Treatment Options Under Clinical Evaluation
Current Clinical Trials

Chronic myelogenous leukemia (CML) accounts for only 5% of all childhood leukemia, and 80% of the cases occur in children older than 4 years. The cytogenetic abnormality most characteristic of CML is the Philadelphia chromosome (Ph), which represents a translocation of chromosomes 9 and 22 (t[9;22]) resulting in a bcr-abl fusion protein. CML is characterized by a marked leukocytosis and is often associated with thrombocytosis, sometimes with abnormal platelet function. Bone marrow aspiration or biopsy reveals hypercellularity with relatively normal granulocytic maturation and no significant increase in leukemic blasts. Although reduced leukocyte alkaline phosphatase activity is seen in CML, this is not a specific finding.

CML has three clinical phases: chronic, accelerated, and blast crisis. Chronic phase, which lasts for approximately 3 years, usually presents with side effects secondary to hyperleukocytosis such as weakness, fever, night sweats, bone pain, respiratory distress, priapism, left upper quadrant pain (splenomegaly), and, rarely, hearing loss and visual disturbances. The accelerated phase is characterized by progressive splenomegaly, thrombocytopenia, and increased percentage of peripheral and bone marrow blasts, along with accumulation of karyotypic abnormalities in addition to the Ph chromosome. Blast crisis is notable for the bone marrow, showing greater than 30% blasts and a clinical picture that is indistinguishable from acute leukemia. Approximately two-thirds of blast crisis is myeloid and the remainder lymphoid, usually of B lineage. Patients in blast crisis will die within a few months.[1] The only curative treatment for CML is allogeneic hematopoietic stem cell transplantation (HSCT). When an HLA-matched family donor is used in the treatment of patients in early chronic phase, survival of up to 85% can be expected.[2] Transplantation in accelerated or blast crisis as well as a second chronic phase significantly reduces survival to under 50%.[2] Matched-unrelated-donor transplantation is also nearly as effective therapy as matched-family-donor transplantation in patients 30 years or younger.[2] The use of T-lymphocyte depletion to avoid graft-versus-host disease results in a higher relapse rate and overall decreased survival.[3] Although autologous bone marrow transplantation has been used, particularly in adult patients in chronic phase, there is essentially 100% relapse.[3]

The introduction of imatinib mesylate (Gleevec) as a therapeutic drug targeted at inhibiting the bcr-abl fusion kinase has revolutionized the treatment of patients with CML.[4] Imatinib mesylate treatment can achieve clinical, cytogenetic, and molecular remissions (as defined by the absence of bcr-abl fusion transcripts) in a high proportion of patients when treated in chronic phase.[3,5] Imatinib mesylate has essentially replaced the use of alpha-interferon, which has a lower response rate and has significantly more severe adverse side effects.[3] Although imatinib mesylate is quite an effective treatment, there is little evidence that it cures patients with CML and should not be viewed as a replacement for allogeneic HSCT in children for whom there is a suitable HLA-matched donor.[2]

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• In an attempt to reduce the adverse side effects of myeloablative HSCT, investigators are testing nonablative or mini HSCT.[6]



• Combinations of imatinib mesylate with alpha-interferon or with chemotherapy are also being tested.



• There is significant evidence that achievement of at least a 3-log reduction in the BCR-ABL/ABL ratio conveys a superior survival.[7,8] The optimal approach to molecular monitoring is still, however, under investigation in prospective trials.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. O'Dwyer ME, Mauro MJ, Kurilik G, et al.: The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 100 (5): 1628-33, 2002.  [PUBMED Abstract]
   
   
2. Pulsipher MA: Treatment of CML in pediatric patients: should imatinib mesylate (STI-571, Gleevec) or allogeneic hematopoietic cell transplant be front-line therapy? Pediatr Blood Cancer 43 (5): 523-33, 2004.  [PUBMED Abstract]
   
   
3. Druker BJ, O'Brien SG, Cortes J, et al.: Chronic myelogenous leukemia. Hematology (Am Soc Hematol Educ Program) : 111-35, 2002.  [PUBMED Abstract]
   
   
4. Druker BJ: Perspectives on the development of a molecularly targeted agent. Cancer Cell 1 (1): 31-6, 2002.  [PUBMED Abstract]
   
   
5. Millot F, Guilhot J, Nelken B, et al.: Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation. Leukemia 20 (2): 187-92, 2006.  [PUBMED Abstract]
   
   
6. Burroughs L, Storb R: Low-intensity allogeneic hematopoietic stem cell transplantation for myeloid malignancies: separating graft-versus-leukemia effects from graft-versus-host disease. Curr Opin Hematol 12 (1): 45-54, 2005.  [PUBMED Abstract]
   
   
7. O'Brien S, Tefferi A, Valent P: Chronic myelogenous leukemia and myeloproliferative disease. Hematology (Am Soc Hematol Educ Program) : 146-62, 2004.  [PUBMED Abstract]
   
   
8. Hughes TP, Kaeda J, Branford S, et al.: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349 (15): 1423-32, 2003.  [PUBMED Abstract]
   
   

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