Correlation of acute myeloid leukemia (AML) stem cell phenotype with cytogenetic/molecular features and prognosis.

Leukemia, Myelodysplasia, and Transplantation
Session Type and Session Title: 
Oral Abstract Session, Leukemia, Myelodysplasia, and Transplantation
Abstract Number: 


J Clin Oncol 33, 2015 (suppl; abstr 7000)
Jonathan Michael Gerber, Joshua F. Zeidner, Sarah Morse, Amanda Blackford, Brandy Perkins, Breann Yanagisawa, Hao Zhang, Laura Morsberger, Judith E. Karp, Yi Ning, Christopher D Gocke, Gary L. Rosner, B. Douglas Smith, Richard J. Jones; Levine Cancer Institute, Charlotte, NC; UNC Chapel Hill Lineberger Comprehensive Cancer Center, Chapel Hill, NC; UC Irvine, Irvine, CA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Johns Hopkins University, Baltimore, MD

Abstract Disclosures


Background: Emerging evidence supports the clinical significance of leukemia stem cells (LSCs).We previously found that patients with AML exhibited 1 of 3 distinct LSC phenotypes based on CD34, CD38, and aldehyde dehydrogenase (ALDH): 1. CD34-, 2. CD34+CD38-ALDHintermediate (ALDHint), or 3. CD34+CD38-ALDHhigh (ALDHhigh) [Gerber, et al. Blood, 2012]. We hypothesized that LSC phenotypes might correlate with cytogenetic/molecular features and treatment outcomes. Methods: Diagnostic samples from 98 patients with newly diagnosed normal or unfavorable cytogenetic AML, enrolled on clinical protocol NCT01413880, were analyzed by FACS. Sorted cell populations were assayed by FISH and/or PCR for leukemia-specific abnormalities. Fisher’s exact and Mantel-Haenszel tests were used to analyze differences in risk factors and outcomes by LSC phenotype. Results: LSCs were CD34- in 21 cases; ALDHint in 44; and ALDHhigh in the remaining 33. Poor risk cytogenetics and/or FLT3-ITD mutations were uncommon in the CD34- (4/21 = 19%) and ALDHint (17/44 = 39%) cases, but were frequent in the ALDHhigh cases (28/33 = 85%, p < 0.001). NPM1 mutations were detected in 14/21 (67%) of the CD34- LSC patients vs. just 8/77 (10%) of the patients with CD34+ LSCs ( p < 0.001). Both patients with t(9;11) had CD34- LSCs (p < 0.001), while antecedent MDS or MPN (p = 0.04) were more common in patients with ALDHhigh LSCs. Only 15/33 patients (45%) with ALDHhigh LSCs achieved complete remission, compared to 29/43 patients (69%) with ALDHint LSCs and 19/22 patients (86%) with CD34-LSCs (p < 0.01). Among patients who did not undergo allogeneic stem cell transplant, long term disease-free survival was 0% (0/6) in patients with ALDHhigh LSCs vs. 31% (4/13) with ALDHint and 62% (8/13) with CD34- LSCs (p = 0.04). Conclusions: LSC phenotype correlates with cytogenetic/molecular risk factors and response, permitting rapid risk-stratification of AML patients. This may be of particular use for patients with ALDHhigh LSCs, who appear to be at high risk – more likely to harbor adverse cytogenetic/molecular features and prove refractory to chemotherapy. Earlier identification would facilitate access to clinical trials of novel induction approaches.