Genetic Biomarkers in Acute Myeloid Leukemia

Will the Promise of Improving Treatment Outcomes Be Realized?

Jay Yang; Charles A Schiffer

Disclosures

Expert Rev Hematol. 2012;5(4):395-407. 

In This Article

Treatment Implications of Prognostic Markers

Most research to date has focused on the discovery, frequency, association and prognostic impact of these novel mutations. Future studies are needed to examine the impact of different treatment regimens, including allogeneic hematopoietic stem cell transplant (SCT), on molecular subgroups of patients. Despite this, the discovery of novel prognostic markers has led to several changes in the therapy of AML.

Risk-adapted Therapy

Perhaps the most immediate application of novel prognostic markers is its influence on the decision whether or not to proceed to SCT in first CR based on a risk-adapted approach. Recommendations are often based on retrospective studies that have reported comparative outcomes based on a donor versus no-donor analysis, with its inherent limitations.

Favorable-risk patients, as defined by cytogenetics, do relatively well with standard chemotherapeutic approaches that include intensive induction and consolidation with high-dose cytarabine. Accordingly, a benefit for SCT in these patients has not been shown. Patients with adverse-risk cytogenetics do poorly with chemotherapy and are typically offered SCT if a suitably matched donor exists. Several analyses have shown improved survivals with SCT in these high-risk patients, presumably because the benefit of a graft-versus-leukemia effect outweighs the risk of transplant-related death.[84,85] As described earlier, outcomes with chemotherapy are extremely poor for those with an MK.[11,12] Four-year survival rates of approximately 25% have been reported in younger patients with an MK after SCT, suggesting that this procedure is appropriate for this group of patients even though the overall results remain unsatisfactory.[86] However, in patients older than 60 years, outcomes even after SCT are dismal (4-year OS of 6%) and these patients should be strongly considered for experimental, protocol-based therapies.

For IR-AML patients, therapy decisions are more complex and need to account for multiple variables, including age, comorbidities, disease status, response to chemotherapy, sibling or matched related donor availability and patient preference. Large meta-analyses based on donor–no donor comparisons have shown somewhat better outcomes in IR patients who have a donor.[84,85] Some have advocated the consideration of SCT once the risk of relapse exceeds 35%, citing a beneficial effect of transplant.[85]

IR-AML is markedly heterogeneous, however, and it is difficult to apply these aggregate results to individual patients. Several groups, including the European LeukemiaNet (ELN), have recently proposed updated risk classification schemes integrating cytogenetic and molecular factors.[59,87,88] The ELN has included CN-AML with NPM1+/FLT3 or CEBPA+ in the 'favorable-risk' group. Intermediate risk has been divided into two groups: 'intermediate-1' includes CN-AML with NPM1/FLT3, NPM+ /FLT3+ or NPM1/FLT3+, and 'intermediate-2' includes t(9;11) and other karyotypic abnormalities that are considered neither favorable nor adverse. The discriminatory value of the ELN classification scheme has been validated in an independent, albeit retrospective, cohort.[89] This analysis of the ELN-defined risk groups was able to predict time to relapse, relapse-free survival and OS (Table 2).

Patients who are NPM1+/FLT3 have a prognosis similar to CBF leukemias and do not appear to benefit from SCT consolidation, but this conclusion is largely based on a small group of 38 patients in one study who had a donor.[90] Similarly, those with CEBPA-DM also have a favorable prognosis, but no specific comparative data regarding SCT in CEBPA-DM patients exist. Owing to its favorable prognosis, SCT is not routinely considered for this group of patients. For CN-AML with FLT3 mutations, the available data provide a mixed picture regarding the potential benefit of SCT.[39,90] Many have advocated the use of SCT due to poor outcomes compared with FLT3 patients, but it should be emphasized that the level of evidence for this recommendation cannot be considered strong at this time. In fact, even after allogeneic transplantation there is an increased risk of relapse for patients with the FLT3-ITD compared with those without the FLT3-ITD.[91]

The Rich Get Richer

Earlier studies have shown that patients with CBF leukemias who are in remission after induction therapy appear to preferentially benefit from consolidation intensification with high-dose cytarabine.[92–94]

Attempts at intensifying induction had been unsuccessful for many years, so it was a welcome surprise that in an Eastern Cooperative Oncology Group study, induction therapy with cytarabine and higher-dose daunorubicin (DNR; 90 mg/m2) was found to be superior to cytarabine and conventional-dose DNR (45 mg/m2) in younger (age <60 years) patients with AML, due to higher rates of CR and OS.[95] Subgroup analysis confirmed this benefit in patients with cytogenetically determined favorable and IR patients, but not in poor-risk patients. In addition, FLT3-positive or MLL-PTD patients did not benefit from DNR dose intensification. In a similar study comparing 90 versus 45 mg/m2 of DNR in older adults, there was no difference in outcomes. By subgroup analysis, however, patients with CBF leukemias appeared to benefit from dose intensification – again suggesting that CBF leukemias are more chemosensitive and that even older adults with this subtype of AML should be given intensive chemotherapy whenever possible. Although studies analyzing the impact of different therapies on novel molecular mutational subgroups are critically lacking, a recently published, ambitious analysis of patient samples from the aforementioned Eastern Cooperative Oncology Group study suggested that only those with NPM1 or DNMT3A mutations or MLL translocations benefited from DNR dose escalation.[96]

Gemtuzumab ozogamicin, an antibody–drug conjugate targeting the surface antigen CD33 on myeloid blasts, was the first targeted therapy approved by the US FDA for the treatment of AML in 2000. However, the drug was removed from the market in 2010 when postapproval studies showed no benefit in randomized trials. Despite this, there is some evidence from randomized trials that gemtuzumab ozogamicin may have preferential activity in patients with CBF leukemias.[97,98] Recent reports have also shown that all-trans retinoic acid added to conventional chemotherapy may improve the outcomes in patients with NPM1 mutations.[99,100] Both of these observations need additional validation.

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