Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of the primitive hemopoietic stem cell. The disease is monoclonal in origin, affecting myeloid, monocytic, erythroid, megakaryocytic, B-cell, and, sometimes, T-cell lineages.
CML accounts for 15% of all leukemias in adults. In adults the incidence is approximately 1 to 1.5 cases per 100,000 population.
Estimated new cases and deaths from chronic myeloid leukemia in the United States in 2005:
- New cases: 4,600
- Deaths: 850
The male-to-female ratio is 1.4 to 2.2:1.
The median age of patients with Ph1-positive CML (Chronic Myeloid Leukemia) is 67 years of age.
Race and ethnicity
Incidence rates are similar among all race/ethnicities.
CML has been observed in studies following the atom bomb explosions in Japan in 1945.
Causes and risk factors
In the great majority of patients, a causative factor cannot be identified. Some associations with genetic and environmental factors have been reported, but in most cases, no such factors can be identified.
Nuclear and radiation exposures, including therapeutic radiation, have been associated with the development of CML. CML has been observed in studies following the atom bomb explosions in Japan in 1945, and by earlier studies in radiologists and in patients with ankylosing spondylitis treated with radiation therapy. However, this accounts for only a small portion of cases.
Exposure to chemicals has not been associated with greater risk except for the use of benzene.
There is little evidence linking genetic factors to CML. Offspring of parents with CML do not have a higher incidence of CML than the general population.
Symptoms and signs
The disease usually has a biphasic, and sometimes triphasic, course.
The initial phase is the chronic phase, which is frequently asymptomatic. Patients with symptoms usually have a gradual onset of:
- Fatigue, anorexia, weight loss, increased sweating,
- Left upper quadrant discomfort, and early satiety as a result of splenic enlargement.
- Rare patients with very high counts of white blood cells (WBCs) may have manifestations of hyperviscosity, including priapism, tinnitus, stupor, visual changes from retinal hemorrhages, and even cerebrovascular accidents.
On physical exam, splenomegaly is the most common finding which is sometimes associated with liver enlargement. The spleen may be enormous, filling most of the abdomen and presenting a significant clinical problem, or the spleen may be only minimally enlarged. In about 10% of patients, the spleen is neither palpable nor enlarged on splenic scan.
The accelerated phase is an ill-defined transitional phase that is frequently asymptomatic. The diagnosis is made from changes in peripheral blood or bone marrow. There is greater than 5% blasts in the peripheral blood or bone marrow but less than 30% blasts in both the peripheral blood and bone marrow. Some patients may have fever, night sweats, and progressive enlargement of the spleen. At least 20% of patients enter a blastic phase without evidence of having had accelerated phase.
Signs and symptoms commonly heralding such a change include the following:
- Progressive leukocytosis.
- Thrombocytosis or thrombocytopenia.
- Increasing and painful splenomegaly or hepatomegaly.
- Bone pain.
- Development of destructive bone lesions.
- Thrombotic or bleeding complications.
The diagnosis of blastic phase requires the presence of at least 30% of blasts in the bone marrow or peripheral blood.
Patients in the blastic phase are more likely to have symptoms, including:
- Weight loss, fever, night sweats, and bone pains.
- Symptoms of anemia, infectious complications, and bleeding are commonly seen.
- Signs of central nervous system (CNS) leukemia can also be seen in this phase.
- In the blastic phase, tissue infiltration can occur, most frequently to the lymph nodes, skin, subcutaneous tissues, and bone.
The annual rate of progression from chronic phase to blast crisis is 5% to 10% in the first 2 years and 20% in subsequent years. At least 20% of patients enter a blastic phase without evidence of having had accelerated phase.
Complete blood count (CBC)
- The most common feature of CML is an elevated WBC count, usually > 25,000 and frequently > 100,000.
- The finding of unexplained, persistent leukocytosis (> 12,000) in the absence of infections or other causes of WBC count elevation should prompt a work-up for CML.
The WBC differential usually shows granulocytes in all stages of maturation, from blasts to mature, morphologically normal granulocytes.
- Basophils are elevated, but only 10%-15% of patients have = 7% basophils in the peripheral blood.
- Eosinophils may also be mildly increased.
- The absolute lymphocyte count is elevated at the expense of T lymphocytes.
- The platelet count is elevated in 30%-50% of patients and is higher than 1,000 - 109/L in a small percentage of patients with CML.
However, in some cases blood elements may be decreased:
- Thrombocytopenia is usually signals disease acceleration.
- Some patients have mild anemia at diagnosis.
- Neutrophil function is usually normal or only mildly impaired, but natural killer (NK) cell activity is impaired.
- As in the other myeloproliferative diseases, platelet function is frequently abnormal and nonspecific; it may have no clinical significance. Clinically, thrombosis and hemorrhage are not common despite elevated platelet counts and platelet function abnormality.
Bone marrow examination
All stages of maturation of the WBC series are usually seen, but the myelocyte predominates. Histopathologic examination of bone marrow aspirate demonstrates a shift in the myeloid series to immature forms that increase in number as patients progress to the blastic phase of the disease.
- The marrow is hypercellular with cellularity of 75%-90% and maybe accompanied by increased numbers of eosinophils or basophils, and sometimes monocytosis is seen.
- Increased megakaryocytes are often found in the marrow, and sometimes fragments of megakaryocytic nuclei are present in the blood, especially when the platelet count is very high.
- The percentage of lymphocytes is reduced in both the marrow and blood in comparison with normal subjects, and the myeloid/erythroid ratio in the marrow is usually greatly elevated (usually 10-30:1).
Neutrophil alkaline phosphatase
The leukocyte alkaline phosphatase enzyme is either absent or markedly reduced in the neutrophils of patients with chronic myelogenous leukemia.
The Philadelphia chromosome
CML (Chronic Myeloid Leukemia) is a clonal disorder that is usually easily diagnosed because the leukemic cells of more than 95% of patients have a distinctive cytogenetic abnormality, the Philadelphia chromosome (Ph1).
The Philadelphia chromosome (Ph1) is usually more readily apparent in marrow metaphases than in peripheral blood metaphases; in some cases, it may be mashed and reverse transcriptase-polymerase chain reaction (RT-PCR) or fluorescent in situ hybridization (FISH) analyses on blood or marrow aspirates may be necessary to demonstrate the 9;22 translocation.
- Conventional cytogenetics has a sensitivity 1 in 20 cells.
- FISH has a sensitivity 1 in 500 cells.
- PCR has a sensitivity of 1 in 10,000 to 1,000,000.
The Philadelphia chromosome
The Ph1 results from a reciprocal translocation between the long arms of chromosomes 9 and 22 t(9;22)(q34;q11) and is demonstrable in all hematopoietic precursors. This in turn results in a fused bcr-abl gene and in the production of an abnormal tyrosine kinase protein that causes the disordered myelopoiesis found in CML.
- In chromosome 9: The c-abl proto-oncogene located in chromosome 9q34 encodes for a nonreceptor protein-tyrosine kinase expressed in most mammalian cells.
- In chromosome 22: The breakpoint occurs within the BCR gene and usually involves an area known as the breakpoint cluster region (bcr), located either between exons b3 and b4 or between exons b2 and b3.
- The fusion: There are two different fusion genes can be formed, both of them joining exon 2 of abl with either exon 2 (b2a2) or exon 3 of bcr (b3a2).
Upon translation, a new protein with a molecular weight of 210 kd (p210BCR-ABL) is synthesized, which, compared to the normal c-abl, has markedly increased kinase activity and can transform transfected cells and induce leukemia in transgenic mice. The mechanism of oncogenesis of p210BCR-ABL is unclear, but, upon phosphorylation, it can activate several intracellular pathways, including ras and the MAP kinase pathway, the Jak-Stat pathway, the PI3 kinase pathway, and the myc pathway. Ultimately, this leads to altered adhesion to extracellular matrix and stroma, constitutive activation of mitogenic signals, and inhibition of apoptosis.
Philadelphia negative CML
Philadelphia negative CML differs from typical CML and may be a different disease. The age profile is different with the Philadelphia negative variety favoring young children and elderly persons. The leucocyte and platelet counts tend to be lower. The bone marrow tends to show more immature cells in the myeloid series. The NAP score is higher. The prognosis of this type of CML is poorer.
Clonal studies have demonstrated that CML is a clonal disease of an abnormal stem cell. Myeloid, erythroid, megakaryocytic and most lymphoid cells are involved in the malignant clone.
Staging and prognostic factors
Staging of CML
- See staging of CML (Chronic Myeloid Leukemia)
The following factors predict for a shorter chronic phase.
- Increased splenomegaly
- Older age
- Male sex
- Elevated serum lactate dehydrogenase,
- Cytogenetic abnormalities in addition to the Ph chromosome,
- A higher proportion of marrow or peripheral blood blasts, basophilia, eosinophilia, thrombocytosis, and anemia
At initial diagnosis, consideration should be given to referral of patients younger than age 60 years to centers with bone marrow transplantation when appropriate donors are available. This should be done during the first year of diagnosis.
In chronic phase CML, a hematologic response was defined as a 50% reduction in WBC counts from baseline sustained for at least 2 weeks. A Complete Hematologic Response (CHR) was defined as WBC < 10,000 per mm3and platelet count < 450,000 per mm3 maintained for at least 4 weeks.
In blast crisis CML, a hematologic response is defined as a decrease in bone marrow blast count to < 5%, the disappearance of blasts in the peripheral blood, an absolute neutrophil count > 1000 cells/mm3and platelet count > 100,000 cells/mm3. Patients who did not meet the criteria for a complete hematologic response may be categorized according to marrow response.
A marrow response is defined as either a decrease in the blast count to < 5% or between 5-15% regardless of peripheral blood cell counts.
- Disease progression is defined as an increase in marrow blasts > 15%, increase in peripheral blood blasts > 5% or WBC > 20,000 cells/mm3.
- A relapse is defined as evidence of disease progression or death.
Cytogenetic responses (CR) were defined in terms of percentage of cells in metaphase existing within the bone marrow that were Philadelphia (Ph) chromosome positive. These responses were based upon a sample size of twenty cells in metaphase.
- A Complete Cytogenetic Response (CCR) was defined as no Ph(+) cells.
- A partial CR was defined as < 35% cells that were Ph(+).
- A minor CR was defined as 35-65% cells that were Ph(+).
- A lack of CR was identified when >65% cells were Ph(+).
- A major cytogenetic response (MCR) is comprised of complete and partial responses.
Standardization studies are ongoing and definition of molecular response currently vary.
- Complete molecular response: no detectable bcr-abl transcripts by RT-PCR.
- Major molecular response: = 3-log reduction in the level of bcr-abl transcripts or bcr-abl/abl ratio ≤ 0.05%.
Imatinib mesylate (Glivec)
Imatinib mesylate (STI571) also know as Glivec specifically inhibits the proliferation of CML-derived cell-lines and the clonogenic growth of cells from the bone marrow of patients with CML.
It has demonstrated significant activity in patients with CML in all phases of the disease, whether they have received prior therapy or not.
The standard dose of imatinib mesylate is 400 mg daily for chronic phase and 600 mg for accelerated and blastic phases. At this time, the duration of therapy is unclear. A minority of patients have reached undetectable levels of disease by PCR, and few have discontinued therapy. Thus, until further evidence becomes available, patients should continue therapy indefinitely.
- Among patients with chronic - phase CML for whom prior IFN-α therapy failed, 65%-85% of patients achieved a major cytogenetic remission, including 45%-80% with a complete cytogenetic remission. The estimated disease progression-free survival is 89% at 18 months.
- Among patients treated in early chronic-phase CML who had not received prior therapy, the rate of complete cytogenetic response is 75%-90%.
All patients have to be evaluated with cytogenetic analysis before the start of therapy, and a baseline quantitative polymerase chain reaction (PCR) analysis is useful. A cytogenetic analysis every 3 to 6 months during the first year and every 6 to 12 months thereafter is recommended. Quantitative PCR is recommended every 3 to 6 months.
Allogeneic bone marrow transplantation
Allogeneic BMT is potentially curative in CML, although late relapses have been reported.
- Long- term survival rates of 50%-80% and disease free survival rates of 30%-70% can be achieved in the chronic phase.
- 40-50% mortality rate.
Predictors of response
- Early BMT within the first 1-3 years after diagnosis may be associated with a better outcome than BMT later in the course of disease.
- Younger patients also have a better outcome than older patients, with those younger than age 20 having the best prognosis.
- The use of the Gratwohl score helps to separate those patients who may have a better outcome from those who will not.
Alternatives to matched-related donors
For patients who do not have a matched-related donor, matched unrelated donor (MUD) transplants are reasonable alternatives.
The 9-year experience from the National Marrow Donor Program in 1,432 patients reported a 3-year survival rate of 37.5%. Early transplantation results in better outcome, with patients transplanted in chronic phase having a 3-year disease-free survival of 63%.
Relapse after BMT
Donor leukocyte reinfusions are the most effective strategy to treat patients who relapse after BMT. With this strategy, 70%-80% of patients can achieve a cytogenetic complete response; the best results are achieved when patients are treated during cytogenetic relapse.
Imatinib mesylate has also been effective for patients who relapse after BMT. A complete hematologic response in > 70% of patients and a cytogenetic response in 58% have been reported, with the best responses obtained in patients relapsing in chronic phase.
- No compatible related donor Most patients (> 70%) do not have a related HLA-compatible donor
- Matched-related or one-antigen-mismatched donor
- Imatinib mesylate failure
- Although 40%-70% of patients can achieve some degree of suppression of Ph chromosome- positive cells upon engraftment of the autologous transplant, this result is usually short-lived, and most patients relapse within 1 year.
- Some patients previously refractory to rIFN-α may regain sensitivity after autologous BMT.
The role of autologous BMT with cells collected after complete response to imatinib mesylate and with imatinib mesylate-based therapy after transplantation is currently being investigated.
Standard drug therapy (e.g. with hydroyxurea) is administered to diminish WBC count to approximately 10,000 per cubic millimeter without producing marrow hypoplasia. Leukapheresis and platelet pheresis can also be used to rapidly lower extremely high WBC and platelet counts although this is only of temporary benefit and is rarely required in adults in chronic phase.
Its use should be limited to temporary control of hematologic manifestations before definitive therapy (e.g. imatinib mesylate, stem-cell transplantation) is instituted.
Busulfan is usually given at a dose of 0.1 mg/kg/d until the WBC count decreases by 50%, at which point the dose is reduced by 50%. Therapy is discontinued when the WBC count drops below 20 × 109/L and is restarted when it rises above 50 × 109/L.
Busulfan is associated with lung, marrow, and heart fibrosis and can cause an Addison-like disease. In 10% of patients, prolonged myelosuppression may be observed.
Its use should be limited to temporary control of hematologic manifestations before definitive therapy (e.g. imatinib mesylate, stem-cell transplantation) is instituted.
Both busulfan and hydroxyurea can control the hematologic manifestations of CML in more than 70% of all patients, although hydroxyurea results in a longer duration of chronic phase and overall survival than does busulfan. Neither drug significantly reduces the percentage of cells bearing the Ph chromosome, and, therefore, transformation to the blastic phase is unchanged.
Interferon alfa may produce partial or complete remissions in chronic phase CML. Cytogenetic responses have been reported in up to 20% of patients, with delay of disease progression and prolongation of overall survival.
- A complete hematologic response is induced in 70%-80% of patients
- A cytogenetic response is achieved in 40%-60% of patients (in which there is some degree of suppression of Ph chromosome-positive cells)
- A complete cytogenetic response in 5% of patients
- A major cytogenetic response in approximately 15%
- Complete cytogenetic responses are durable in = 80% of cases. These patients also have a 10-year survival rate of 75% or more
The addition of cytarabine (Ara-C) can improve the rate of both complete and major cytogenetic responses but with increased toxicity.
Accelerated or blastic phases
In accelerated phase:
- 71% of patients treated with 600 mg/d of imatinib mesylate had a hematologic response.
- The major cytogenetic response rate was 24%, with a time to disease progression of 12 months at 67%.
In blast phase:
- 52% of patients achieved a hematologic remission and 31% a sustained remission lasting at least 4 weeks with imatinib mesylate.
- However, the median response duration is only 10 months, even when considering only patients with sustained remission (i.e., lasting at least 4 weeks).
Patients with clonal evolution have a lower probability of response and shorter survival than patients without clonal evolution when treated with imatinib mesylate. Imatinib mesylate is also effective for patients with CML in transformation.
Patients with clonal evolution as their only criterion of accelerated disease may respond to interferon, especially when < 16% of metaphases bear the additional abnormality and the cytogenetic abnormality occurs within the first 24 months of diagnosis.
Intensive chemotherapy regimens, including high-dose Ara-C and daunorubicin (Cerubidine), induce remissions in only 25%-35% of patients in accelerated or blast phase (median survival durations of 8-18 months and 3 months, respectively).
Patients with a lymphoid blastic phase treated with therapy similar to that given for acute lymphocytic leukemia (i.e. vincristine, doxorubicin, and dexamethasone, with or without cyclophosphamide) have a complete response rate of 60%.
New agents and combination regimens are currently being evaluated. The combination of imatinib mesylate with chemotherapy regimens is under evaluation. The role of cyclophosphamide, Ara-C, farnesyl transferase inhibitors, and topotecan [Hycamtin] are currently being evaluated.
Decitabine is a hypomethylating agent with promising activity in patients in accelerated or blast phase. Decitabine achieved an objective response in 33% of patients in blast phase and 66% of those in accelerated phase. Lower doses of decitabine achieve optimal demethylation with reduced toxicity and are currently being evaluated.
Compared with those results in patients in chronic phase, results with allogeneic BMT are worse in patients in accelerated or blastic phase, with 4-year survival rates of only 10%-30%.
Patients in accelerated phase (determined on the basis of clonal evolution only) who undergo BMT < 1 year after diagnosis have a 4-year probability of survival of 74%.
Prognosis and survival
The median survival is 4 to 6 years, with a range of less than 1 year to more than 10 years. Survival after development of an accelerated phase is usually less than 1 year and after blastic transformation is only a few months.