Treatment of Acute Myeloid Leukemia With Hematopoietic Stem Cell Transplantation

Cortney V. Jones; Edward A. Copelan

Disclosures

Future Oncol. 2009;5(4):559-568. 

In This Article

Allogeneic Transplantation in First Remission

Patients with good-risk disease, that is to say a favorable prognosis, are those with core binding factor AML (identified by inv 16 or t [8;21]), which has a favorable cure rate with high-dose cytarabine post-remission[26,27,28] or acute promyelocytic leukemia (t[15;17]), which has an excellent outcome with regimens containing all-transretinoic acid (ATRA) and arsenic in addition to chemotherapy.[34] Allogeneic transplantation, when performed in first remission, does not improve outcome in these populations.

In contrast, patients with poor-risk AML, as identified by cytogenetic analysis, have dismal outcomes with standard induction and post-remission chemotherapy alone. Sustained survival rates are consistently below 15%.[28,31] While poor-risk cytogenetics adversely influence transplantation outcome as well, their influence is less profound than for chemotherapy alone. Most studies report sustained survival rates with allotransplantation more than double that achieved with chemotherapy alone.[32,33] A large prospective study that identified patients as 'high-risk' on the basis of unfavorable cytogenetics or persistent blasts on day 15 marrow reported survival at 4 years in the majority of patients undergoing allogeneic transplantation from sibling or unrelated donors.[35]

Approximately 40% of patients do not have cytogenetic abnormalities detected by standard cytogenetic analysis and are classified as intermediate risk. Choice of post-remission therapy in these patients varies widely among clinicians and institutions, but various genetic aberrations, undetectable by standard cytogenetic analysis, can be detected by commercially available tests. These include mutations of the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene due to internal tandem duplications (FLT3-ITD) and the CCAAT/enhancer binding protein α gene (CEPBA). A large retrospective analysis by the German-Austrian AML study group found that significant benefit of transplantation was demonstrable only in those who had FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD.[36] Thus, genetic abnormalities that can not be detected with standard cytogenetic analysis can be used to assess prognosis and select treatment.

Some experts argue that allogeneic transplantation has not been consistently 'proven' superior in prospective randomized studies in patients with AML in first remission,[37,38,39,40,41,42,43,44,45] in part explaining the large number of patients with AML who are either referred for transplant beyond first remission or never referred. These prospective studies of allogeneic transplantation in first remission have had substantial limitations that are important to recognize. Selection of treatment has been based on 'genetic' randomization - that is to say, patients with HLA-identical siblings are selected to undergo allotransplantation; those who do not undergo chemotherapy or autotransplantation. Analyses of patient subsets, based on cytogenetic categorization, are generally retrospective and the groups are often small. Most significantly, in most studies, large proportions of individuals in the allogeneic transplant group do not undergo transplantation in first remission. Since all trials are now analyzed on an intent-to-treat basis, they consistently underestimate the impact of transplantation on outcome. Only the recently reported HOVON-SAKK trial achieved high compliance rates (82%) for patients intended for allogeneic transplantation.[45] It demonstrated significantly better survival in patients assigned to allotransplantation. Meta-analysis of 4000 AML patients demonstrates a significant survival benefit at 4 years for patients with poor- or intermediate-risk cytogenetics who had an HLA-identical donor.[45] The identification of prognostic factors, for example genetic mutations, indicative of more favorable results with chemotherapy, should be used to select patients who are not best served by transplantation in first remission.

Other prognostic factors also exert differential affects and should be used, in conjunction with cytogenetic analysis, to determine treatment. High presenting white blood count,[28,47] requirement for more than one induction cycle to achieve remission[28,47] and AML secondary to previous chemotherapy or radiation exert a more adverse prognostic influence on chemotherapy treatment than on transplantation.[29,30,31]

In contrast, comorbidities that substantially increase the mortality risk with allogeneic transplantation may less adversely influence risk with chemotherapy. The systematic assessment of comorbidities is important, but underutilized[48] in determining appropriate treatment, and should be performed routinely in patients with AML. The hematopoietic cell transplantation-specific comorbidity index was developed as a prognostic tool to estimate risk with transplantation,[49,50] but has predictive capability for patients undergoing chemotherapy treatment of AML as well.[51]

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