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

Response to Therapy

A rather intuitive prognostic marker is a patient's response to therapy. Achievement of CR is essential for durable control of disease and cure. Requiring two cycles of induction chemotherapy to achieve CR has been associated in most, but not all studies, with a poorer prognosis.[16] The quality of CR is also important. The presence of residual abnormal metaphases despite a morphological CR at the end of induction predicts for relapse, compared with those who achieve a complete cytogenetic response.[17,18] Recently, some protocols have reported the results for CR rates to include both CR and CRp (CR with incomplete recovery of platelets). A clear distinction between these two should be made for clinical practice, as well as for research purposes, since CRp is associated with a clinical benefit but not nearly to the extent of a true CR.[19]

Minimal Residual Disease

The measurement of minimal residual disease (MRD) in patients in a morphologic CR has improved with the development of more sophisticated PCR and multiparameter flow cytometry technologies.[20] The value of MRD measurements is that it provides a dynamic, patient-specific assessment of the quality of response that is highly predictive of relapse risk. It is well established that patients in remission with APL who have detectable PML/RARA transcripts by PCR at the end of consolidation will invariably relapse.[21] Therefore, it is now routine to monitor for MRD in APL patients in remission, with recommendations to consider intensification of therapy with transplantation for those with detectable disease.[22] Similarly, patients with CBF leukemias who have MRD as measured by flow cytometry or PCR have a markedly increased risk of relapse compared with MRD-negative patients.[23] However, somewhat distinct from APL, there are long-term survivors with CBF leukemias and measurable MRD who do not relapse, making the immediate applicability of MRD in this setting less straightforward.

The discovery of new molecular prognostic markers in AML has led to their study as markers for MRD. For this purpose, it is important to choose a marker that is quantifiable and stable throughout its disease course, including relapse. NPM1 mutations meet both of these requirements.[24] In a multivariate analysis, the level of mutated NPM1 transcripts was the most powerful prognostic factor for relapse during treatment.

Although many technical issues remain, such as the optimal timing of MRD measurements, it will probably become a clinically useful tool to predict the risk of relapse. It may ultimately be best used in conjunction with pretreatment variables to stratify patients into specific risk categories, particularly those with IR-AML.[20] Measureable or increasing levels of MRD may be an indication for either allogeneic transplantation or other investigational preemptive therapies. Prospective studies using MRD to guide therapeutic decision-making are required since retrospective analyses have indicated that measurable MRD prior to transplant is still associated with a markedly increased risk of relapse and death, even after transplantation.[25]

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