August 2015, Vol 4, No 4
Leukemia Stem Cell Phenotypes Associated with Outcomes
Three distinct, mutually exclusive subtypes of leukemia stem cells (LSCs) have been identified, and these are correlated with specific cytogenetic/molecular risk factors and are also correlated with
response and outcomes.
LSCs comprise less than 1% of cells at diagnosis of acute myeloid leukemia (AML), and these stem cells are thought to be more resistant and persist below the level of detection, with the ability to regrow the disease.
“There are several clinical issues in acute myeloid leukemia, including the fact that remission does not equal cure. Current prognostic factors [cytogenetics] are limited, and it can take over a week to get test results, which is not good for such an explosive disease,” stated Jonathan Gerber, MD, Levine Cancer Institute, Charlotte, NC.
“Grouping AML patients according to LSC phenotype may permit rapid risk stratification of AML patients and may permit rapid risk stratification without identifying molecular/cytogenetic features,” he added.
Gerber and colleagues previously identified 3 distinct LSC phenotypes based on CD34, CD38, and aldehyde dehydrogenase (ALDH) expression:
- CD 34-negative (CD34–)
- CD34+, CD38–, ALDH intermediate (most common subtype)
- XD34+, CD38–, ALDH high.
NCTG01413880 was a phase 2 trial with tissue samples available for 98 of 165 newly diagnosed patients with normal or unfavorable cytogenetic AML. Mean age was 60 years; 40% harbored adverse cytogenetics. Fluorescence in situ hybridization and/or polymerase chain reaction was used to analyze the cell populations for leukemia-specific abnormalities. LSC phenotypes were found to correlate with specific cytogenetic and molecular risk factors.
Poor-risk cytogenetics and/or FLT3/ITD mutations were uncommon in the CD34– phenotype (4 of 22 patients, 18%) and the ALDH-intermediate phenotype (17 of 43, 35%) but were found in 28 of 33 (85%) in the ALDH-high group (P <.001).
NPM1 mutations, associated with good prognosis, were found in 14 patients (64%) in the CD34– group versus 6 (14%) in the ALDH-intermediate and 2 of 33 patients (6%) of the ALDH-high group (P <.001).
Outcomes were different in the 3 LSC phenotypes. The rate of complete remission was 86% in the CD34– group, 67% in the ALDH-intermediate group, and 45% in the ALDH-high group.
Median event-free survival (EFS) was 13 months, 11.3 months, and 2.2 months for the 3 phenotypes, respectively. The rate of 2-year EFS was 46%, 26%, and 0% for the 3 phenotypes, respectively.
Overall survival was not yet reached in the CD34– patients, was 18.7 months in the ALDH-intermediate group, and 2.2 months in the ALDH-high group.
“Risk stratification according to LSC phenotype makes it possible to divert high-risk (ALDH-high) patients to earlier novel forms of therapy and transplant. These patients don’t do well on conventional chemotherapy,” Gerber said.
When they looked at patients with complete remissions, they saw 2 patterns: one was normal with no ALDH and no LSC; the other was minimal residual disease (MRD) with persistent ALDH expression. The presence of MRD predicted prognosis; 6 of 7 patients with MRD relapsed. All patients without evidence of MRD remained in clinical remission more than 4 years later.
“This work can improve understanding of the leukemia stem cell and the course of disease. Many investigators are working in this area. Specific mutations lead to preleukemia, and additional mutations lead to leukemia,” said Wendy Stock, MD, University of Chicago, IL.
Remissions in AML are variable. “We are hopeful they will remain in remission. Eventually many of these patients relapse. Some do so quickly because we have only deactivated a small clone, but others are lucky where we have eradicated a leukemic population and achieved normal progenitor cells. This technique might help us identify what lurks in these residual marrows,” Stock said.
“Moving forward, AML evolutional heterogeneity is a challenge for risk assessment and development of new effective therapies. It is important to study leukemic stem cells. ALDH expression in remission may be a method to help identify patients at high risk of relapse,” she said.
Now that new tests are changing the landscape of genetic testing, challenges are emerging in communicating results to patients, according to presenters at an education session on “Genetic Testing in 2015: Who Owns the Data, How Do You Return Results, and Other Clinical Dilemmas.” Multigene panels can now be offered [ Read More ]
The Fourth Annual World Cutaneous Malignancies Congress (WCMC) took place in Seattle, WA, on July 24-25, 2015. The WCMC is a 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, squamous cell [ Read More ]