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Imaging, Diagnosis, Prognosis |
Authors' Affiliations: 1 Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands and 2 Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands
Requests for reprints: Gerrit Jan Schuurhuis, Department of Hematology, VU University Medical Center, brug 240, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. Phone: 31-20-444-2604; Fax: 31-20-444-2601; E-mail: gj.schuurhuis{at}vumc.nl.
Purpose: In CD34-positive acute myeloid leukemia (AML), the leukemia-initiating event originates from the CD34+CD38– stem cell compartment. Survival of these cells after chemotherapy may lead to minimal residual disease (MRD) and subsequently to relapse. Therefore, the prognostic impact of stem cell frequency in CD34-positive AML was investigated.
Experimental Design: First, the leukemogenic potential of unpurified CD34+CD38– cells, present among other cells, was investigated in vivo using nonobese diabetic/severe combined immunodeficient mice transplantation experiments. Second, we analyzed whether the CD34+CD38– compartment at diagnosis correlates with MRD frequency after chemotherapy and clinical outcome in 92 AML patients.
Results: In vivo data showed that engraftment of AML blasts in nonobese diabetic/severe combined immunodeficient mice directly correlated with stem cell frequency of the graft. In patients, a high percentage of CD34+CD38– stem cells at diagnosis significantly correlated with a high MRD frequency, especially after the third course of chemotherapy. Also, it directly correlated with poor survival. In contrast, total CD34+ percentage showed no such correlations.
Conclusions: Both in vivo data, as well as the correlation studies, show that AML stem cell frequency at diagnosis offers a new prognostic factor. From our data, it is tempting to hypothesize that a large CD34+CD38– population at diagnosis reflects a higher percentage of chemotherapy-resistant cells that will lead to the outgrowth of MRD, thereby affecting clinical outcome. Ultimately, future therapies should be directed toward malignant stem cells.
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