a much more difficult task.
The most common method, direct nucleotide sequencing, can detect an Abl tyrosine kinase domain mutation if it composes 10% to 20% of the total BCR-ABL sampled population. The prevalence of abl mutations increases with the “disease time”—that is, these mutations are rare in newly diagnosed chronic-phase CML and increase with late chronic-phase and advanced-phase disease (ie, with increasing Sokal score).Thus, abl mutations occur as part of the natural history of CML, rather than a merely a manifestation of selective pressure from TKI therapy.
Several studies have demonstrated that these mutations are associated with both an increase in loss of cytogenetic response and progression to advanced-phase disease. However, in some cases, particularly in those patients with a low disease burden, mutations can be detected yet remain at a low level and do not cause problems. One should use caution and reason concerning the “2-fold” rule because an increase from a PCR-negative status to a level of 0.0001% would be an infinite increase in BCR-ABL but should not cause much worry.
Thus, screening for mutations would be reasonable in any of the following:
Patients with advanced-phase CML
Patients with chronic-phase CML who are not achieving cytogenetic milestones
Patients with a rising BCR-ABL level, especially one nearing or passing the MMR level
Testing frequency
The European LeukemiaNet (ELN) and National Comprehensive Cancer Network (NCCN) guidelines suggest peripheral blood testing every 3 months for quantitative PCR. On a practical note, however, if a patient has been in an MMR (or, better yet, complete molecular remission) for months, it may be reasonable to extend the testing interval to every 6 months. If a significant change in BCR-ABL level occurs (negative to positive, or a > 2- to 5-fold increase in patients with detectable disease), then resuming more frequent testing is prudent.
Discontinuation of TKI therapy
Discontinuing TKI therapy for certain patients, an approach first put forward in 2006, has the potential to reduce adverse effects associated with lifelong TKI therapy and to be cost-effective measure. Treatment-free remission (TFR) is achieved when a patient who has discontinued TKI therapy maintains an MMR and does not need to restart therapy.
Several guidelines provide recommendations on discontinuation of TKI treatment. ELN guidelines recommend that patients with CML who are responding optimally to treatment continue it indefinitely, but advise that treatment discontinuation may be considered in individual patients, especially women of childbearing age who have achieved an optimal response and are considering pregnancy.[20]
European Society for Medical Oncology (ESMO) guidelines advise that treatment discontinuation may be considered in individual patients, provided that proper, high-quality and certified monitoring can be ensured.[40] ESMO prerequisites for safe discontinuation include the following:
Meeting institutional requirements for safe supervision
Identification of typical BCR-ABL1 transcripts at diagnosis
At least 5 years of TKI therapy
Achievement of MR4.5 (ie, molecular response with 4.5-log reduction)
Stability of deep molecular remission (at least MR4) for at least 2 years
NCCN guidelines state that discontinuation of TKI therapy appears to be safe in select CML patients, but recommend consultation with a CML specialist to review the appropriateness for TKI discontinuation and potential risks and benefits, and advise that some patients have experienced significant adverse events that are believed to be due to TKI discontinuation.[26] NCCN criteria for discontinuation are as follows:
Age ≥18 years.
Chronic phase CML, with no prior history of accelerated or blast phase CML
On approved TKI therapy for at least 3 years.
Prior evidence of quantifiable BCR-ABL1 transcript
Stable molecular response (MR4; BCR-ABL1 ≤0.01% IS) for ≥2 years, as documented on at least 4 tests, performed at least 3 months apart.
Access to a reliable quantitative PCR test with a sensitivity of detection of at least MR4.5 (BCR-ABL1 ≤0.0032% International Scale [IS])
For monitoring after TKI discontinuation, the NCCN recommends monthly molecular monitoring for 1 year, then every 2 months for the second year, and every 3 months thereafter (indefinitely) in patients who remain in MMR (MR3; BCR-ABL1 ≤0.1% IS)
The NCCN recommends prompt resumption of TKI within 4 weeks of a loss of MMR, monthly molecular monitoring until MMR is re-established, then every 3 months thereafter, indefinitely. In patients who fail to achieve MMR after 3 months of TKI resumption, BCR-ABL1 kinase domain mutation testing should be performed, and monthly molecular monitoring should be continued for another 6 months.[26]
In general, patients in the chronic phase of CML with a stable, prolonged, and deep molecular response (DMR) for ≥2 years might be ready to discontinue TKI therapy.[77, 78, 26, 79]
Patients who have achieved an MMR/MR but have not reached a DMR and are therefore not eligible to attempt TFR should be reassured by their physicians that they have still reached a treatment goal or safe haven and can continue receiving TKI treatment and have a similar life expectancy to that of the general population. If these patients continue to adhere to treatment they may in time reach a deeper molecular response, at which point, once sustained, TFR might be an option.
If a patient wishes to stop treatment because of problems with the TKI, the physician should discuss with the patient the possibility of switching to a different TKI that might enable achievement of a deeper molecular response. At this time, the patient should be advised about the adverse-effect profiles of TKI treatments.
Before discontinuing TKI therapy, the physician needs to confirm that the patient understands the need to attend more-frequent routine clinic visits (eg, montlhly for the first year) and undergo regular and lifelong monitoring. TFR does not mean a cure, and molecular recurrence can develop at any time, requiring TKI treatment to be restarted. Clinical monitoring will also enable the identification of long-term toxicity of previous TKI therapy.
The treating physician should discuss TKI withdrawal syndrome with patients thinking about discontinuing TKI therapy. TKI withdrawal syndrome is seen in up to 30% of patients and can last for months. The syndrome consists principally of musculoskeletal pain. Generally, the pain can be managed with over-the-counter pain medications such as acetaminophen or nonsteroidal anti-inflammatory drugs. In more severe cases, corticosteroids may be indicated.
TKI withdrawal syndrome does not appear to be dependent on the particular TKI the patient was taking, and its occurrence has been associated with a greater chance of achieving successful TFR.
Screening for potential psychological issues associated with TFR should form a part of routine monitoring, because certain patients may require professional psychological help. Physicians should also be aware that patients could experience anxiety as a result of fluctuating BCR-ABL blood levels during TFR. The main anxiety that patients have experienced is a fear of disease recurrence or progression.
About 82% of patients would be willing to stop TKI therapy if their disease were likely to remain stable and, if treatment needed to be restarted, the probability of a response to TKI therapy were high.[77] Patients were also more likely to attempt TFR if their risk of recurrence was < 30%; in fact, 40% to 60% of patients sustain TFR for longer than 1 to 2 years. Most cases of molecular recurrence will develop within the first 6 months of stopping TKI therapy, and the confirmed loss of MMR should be seen as an indication to restart therapy. Late molecular recurrences do develop; thus, patient adherence to monitoring during TFR is vital to detect recurrence and ensure protection from disease progression.
Factors that are potentially predictive of molecular recurrence include previous TKI treatment duration and previous duration of DMR. Studies have shown that resuming TKI therapy immediately after the loss of MMR results in regaining MMR in almost all patients. No risk, to date, has been found of developing resistance to TKIs, and attempting a second TKI discontinuation after molecular recurrence is possible, once a prolonged DMR has again been achieved. Some data have shown this might be effective in ∼30% of cases after an adequate duration of the re-achieved DMR. The speed of molecular recurrence after the first attempt at TFR was the only factor associated with a poorer outcome with the second attempt.
Worldwide, more than 2000 patients with CML have attempted TFR, and no instances of disease progression have been reported. Attempting TFR may become a standard part of CML care, and with patients’ concerns addressed in patient–physician discussions, a greater number of eligible patients will be willing to discontinue TKI therapy and attempt TFR outside a clinical trial.
Guidelines contributor:Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Guidelines for the management of chronic myelogenous leukemia (CML) have been issued by the following organizations:
National Comprehensive Cancer Network (NCCN)[26]
European LeukemiaNet (ELN)[20]
European Society of Medical Oncology (ESMO)[40]
Diagnosis
NCCN guidelines recommend that the workup in patients with suspected CML include the following[26] :
History and physical examination, including spleen size by palpation (cm below costal margin)
Complete blood cell count (CBC) with differential
Chemistry profile
Bone marrow aspirate and biopsy for morphologic review and cytogenetic evaluation
Quantitative reverse transcriptase polymerase chain reaction (qPCR) using International Scale (IS) for BCR-ABL1 in peripheral blood
Hepatitis B panel, as reactivation has been reported in patients receiving tyrosine kinase inhibitors (TKIs)
ELN guidelines recommend the following as a baseline diagnostic workup for CML[20] :
Physical examination with particular reference to spleen and liver size
CBC with microscopic differential
Bone marrow aspirate for cytologic examination and cytogenetics; core biopsy if dry tap
Chromosome banding analysis (CBA)
Fluorescence in situ hybridization (FISH) only in case of Ph negativity
qPCR for the detection of BCR-ABL1 transcripts and identification of the transcript type
Electrocardiogram
Standard biochemical profile with hepatitis B serology
ESMO guidelines recommend the following as a baseline diagnostic workup for CML[40] :
CBC with differential
Bone marrow cytology and karyotype
Qualitative RT-PCR (ESMO recommends quantitative PCR only for assessing and monitoring treatment response)
Mutational analysis, only for patients in accelerated or blast phase
Treatment
For chronic-phase CML, treatment recommendations are as follows:
All of the guidelines recommend the TKIs imatinib, nilotinib, or dasatinib as first-line treatment for CML; NCCN and ELN also include bosutinib, and ESMO notes that other strategies include using higher doses of imatinib or combining a TKI with an additional agent, such as interferon-α.
All the guidelines agree that the selection of first-line TKI therapy should be based on the patient's risk score, ability to tolerate therapy, and comorbid conditions and the adverse effect profile of the TKI
In case of intolerance, patients can be switched to another TKI; ESMO and ELN list bosutinib as an option in this setting
All TKIs can be used as second-line treatment; doses may differ in the second-line setting, depending on the agent chosen
BCR-ABL kinase domain mutation analysis, evaluation of drug interactions, and compliance to therapy are recommended before the start of second-line TKI therapy.
Ponatinib is the preferred treatment option for patients with the BCR-ABL T315I mutation and for those with resistance to or intolerance of several TKIs.
Allogeneic hematopoietic stem cell transplantation (HSCT) should be considered in the case of failure of two TKIs.
For accelerated-phase CML, all the guidelines recommend the following:
Choice of TKI is based on prior therapy and/or BCR-ABL kinase domain mutation status
Recommended doses of imatinib, nilotinib, and dasatinib are higher for accelerated phase than for chronic phase
If resistance and/or intolerance to two or more TKIs occurs, consider omacetaxine
Consider HSCT, based on treatment response and patient age
For blast-phase CML, all the guidelines recommend the following:
HSCT, preferably after response to induction therapy
Patients in lymphoid blast phase can be treated with acute lymphoblastic leukemia (ALL) induction chemotherapy regimens in combination with a TKI
Patients in myeloid blast crisis can be treated with acute myeloid leukemia (AML) induction chemotherapy regimens in combination with a TKI
The ELN notes that the second-generation TKIs have never been tested against each other, but the guidelines include recommendations for selection of a TKI in patients with identified BCR-ABL1 resistance mutations.[20] See the table below.
Table 1. BCR-ABL mutations and recommended tyrosine kinase inhibitors
View Table
See Table
The ELN notes that some in vitro data suggest that the E255K and, to a lesser extent, the E255V mutation might be poorly sensitive to bosutinib, but in vivo data on this question are limited.
Monitoring
NCCN, ELN, and ESMO guidelines recommend the following tests for monitoring response to TKI therapy[26, 40] :
Bone marrow cytogenetics
Quantitative reverse transcription polymerase chain reaction (qPCR) standardized by International Scale (IS)
The three guidelines vary in their recommendations regarding response to first-line treatment, as outlined below.
NCCN Recommendations
NCCN guidelines include criteria for complete hematologic response, cytogenetic response, and molecular response.[26] The criteria for complete hematologic response are as follows:
Complete normalization of peripheral blood counts, with leukocyte count < 10 × 109/L
Platelet count < 450 × 109/L
No immature cells (eg, myelocytes, promyelocytes, or blasts) in peripheral blood
No signs and symptoms of disease, with resolution of palpable splenomegaly
The criteria for cytogenetic response are as follows:
Complete cytogenetic response (CCyR): No Philadelphia chromosome positive (Ph+) metaphases
Major cytogenetic response (MCyR): 0%–35% Ph+ metaphases
After BCR-ABL1 (IS) ≤1% (> 0.1%–1%) has been achieved, qPCR testing should be repeated every 3 months for 2 years and every 3–6 months thereafter; if there is 1-log increase in BCR-ABL1 transcript levels with major molecular response, qPCR should be repeated in 1-3 months.
European LeukemiaNet
The optimal responses to first-line treatment are as follows[20] :
3 months: BCR-ABL1 transcripts ≤10%
6 months: BCR-ABL1 transcripts ≤1%
12 months: BCR-ABL1 transcripts ≤0.1%
Any time: BCR-ABL1 transcripts ≤0.1%
European Society for Medical Oncology (ESMO)
The optimal responses to first-line treatment are as follows[40] :
The medications used for patients with chronic-phase chronic myelogenous leukemia (CML) aim at delaying the onset of the accelerated or blastic phase. This historically included a myelosuppressive agent to achieve hematologic remission, but in recent decades more effective drugs—successively, interferon alfa, then targeted therapy with tyrosine kinase inhibitors (TKIs), starting with imatinib—have taken precedence. Nevertheless, the older agents continue to play a limited role (eg, use of interferon in combination with TKI therapy). Chemotherapy may be used, particularly in preparation for hematopoietic stem cell transplantation.
Clinical Context:
Hydroxyurea is an inhibitor of deoxynucleotide synthesis. This agent is used to control high WBC counts before testing has confirmed the presence of BCR-ABL1 fusion, or during induction with imatinib; it is discontinued once control is established. Hydroxyurea is less leukemogenic than alkylating agents such as busulfan, melphalan, or chlorambucil. Myelosuppressive effects last a few days to a week and are easier to control than with alkylating agents.
Clinical Context:
Busulfan is a potent cytotoxic drug that, at recommended dosage, causes profound myelosuppression. As an alkylating agent, the mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. It is used in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation for CML.
Clinical Context:
Omacetaxine is a protein synthesis inhibitor that is independent of direct Bcr-Abl binding. It binds to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit from a strain of archaeabacteria. It is indicated for chronic- or accelerated-phase CML with resistance and/or intolerance to ≥2 tyrosine kinase inhibitors.
To control the underlying hyperproliferation of the myeloid elements, a myelosuppressive agent is used to bring down WBC counts and, occasionally, elevated platelet counts. Spleen size correlates with WBC counts, and it shrinks as WBC counts approach the reference range. Also, intermediate and myeloblast cells disappear from the circulation.
Clinical Context:
Imatinib is specifically designed to inhibit the tyrosine kinase activity of BCR-ABL kinase in Ph1-positive leukemic CML cell lines. It is indicated for treatment of Ph+ CML in chronic phase (newly diagnosed) in adults and children and treatment of Ph+ CML in blast crisis, accelerated phase, or chronic phase after failure of interferon-alfa therapy.
Clinical Context:
Dasatinib is a multiple tyrosine kinase inhibitor. It inhibits growth of cell lines overexpressing BCR-ABL. It has been able to overcome imatinib resistance resulting from BCR/ABL kinase domain mutations.
Dasatinib is indicated for newly diagnosed adults with Philadelphia chromosome-positive (Ph+) CML in chronic phase, adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib, adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy, and pediatric patients with Ph+ CML in chronic phase.
Clinical Context:
Nilotinib is a selective tyrosine kinase inhibitor that targets BCR-ABL kinase, c-KIT and platelet derived growth factor receptor (PDGFR). Nilotinib inhibits BCR-ABL mediated proliferation of leukemic cell lines by binding to the ATP-binding site of BCR-ABL and inhibiting tyrosine kinase activity. Nilotinib has activity in imatinib-resistant BCR-ABL kinase mutations. It is indicated in adults for the treatment of newly diagnosed Ph+ CML and chronic or accelerated phase Ph+ CML resistant to or intolerant to prior therapy that included imatinib. Also indicated in pediatric patients (≥1 year) for the treatment of newly diagnosed Ph+ CML and chronic phase Ph+ CML resistant or intolerant to prior tyrosine-kinase inhibitor (TKI) therapy.
Clinical Context:
Bosutinib is a tyrosine kinase inhibitor. It inhibits the Bcr-Abl kinase that promotes CML, and it also inhibits SRc-family kinases, including Src, Lyn, and Hck. It inhibits 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines, but does not inhibit T315I and V299L mutant cells.This kinase inhibitor indicated for treatment of adults and pediatric patients 1 year of age and older with chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) that is newly diagnosed (ND) or resistant or intolerant (R/I) to prior therapy.
Clinical Context:
Ponatinib is a kinase inhibitor indicated for patients with CML or Ph+ ALL that is resistant or intolerant to prior tyrosine kinase inhibitor therapy, including those with the T315I mutation. Because of its high risk for thromboembolic events, it is indicated for patients with T315I-positive, Ph+ ALL for whom no other TKI therapy is indicated.
Clinical Context:
Asciminib is a kinase inhibitor that binds to the ABL-myristoyl pockets and inhibits ABL1-kinase activity. It has been granted accelerated approval for CML in chronic-phase Ph+ CML (Ph+ CML-CP) in adults who have been previously treated with 2 or more tyrosine kinase inhibitors. It is also indicated for Ph+ CML-CP in adults with T3151 mutation.
Clinical Context:
Orally bioavailable inhibitor of the FGFR types 1, 2, and 3 (FGFR1/2/3). Pemigatinib inhibits FGFR 1/2/3 phosphorylation and signaling, and decreases cell viability in cancer cell lines with activating FGFR amplifications and fusions. It is indicated for relapsed or refractory MLNs in adults with FGFR1 rearrangement.
Clinical Context:
Alfa, beta, and gamma are the 3 types of interferons known to date. The alfa group has been found to inhibit propagation of Ph1-positive hematopoietic clones, allowing return of normal cells in bone marrow.
Alfa, beta, and gamma are the 3 types of interferons known to date. The alfa group has been found to inhibit propagation of Ph-positive hematopoietic clone, allowing return of normal cells in bone marrow.
How is chronic myelogenous leukemia (CML) characterized?What are the signs and symptoms of chronic myelogenous leukemia (CML)?What are the signs and symptoms of progressive myelogenous leukemia (CML)?How is chronic myelogenous leukemia (CML) diagnosed?Which lab tests are performed in the workup of chronic myelogenous leukemia (CML)?Which blood count and peripheral smear findings suggest chronic myelogenous leukemia (CML)?Which bone marrow findings suggest chronic myelogenous leukemia (CML)?What are the goals of treatment of chronic myelogenous leukemia (CML)?Which medications are used in the treatment of chronic myelogenous leukemia (CML)?What is the role of allogeneic bone marrow transplantation (BMT) or stem cell transplantation in the treatment of chronic myelogenous leukemia (CML)?What is supportive care for chronic myelogenous leukemia (CML)?What is chronic myelogenous leukemia (CML)?What is the pathophysiology of chronic myelogenous leukemia (CML)?What is the prevalence of chronic myelogenous leukemia (CML)?What is the prognosis of chronic myelogenous leukemia (CML)?How is chronic myelogenous leukemia (CML) staged?Which scores are used to determine the prognosis for chronic myelogenous leukemia (CML)?What a combined prognostic model for chronic myelogenous leukemia (CML)?What are the clinical and lab poor prognostic factors for chronic myelogenous leukemia (CML)?Which therapy-associated factors may indicate a poor prognosis of chronic myelogenous leukemia (CML)?What is the median survival according to treatment used in chronic myelogenous leukemia (CML)?What is the efficacy of imatinib in the treatment of chronic myelogenous leukemia (CML)?How do additional chromosomal abnormalities (ACAs) affect the prognosis of chronic myelogenous leukemia (CML)?Where can patients find information about chronic myelogenous leukemia (CML)?Which clinical history findings are characteristic of chronic myelogenous leukemia (CML)?Which physical findings are characteristic of chronic myelogenous leukemia (CML)?Which conditions are included in the differential diagnoses of chronic myelogenous leukemia (CML)?What are the differential diagnoses for Chronic Myelogenous Leukemia (CML)?How is chronic myelogenous leukemia (CML) diagnosed?What is the role of blood count and peripheral smear in the workup of chronic myelogenous leukemia (CML)?What is the role of bone marrow analysis in the workup of chronic myelogenous leukemia (CML)?What is the goal of treatment for chronic myelogenous leukemia (CML)?How is chronic myelogenous leukemia (CML) treated?How is the choice of (TKI) made for the treatment of chronic myelogenous leukemia (CML)?What is the role of second-generation TKIs in the treatment of chronic myelogenous leukemia (CML)?What is the role of dasatinib in the treatment of chronic myelogenous leukemia (CML)?What is the role of nilotinib in the treatment of chronic myelogenous leukemia (CML)?What is the role of bosutinib in the treatment of chronic myelogenous leukemia (CML)?What is the role of ponatinib in the treatment of chronic myelogenous leukemia (CML)?Which factors should be weighed in the selection of in the selection of a specific tyrosine kinase inhibitor (TKI) to treat chronic myelogenous leukemia (CML)?What is the role of protein translation inhibitors in the treatment of chronic myelogenous leukemia (CML)?What is the role of myelosuppressive therapy in the treatment of chronic myelogenous leukemia (CML)?What is the role of hydroxyurea in the treatment of chronic myelogenous leukemia (CML)?What is the role of busulfan in the treatment of chronic myelogenous leukemia (CML)?What is the role of leukapheresis in the treatment of chronic myelogenous leukemia (CML)?What is the role of interferon alfa in the treatment of chronic myelogenous leukemia (CML)?What is the role of allogeneic bone marrow transplantation (BMT) in the treatment of chronic myelogenous leukemia (CML)?What are the mortality rates for chronic myelogenous leukemia (CML) following allogeneic BMT?What is the role of splenectomy in the treatment of chronic myelogenous leukemia (CML)?What causes the BCR-ABL PCR result to rise in patients with chronic myelogenous leukemia (CML)?What is included in long-term monitoring of chronic myelogenous leukemia (CML)?What are the standard therapeutic milestones achieved following treatment of chronic myelogenous leukemia (CML)?What are the indications for BCR/ABL mutation screening in patients with chronic myelogenous leukemia (CML)?What is the recommended interval for peripheral blood testing in patients with chronic myelogenous leukemia (CML)?When should tyrosine kinase inhibitor (TKI) therapy be discontinued for chronic myelogenous leukemia (CML)?What is the role of imatinib mesylate in the treatment of chronic myelogenous leukemia (CML)?What organizations have issued guidelines on the treatment of chronic myelogenous leukemia (CML)?What are treatment guidelines for chronic-phase chronic myelogenous leukemia (CML)?What are the treatment guidelines for accelerated-phase chronic myelogenous leukemia (CML)?What are the treatment guidelines for blast-phase chronic myelogenous leukemia (CML)?Which tests are recommended by the guidelines for monitoring response to tyrosine kinase inhibitor (TKI) therapy of chronic myelogenous leukemia (CML)?What are the NCCN guidelines desired responses to first-line treatment for chronic myelogenous leukemia (CML)?What are the ELN guidelines optimal responses to first-line treatment of chronic myelogenous leukemia (CML)?What are the ESMO guidelines concerning optimal responses to first-line treatment of chronic myelogenous leukemia (CML)?What is the role of medications in the treatment of chronic myelogenous leukemia (CML)?Which medications in the drug class FGFR Inhibitors are used in the treatment of Chronic Myelogenous Leukemia (CML)?Which medications in the drug class Tyrosine Kinase Inhibitors are used in the treatment of Chronic Myelogenous Leukemia (CML)?Which medications in the drug class Antineoplastic Agents are used in the treatment of Chronic Myelogenous Leukemia (CML)?
Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Disclosure: Nothing to disclose.
Chief Editor
Sara J Grethlein, MD, MBA, FACP, Executive Medical Director and Medical Oncologist, Swedish Cancer Institute
Disclosure: Nothing to disclose.
Additional Contributors
Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.
Acknowledgements
Bruce Buehler, MD Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.
Maurie Markman, MD Vice President for Medical Oncology Services, National Director for Medical Oncology, Cancer Treatment Centers of America
Maurie Markman, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, and American Society of Hematology
Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center
Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership
Clarence Sarkodee-Adoo, MD Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program
Disclosure: Takeda Millenium Honoraria Speaking and teaching
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
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Chronic myelogenous leukemia. Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows). Courtesy of Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine.
Chronic myelogenous leukemia. Blood film at 400X magnification demonstrates leukocytosis with the presence of precursor cells of the myeloid lineage. In addition, basophilia, eosinophilia, and thrombocytosis can be seen. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Chronic myelogenous leukemia. Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Chronic myelogenous leukemia. Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Chronic myelogenous leukemia. Bone marrow film at 400X magnification demonstrates clear dominance of granulopoiesis. The number of eosinophils and megakaryocytes is increased. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows). Courtesy of Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine.
Chronic myelogenous leukemia. Fluorescence in situ hybridization using unique-sequence, double-fusion DNA probes for bcr (22q11.2) in red and c-abl (9q34) gene regions in green. The abnormal bcr/abl fusion present in Philadelphia chromosome–positive cells is in yellow (right panel) compared with a control (left panel). Courtesy of Emmanuel C. Besa, MD.
Chronic myelogenous leukemia. Blood film at 400X magnification demonstrates leukocytosis with the presence of precursor cells of the myeloid lineage. In addition, basophilia, eosinophilia, and thrombocytosis can be seen. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Chronic myelogenous leukemia. Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Chronic myelogenous leukemia. Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Chronic myelogenous leukemia. Bone marrow film at 400X magnification demonstrates clear dominance of granulopoiesis. The number of eosinophils and megakaryocytes is increased. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows). Courtesy of Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine.
Chronic myelogenous leukemia. Fluorescence in situ hybridization using unique-sequence, double-fusion DNA probes for bcr (22q11.2) in red and c-abl (9q34) gene regions in green. The abnormal bcr/abl fusion present in Philadelphia chromosome–positive cells is in yellow (right panel) compared with a control (left panel). Courtesy of Emmanuel C. Besa, MD.
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