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Expedited Assay and Analysis to Determine Acute Myeloid Leukemia Patient Prognosis


An inexpensive high-throughput clinical diagnostic method for assessing genomic DNA methylation at multiple specific loci coupled with a scoring system allowing for AML prognosis classification. 



Martin Carroll, MD, Gerald Wertheim, PhD, MD



Acute myeloid leukemia (AML) is the most common acute leukemia in adults and affects 12.2 per 100,000 people older than 65 years old. Only 50-80% of patients reach complete remission (CR) as a result of standard chemotherapy while the rest suffer from side effects without significant benefit to their health. Variable response to chemotherapy in AML represents a major treatment challenge. While clinical and genetic features incompletely predict outcome, there is a clear correlations between patient outcome in AML and DNA methylation patterns. However, tests directly measuring multiple-locus DNA methylation are expensive and technically challenging. There is a need for a better, cheaper, and readily available diagnostic test to inform clinicians about appropriate treatment and better identify AML patients who are likely to achieve remission.  



Dr. Carroll and Dr. Wertheim have developed a strategy, termed multi-locus microsphere HpaII tiny fragment enrichment by ligation-mediated PCR (xMELP), to simultaneously analyze the DNA methylation pattern at up to 50 loci. This technique is inexpensive and easily performed in a clinical molecular pathology laboratory. Inventors used xMELP to analyze methylation pattern at 18 loci in AML patients and determined methylation statistic (M-score) for 166 patients with de novo AML and in independent cohort of 383 patients from the Eastern Cooperative Oncology Group (ECOG). M Score segregates AML patients into prognostic subgroups with significantly distinct mortality risk (P = 0.009). In the ECOG study, M-score was associated with death (P = 0.011) and failure to achieve CR (P = 0.034). Median survival was 26.6 months versus 10.6 months for low and high M-score groups. Thus, the xMELP assay and associated M-score can be used for prognosis and for clinical decision making in AML patients.



• Quantifiable

• Inexpensive and simple (2 reaction tubes needed)

• Fast (2 days)

• Utilizes standard clinical lab equipment



• Simultaneous analysis of DNA methylation at up to 50 loci

• AML mortality prognosis to inform clinicians on appropriate treatments

• Method can be applied for development of prognostic test for cancers with demonstrated correlation between DNA methylation and clinical prognosis  (T-cell and B-cell lymphoblastic leukemia, NSCLC, ovarian carcinoma, melanoma etc)




Stage of Development

Developed xMELP assay and random forest classifier with a training set of an AML patient cohort

Validated in three cohorts of patients from UPENN, ECOG and MD Anderson.


Reference Media

Wertheim et al.  Clin Chem. 2015 Jan; 61(1): 249

DiNardo et al. Am J Hematol 2016; Epub

Luskin et al. JCI Insight 2016, 1(9): e87323

Wertheim et al, J Mol Diagn 2014 16(2): 207


Desired partnerships

• License



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Docket #  15-7238 

Patent Information:
For Information, Contact:
Linara Axanova
Associate Director, PSOM Licensing Group
University of Pennsylvania
Martin Carroll
Gerald Wertheim