Prognostic Factors in Childhood Acute Myeloid Leukemia

The mainstay of the therapeutic approach is systemically administered combination chemotherapy.[1] Future approaches involving risk-group stratification and biologically-targeted therapies are being tested to improve antileukemic treatment while sparing normal tissues.[2] Optimal treatment of acute myeloid leukemia (AML) requires control of bone marrow and systemic disease. Treatment of the central nervous system (CNS), usually with intrathecal (IT) medication, is a component of most pediatric AML protocols but has not yet been shown to contribute directly to an improvement in survival. CNS irradiation is not necessary in patients either as prophylaxis or for those presenting with cerebrospinal fluid leukemia that clears with IT and systemic chemotherapy.

Treatment is ordinarily divided into two phases: (1) induction (to attain remission), and (2) postremission consolidation/intensification. Postremission therapy may consist of varying numbers of courses of intensive chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). For example, currently ongoing trials of the Children’s Oncology Group (COG) and the United Kingdom Medical Research Council (MRC) utilize similar chemotherapy regimens consisting of two courses of induction chemotherapy followed by two MRC or three COG additional courses of intensification chemotherapy.[3]

Maintenance therapy is not part of most pediatric AML protocols except for acute promyelocytic leukemia (APL); exceptions are the Berlin-Frankfurt-Munster (BFM) protocols. Treatment of AML is usually associated with severe and protracted myelosuppression along with other associated complications. Treatment with hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF], granulocyte colony-stimulating factor [G-CSF]) has been used in an attempt to reduce the toxicity associated with severe myelosuppression but does not influence ultimate outcome.[4] Virtually all adult randomized trials of hematopoietic growth factors (GM-CSF, G-CSF) have demonstrated significant reduction in the time to neutrophil recovery,[5-8] but varying degrees of reduction in morbidity and little if any effect on mortality.[4] The BFM 98 study confirmed a lack of benefit for the use of G-CSF in a randomized pediatric AML trial.[9]

Because of the intensity of therapy utilized to treat AML, children with this disease must have their care coordinated by specialists in pediatric oncology, and they must be treated in cancer centers or hospitals with the necessary supportive care facilities (e.g., to administer specialized blood products; to manage infectious complications; to provide pediatric intensive care; and to provide emotional and developmental support). Approximately one-half of the remission induction failures are due to resistant disease and the other half to toxic deaths. For example, in the MRC 10 and 12 AML trials, there was a 4% resistant disease rate in addition to a 4% induction death rate.[3] With increasing rates of survival for children treated for AML comes an increased awareness of long-term sequelae of various treatments. For children who receive intensive chemotherapy, including anthracyclines, continued monitoring of cardiac function is critical. Periodic renal and auditory examinations are also suggested. In addition, total-body irradiation before HSCT increases the risk of growth failure, gonadal and thyroid dysfunction, and cataract formation.[10]

Several prognostic factors in childhood AML have been identified and can be categorized as follows:

• Patient characteristics (age):Several reports published since 2000 have identified older age as being an adverse prognostic factor.[11-14] The age effect is not large, but there is consistency in the observation that adolescents have a somewhat poorer outcome than younger children.



• Patient characteristics (race/ ethnicity): In both the CCG-2891 and CCG-2961 studies, Caucasian children had higher overall survival rates than African-American and Hispanic children.[13,15] A trend for lower survival rates for African-American children, compared to Caucasian children, was also observed for children treated on St. Jude Children’s Research Hospital AML clinical trials.[16]



• Clinical characteristics: White blood cell count at diagnosis has been consistently noted to be inversely related to survival.[17] Associations between FAB subtype and prognosis have been more variable. Recent studies have consistently demonstrated a relatively good outcome for M3 (APL).[18-20] Some studies have indicated a relatively poor outcome for M7 (megakaryocytic leukemia) in patients without Down syndrome,[21,22] though more recent reports suggest an intermediate prognosis for this group of patients.[3,23] The M0, or minimally differentiated subtype, has been associated with a poor outcome.[24]



• Response to therapy: Response to therapy, defined either by standard morphologic examination of bone marrow[25,26] by cytogenetic analysis, [27] or by more sophisticated techniques to identify minimal residual disease..[28,29]



• Cytogenetic and molecular characteristics: Cytogenetic and molecular characteristics are also associated with prognosis. (Refer to the Cytogenetic evaluation and molecular abnormalities section in the Classification of Pediatric Myeloid Malignancies subsection of this summary for detailed information.) Cytogenetic and molecular characteristics that are used in clinical trials for treatment assignment include the following:
  • Favorable: (inv(16)/t(16;16)) and t(8;21).
  • Unfavorable: monosomy 7, monosomy 5/del(5q), and FLT3-ITD with high-allelic ratio.

References

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3. Hann IM, Webb DK, Gibson BE, et al.: MRC trials in childhood acute myeloid leukaemia. Ann Hematol 83 (Suppl 1): S108-12, 2004.  [PUBMED Abstract]
   
   
4. Ozer H, Armitage JO, Bennett CL, et al.: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18 (20): 3558-85, 2000.  [PUBMED Abstract]
   
   
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17. Chang M, Raimondi SC, Ravindranath Y, et al.: Prognostic factors in children and adolescents with acute myeloid leukemia (excluding children with Down syndrome and acute promyelocytic leukemia): univariate and recursive partitioning analysis of patients treated on Pediatric Oncology Group (POG) Study 8821. Leukemia 14 (7): 1201-7, 2000.  [PUBMED Abstract]
    
    
18. de Botton S, Coiteux V, Chevret S, et al.: Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy. J Clin Oncol 22 (8): 1404-12, 2004.  [PUBMED Abstract]
    
    
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