Chronic Myelogenous Leukemia (CML)
(Chronic Granulocytic Leukemia; Chronic Myelocytic Leukemia; Chronic Myeloid Leukemia)
Chronic myelogenous leukemia (CML) occurs when a pluripotent stem cell undergoes malignant transformation and clonal myeloproliferation, leading to a striking overproduction of immature granulocytes. Initially asymptomatic, CML progression is insidious, with a nonspecific “benign” stage (malaise, anorexia, weight loss) eventually giving way to accelerated or blast phases with more ominous signs, such as splenomegaly, pallor, easy bruising and bleeding, fever, lymphadenopathy, and skin changes. Peripheral blood smear, bone marrow aspirate, and demonstration of Philadelphia chromosome are diagnostic. Treatment is with imatinib, which significantly improves response and prolongs survival. The curative potential of imatinib is undefined. Myelosuppressive drugs (eg, hydroxyurea), stem cell transplantation, and interferon alfa are also used.
(See also Overview of Leukemia.)
CML accounts for about 15% of all adult leukemias. CML can strike at any age, although it is uncommon before age 10, and the median age at diagnosis is 45 to 55. CML may occur in either sex.
Classical CML is induced by a translocation known as the Philadelphia (Ph) chromosome. It is a reciprocal translocation t(9;22) in which a piece of chromosome 9 containing the oncogene c-abl is translocated to chromosome 22 and fused to the gene BCR. The fusion gene BCR-ABL is essential in the pathogenesis and expression of CML and results in the production of a specific constitutively tyrosine kinase. CML ensues when an abnormal pluripotent hematopoietic progenitor cell initiates excessive production of granulocytes, primarily in the bone marrow but also in extramedullary sites (eg, spleen, liver). Although granulocyte production predominates, the neoplastic clone includes RBCs, megakaryocytes, monocytes, and even some T and B cells. Normal stem cells are retained and can emerge after drug suppression of the CML clone.
CML has 3 phases:
Chronic phase: An initial indolent period that may last months to years
Accelerated phase: Treatment failure, worsening anemia, progressive thrombocytopenia or thrombocytosis, persistent or worsening splenomegaly, clonal evolution, increasing blood basophils, and increasing marrow or blood blasts
Blast phase: Accumulation of blasts in extramedullary sites (eg, bone, CNS, lymph nodes, skin), blasts in blood or marrow increased to > 20%
The blast phase leads to fulminant complications resembling those of acute leukemia, including sepsis and bleeding. Some patients progress directly from the chronic to the blast phase.
Patients are often asymptomatic early on, with insidious onset of nonspecific symptoms (eg, fatigue, weakness, anorexia, weight loss, fever, night sweats, a sense of abdominal fullness), which may prompt evaluation. Initially, pallor, bleeding, easy bruising, and lymphadenopathy are unusual, but moderate or occasionally extreme splenomegaly is common (60 to 70% of cases).
With disease progression, splenomegaly may increase, and pallor and bleeding occur. Fever, marked lymphadenopathy, and maculopapular skin involvement are ominous developments.
CML is most frequently diagnosed by a CBC obtained incidentally or during evaluation of splenomegaly. Granulocyte count is elevated, usually < 50,000/μL in asymptomatic patients and 200,000/μL to 1,000,000/μL in symptomatic patients. The platelet count is normal or moderately increased. The Hb level is usually > 10 g/dL.
Peripheral smear may help differentiate CML from leukocytosis of other etiology. In CML, the peripheral smear frequently shows immature granulocytes as well as absolute eosinophilia and basophilia. However, in patients with WBC counts ≤ 50,000/μL and even some with higher WBC counts, immature granulocytes may not be seen, making the absence of immature granulocytes nondiagnostic. Leukocytosis in patients with myelofibrosis is usually associated with nucleated RBCs, teardrop-shaped RBCs, anemia, and thrombocytopenia. Leukemoid reaction, defined as a neutrophil count > 50,000/mL not caused by malignant transformation of a hematopoietic stem cell, can result from a variety of causes (eg, cancer, infection, inflammation, other stimuli such as hemorrhage, drugs or electrical shock). Usually the cause is apparent, but apparent benign neutrophilia can be mimicked by chronic neutrophilic leukemia or CML.
The leukocyte alkaline phosphatase score is usually low in CML and increased in leukemoid reactions. Bone marrow examination should be done to evaluate the karyotype as well as cellularity and extent of myelofibrosis.
Diagnosis is confirmed by finding the Ph chromosome in samples examined with cytogenetic or molecular studies., The classic Ph cytogenetic abnormality is absent in 5% of patients, but the use of fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) can confirm the diagnosis.
During the accelerated phase of disease, anemia and thrombocytopenia usually develop. Basophils may increase, and granulocyte maturation may be defective. The proportion of immature cells and the leukocyte alkaline phosphatase score may increase. In the bone marrow, myelofibrosis may develop and sideroblasts may be seen on microscopy. Evolution of the neoplastic clone may be associated with development of new abnormal karyotypes, often an extra chromosome 8 or isochromosome 17.
Further evolution may lead to a blast phase with myeloblasts (60% of patients), lymphoblasts (30%), and megakaryoblasts (10%). In 80% of these patients, additional chromosomal abnormalities occur.
With imatinib, survival is > 90% at 5 yr after diagnosis for chronic phase CML. Before imatinib was used, with treatment, 5 to 10% of patients died within 2 yr of diagnosis; 10 to 15% died each year thereafter. Median survival was 4 to 7 yr. Most (90%) deaths followed a blast phase or an accelerated phase of the disease. Median survival after blast crisis was about 3 to 6 mo or longer if remission was achieved.
Ph chromosome–negative CML, chronic neutrophilic leukemia, and chronic myelomonocytic leukemia have a worse prognosis than Ph chromosome–positive CML and are considered myelodysplastic syndromes.
Except when stem cell transplantation is successful, treatment is not known to be curative. However, when tyrosine kinase inhibitors are used, survival is prolonged and maximum overall survival has not been reached. Some patients may be able to discontinue tryrosine kinase inhibitors and remain in remission. The durability of these remissions is as yet not known.
Imatinib and several newer drugs (dasatinib, nilotinib) inhibit the specific tyrosine kinase that results from the BCR-ABL gene product. Tyrosine kinase inhibitors (TKIs) are dramatically effective in achieving complete clinical and cytogenetic remissions of Ph chromosome–positive CML and are clearly superior to other regimens (eg, interferon with or without cytarabine). Imatinib also is superior to other treatments in the accelerated and blast phases. In the blast phase, combinations of chemotherapy with imatinib have a higher response rate than does therapy with either approach alone. Treatment tolerance is excellent. The high level of durable complete remissions associated with TKI therapy has led to the prospect of cure of the disease. However, the gene products of some BCR-ABL mutations, particularly the T315I mutation, are resistant to current TKIs and remain very difficult to control. Ponatinib has activity in patients with the T315I mutation.
Older chemotherapy regimens are reserved for BCR-ABL–negative patients, patients who relapse after receiving a TKI, and patients in the blast phase. The main agents are busulfan, hydroxyurea, and interferon.
Hydroxyurea is easiest to manage and has the fewest adverse effects. The starting dosage is generally 500 to 1000 mg po bid. Blood counts should be done every 1 to 2 wk and the dosage adjusted accordingly. Busulfan often causes unexpected general myelosuppression, and recombinant interferon causes a flu-like syndrome that frequently is unacceptable to patients; the pegylated form of interferon is better tolerated and more acceptable to patients.
The main benefit of hydroxyurea, busulfan, and interferon is reduction in distressing splenomegaly and adenopathy and control of the tumor burden to reduce the incidence of tumor lysis and gout. None of these therapies prolongs median survival > 1 yr compared with untreated patients; thus, reduction in symptoms is the major goal, and therapy is not continued when patients have significant toxic symptoms.
Allogeneic stem cell transplantation can be useful for patients refractory to therapy.
Although splenic radiation is rarely used, it may be helpful in refractory cases of CML or in patients with terminal disease and marked splenomegaly. Total dosage usually ranges from 6 to 10 Gy delivered in fractions of 0.25 to 2 Gy/day. Treatment should begin with very low doses and with careful evaluation of the WBC count. Response is usually disappointing.
Splenectomy may alleviate abdominal discomfort, lessen thrombocytopenia, and relieve transfusion requirements when splenomegaly cannot be controlled with chemotherapy or irradiation. Splenectomy does not play a significant role during the chronic phase of CML.
CML involves a chromosomal translocation that creates the Philadelphia chromosome.
Peripheral smear (typically showing immature granulocytes, basophilia, and eosinophilia) helps distinguish CML from leukocytosis of other etiologies (eg, leukocytosis due to cancer, infection, myelofibrosis).
Tyrosine kinase inhibitors, such as imatinib, dasatinib or nilotinib, markedly prolong remission of CML and may even be curative.
Chemotherapy may help in the blast phase.
Stem cell transplantation may help patients who do not respond to drug therapy or who progress to accelerated or blast phase.