Treatment Options Under Clinical Evaluation
Current Clinical Trials

Chronic myelogenous leukemia (CML) accounts for less than 5% of all childhood leukemia, and in the pediatric age range, occurs most commonly in older adolescents.[1] 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.[2] 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.[3]

The only currently known curative treatment for CML is allogeneic hematopoietic stem cell transplantation (HSCT). Published reports describe survival rates of 70% to 80% when an HLA-matched family donor (MFD) is used in the treatment of children in early chronic phase, with lower survival rates when HLA-matched unrelated donors are used.[4-6] Relapse rates are low (less than 20%) when transplant is performed in chronic phase.[4,5] The primary cause of death is treatment-related mortality, which is increased with HLA-matched unrelated donors compared with HLA-MFDs in most reports.[4,5] High-resolution DNA matching for HLA alleles may reduce rates of treatment-related mortality leading to improved outcome for HSCT using unrelated donors.[7] As compared with transplant in chronic phase, transplantation in accelerated or blast crisis as well as a second chronic phase results in significantly reduced survival.[4-6] The use of T-lymphocyte depletion to avoid graft-versus-host disease results in a higher relapse rate and overall decreased survival, [8] supporting the contribution of a graft-versus-leukemia effect to favorable outcome following allogeneic HSCT.

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. [9] 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.[10] Imatinib mesylate has replaced the use of alpha-interferon in the initial treatment of CML based on the results of a large phase III trial comparing imatinib mesylate with interferon plus cytarabine.[11,12] Patients receiving imatinib mesylate had higher complete cytogenetic response rates (76% vs. 14%) and had a complete cytogenetic rate of 87% at 5 years. The rate of treatment failure diminished over time, from 3.3% and 7.5% in the first and second years of imatinib mesylate treatment, respectively, to less than 1% by the fifth year of treatment.[12] After censoring for patients who died from causes unrelated to CML or transplantation, the overall estimated survival rate for patients randomly assigned to imatinib mesylate was 95% at 60 months.[12] Guidelines for imatinib mesylate treatment have been developed for adults with CML based on patient response to treatment, including the timing of achieving complete hematologic response, complete cytogenetic response, and major molecular response (defined as attainment of a 3-log reduction in BCR-ABL/control gene ratio).[13-15] Development of BCR-ABL kinase domain mutations during imatinib mesylate treatment also appears to identify a group of patients at high risk of disease progression.[16] Identification of these kinase domain mutations has clinical implications, as there are alternative bcr-abl kinase inhibitors (e.g., dasatinib and nilotinib) that maintain their activity against some (but not all) mutations that confer resistance to imatinib mesylate.[17,18]

An important question is the impact of imatinib mesylate treatment on outcome for patients who subsequently proceed to allogeneic HSCT. A retrospective comparison of 145 patients who received imatinib mesylate prior to transplant compared with a historical cohort of 231 patients who did not, showed no difference in early hepatotoxicity or engraftment delay.[19] In addition, overall survival, disease-free survival, relapse, and nonrelapse mortality were similar between the two cohorts. The only factor associated with poor outcome in the cohort that received imatinib mesylate was a poor initial response to imatinib mesylate. Further evidence for a lack of effect of pretransplant imatinib mesylate on posttransplant outcomes was supplied by a report from the Center for International Blood and Marrow Transplant Research. This report compared outcome for 181 pediatric and adult subjects with CML in first chronic phase treated with imatinib mesylate before HSCT with that for 657 subjects who did not receive the agent before HSCT.[20] Among the patients in first chronic phase, imatinib mesylate therapy before HSCT was associated with better overall survival . Better HLA-matched donors, use of bone marrow, and transplantation within 1 year of diagnosis were also associated with better survival.

Imatinib has shown a high level of activity in children with CML that is comparable to that observed in adults.[21,22] The pharmacokinetics of imatinib in children appears consistent with prior results in adults. The target oral dose in children, determined from the POG 9973 and ADVL0122 trials, is 440 mg/m2/day.[21]Gleevec prescribing information[23]

Although imatinib mesylate is an active treatment for children and adults with CML, there is little evidence that it is curative. Most adults with CML treated with imatinib mesylate continue to have bcr-abl transcripts detectable by highly sensitive molecular methods, although the rate of molecular complete remission does increase with duration of therapy.[24,25] Six of 12 adults with molecularly undetectable disease who stopped imatinib mesylate lost their molecular remission within 18 months of treatment cessation.[26] At this time, therefore, imatinib mesylate can not be viewed as a replacement for allogeneic HSCT in children for whom there is a suitable HLA-matched donor.[27,28]

In patients who develop a hematologic or cytogenetic relapse on imatinib, alternative kinase inhibitors, such as dasatinib or nilotonib, should be considered.[29-31] Patients on kinase inhibitor therapy should be monitored approximately every six months by quantitative retrotranscriptase polymerase chain reaction on peripheral blood. A persistently rising bcr/abl to abl transcript level indicates the likely need to change therapy, usually increasing in the dose of imatinib or changing to a different kinase inhibitor. Patients who show resistance to imatinib should be tested for the presence of the T315I mutation, and, if positive, strong consideration should be given to performing an allogeneic transplant.

The following are examples of national and/or institutional clinical trials that are currently being conducted.

• In an attempt to reduce the adverse side effects of myeloablative HSCT, investigators are testing reduced intensity conditioning HSCT.[32]



• Second generation Bcr-Abl inhibitors (dasatinib and nilotinib) have been approved by FDA for treatment of imatinib-refractory CML in adults.[17,18] These agents are active against many Bcr-Abl mutants that confer resistance to imatinib, although the agents are ineffective in patients with the T315I Bcr-Abl mutation.

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. Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed April 19, 2007. 
   
   
2. Quintás-Cardama A, Cortes J: Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 113 (8): 1619-30, 2009.  [PUBMED Abstract]
   
   
3. 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]
   
   
4. Millot F, Esperou H, Bordigoni P, et al.: Allogeneic bone marrow transplantation for chronic myeloid leukemia in childhood: a report from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Bone Marrow Transplant 32 (10): 993-9, 2003.  [PUBMED Abstract]
   
   
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7. Lee SJ, Klein J, Haagenson M, et al.: High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 110 (13): 4576-83, 2007.  [PUBMED Abstract]
   
   
8. Horowitz MM, Gale RP, Sondel PM, et al.: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75 (3): 555-62, 1990.  [PUBMED Abstract]
   
   
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11. O'Brien SG, Guilhot F, Larson RA, et al.: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348 (11): 994-1004, 2003.  [PUBMED Abstract]
    
    
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19. Oehler VG, Gooley T, Snyder DS, et al.: The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia. Blood 109 (4): 1782-9, 2007.  [PUBMED Abstract]
    
    
20. Lee SJ, Kukreja M, Wang T, et al.: Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia. Blood 112 (8): 3500-7, 2008.  [PUBMED Abstract]
    
    
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22. 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]
    
    
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25. Branford S, Seymour JF, Grigg A, et al.: BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria. Clin Cancer Res 13 (23): 7080-5, 2007.  [PUBMED Abstract]
    
    
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32. 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]
    
    

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