Harrisons Manual of Oncology 2nd Ed.

CHAPTER 27

Chronic Myeloid Leukemia

Karen Ballen

ETIOLOGY AND EPIDEMIOLOGY

Chronic myeloid leukemia (CML) is a clonal disorder of the hematopoietic stem cell affecting every lineage (except T lymphocytes). It affects about 5500 people a year in the United States and has a median age of onset in the sixth decade. The cause of CML is unknown.

PATHOPHYSIOLOGY

CML was one of the first human cancers associated with a chromosomal abnormality, the translocation 9;22, or Philadelphia chromosome. This translocation creates a novel fusion gene, bcr-abl, between the abl gene on chromosome 9 and the bcr gene on chromosome 22. The fusion gene protein product expresses an activated tyrosine kinase. The uncontrolled kinase activity of the bcr-abl takes over the normal functions of the normal ABL enzyme, causing unregulated cellular proliferation and decreased apoptosis.

NATURAL HISTORY

The disease is characterized by a stable phase that may be clinically silent and lasts 3–4 years. Accumulation of genetic damage over that time, particularly mutations in p53, can then lead to disease acceleration and a predominance of myeloblasts in the marrow and peripheral blood. Once disease acceleration occurs, median survival is usually less than 1 year. The development of acute leukemia may be of lymphoid, myeloid, or erythroid differentiation.

DIAGNOSIS

Most patients with CML, particularly in the stable phase (<5% myeloblasts in the bone marrow), are asymptomatic. An elevated WBC may be noted on a routine physical exam. Patients in accelerated phase (5%–20% marrow blasts) may have night sweats, adenopathy, and splenomegaly. The blast crisis (>20% marrow or blood blasts) has similar presentation to acute leukemia. The blood smear and bone marrow in CML will show an abundance of cells in all stages of maturation. (Figure 27-1). The definitive diagnosis can be made by the presence of the bcr-abl translocation in the blood or bone marrow, determined by PCR analysis. Variant chromosomes are seen in 5% of patients and do not affect prognosis (1).

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FIGURE 27-1 Chronic myeloid leukemia in stable phase-peripheral blood. Early myeloid cells and basophilia are characteristic.

• Positive bcr-abl in blood or marrow diagnostic of CML—bone marrow not needed for diagnosis but helpful to rule out more advanced stage of disease.

• Chronic phase: high WBC, often asymptomatic, <5% blasts

• Accelerated phase: may be symptomatic, 5%–20% blasts

• Blast crisis: 70% present as a myeloid acute leukemia, 30% lymphoid, and

TREATMENT

The treatment for CML has changed dramatically since the approval of imatinib (Gleevec) in 2002 (2). Imatinib is a tyrosine kinase inhibitor that blocks the kinase activity of bcr-abl and inhibits the proliferation of Philadelphia chromosome positive progenitors. Chronic phase disease is treated with imatinib at a dose of 400 mg/day. Approximately 95% of chronic phase patients receiving imatinib will have a complete hematologic response, 87% complete cytogenetic response, and 77% major molecular response (3) (see Table 27-1). After 2 years, CML progresses in 3% of patients with a major cytogenetic response (<35% Philadelphia positive metaphases) and 12% of patients without a major cytogenetic response (4). Side effects of imatinib include nausea, rashes, headache, diarrhea, fluid retention, and cytopenias. Patients who are intolerant of imatinib or who do not have a molecular remission should be switched to the second generation tyrosine kinase inhibitors dasatinib or nilotinib. These drugs induce a quicker molecular remission than imatinib, and may also be used for initial therapy (4). In a randomized trial, nilotinib yielded better progression-free survival, as compared to imatinib. Discontinuation of tyrosine kinase inhibitors in patients with a complete molecular response is controversial (5). Patients in remission should have peripheral blood monitoring for the bcr-abl transcript every 3 months until a major molecular response, and every 6 months thereafter.

 

TABLE 27-1 DEFINITIONS OF RESPONSE FOR PATIENTS WITH CHRONIC MYELOGENOUS LEUKEMIA

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Allogeneic stem cell transplantation is now reserved only for very young patients (under age 30 years), for patients who do not attain a molecular remission on imatinib, dasatinib, or nilotinib, for patients with the T315I mutation (who are resistant to tyrosine kinase inhibitors by virtue of steric hindrance of drug binding to the ATP binding site of the kinase), or for patients in accelerated or chronic phase. Cure rates of 70% have been reported with either related or unrelated allogeneic donors. However, the 100-day transplant-related mortality is 10%–15% (see Chapter 37). A significant advance in the transplantation field is the recognition that leukemia control is dependent on an allogeneic graft-versus-leukemia effect, first demonstrated in CML patients. CML patients with graft-versus-host disease have a lower risk of relapse, and patients who relapse after allogeneic transplantation can be cured by donor lymphocyte infusions.

• Initial therapy with imatinib at 400 mg daily.

• Dasatinib or nilotinib for patients who are imatinib intolerant or resistant (these drugs may also be considered for upfront therapy).

• Allogeneic stem cell transplantation for patients with tyrosine kinase inhibitor resistance, the T315I mutation, or accelerated/blast crisis.

• Ponatinib, a new abl kinase inhibitor, was rationally designed to overcome resistance to imatinib and is effective in tumors bearing the T315I mutation (6).

PROGNOSIS

The prognosis for patients with CML has dramatically improved since the introduction of imatinib (7). Patients who achieve a complete cytogenetic remission and a 3-log reduction in bcr-abl transcript have a progression-free survival of 100% at 2 years. Overall survival has improved to about 80% at 10 years (8).

REFERENCES

1. Marzocchi G, Castagnetti F, Luatti S, et al: Variant Philadelphia trans-locations: molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis. Blood. 2011; 117: 6793–6800.

2. Goldman JM, Melo JV. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med. 2003; 349: 1451–1464.

3. Jabbour E, Kantarjian H, O’Brien S, et al. The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood. 2011; 118: 4541–4546.

4. Saglio G, Kim DW, Issarangrisil S, et al: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010; 362: 2251–2259.

5. Mahan FX, Rea D, Guilhot F, et al. Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncology. 2010; 11: 1029–1035.

6. Cortes JE, Kantarjian H, Shah NP, et al. Phase I trial of ponatinib in refractory Ph+ chromosome leukemias. N Engl J Med. 2012; 367: 2075–2088.

7. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogeneous leukemia. N Engl J Med. 2002; 346: 645–652.

8. Kantarjian H, O’Brien S, Jabbour E, et al. Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single institute historical experience. Blood. 2012; 119: 1981–1987.



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