High Stem Cell Frequency in Acute Myeloid Leukemia at Diagnosis Predicts High Minimal Residual Disease and Poor Survival

Abstract

Purpose: In CD34-positive acute myeloid leukemia (AML), the leukemia-initiating event originates from the CD34 + CD38À 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 À cells, present among other cells, was investigated in vivo using nonobese diabetic/severe combined immunodeficient mice transplantation experiments. Second, we analyzed whether the CD34 + CD38À 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 + CD38À 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 + CD38À population at diagnosis reflects a higher percentage of chemotherapyresistant cells that will lead to the outgrowth of MRD, thereby affecting clinical outcome. Ultimately, future therapies should be directed toward malignant stem cells.

Leukemic stem cells: identification and clinical application

“…The fact that there were hardly cases in which leukemia-initiating cells originated from CD34− and/or CD34+/CD38+ without concomitant activity in CD34+/CD38− suggests that the CD34+/CD38− fraction contains the most important leukemia-initiating cells when the other fractions are concomitantly present. This hypothesis is confirmed by other observations: in transplantation experiments using NOD/SCID mice of unfractionated AML, engraftment correlated only with the CD34+/CD38− frequency in the original sample, but not with the CD34+/CD38+ or CD34 frequency [14]. In addition, in line with the finding of in vitro and in vivo therapy resistance [15,16], it was found that it is only the CD34+/CD38− LSC frequency that correlates with therapy outcome and minimal residual disease (MRD) levels, i.e., number of leukemic blasts detected after therapy [5].…”

“…In adult AML, patients with CD34+/ CD38− frequencies higher than 3.5% at diagnosis had a median relapse-free survival of 5.6 months, compared to 16 months in those with lower CD34+/CD38− frequencies [14]. These results were later confirmed in other studies in adult AML [14] and in pediatric AML [38].…”

Flow cytometric maturity score as a novel prognostic parameter in patients with acute myeloid leukemia

“…Since these LSC -particularly in their dormant stage -may survive treatment and give rise to subsequent relapse [19,[28][29][30][31][32][33][34][35][36][37][38][39]. The latter idea is supported by a recent study showing that a higher level of putative CD34 + /CD38 --LSC is associated with a worse prognosis [40].…”

Towards novel paradigms for cancer therapy

“…To date, the only clinical evidence supporting this concept involves acute myeloid leukemia, melanoma and breast cancer patients. When acute myeloid leukemia patients are re-examined after chemotherapy, the persistence of CD34 þ CD38 À cells (proposed to be LICs) predicts a high risk of relapse (van Rhenen et al, 2005). Similarly, the presence of stemness markers within the tumor cells of melanoma and breast cancer patients (ABCB5 þ and CD44 þ , respectively) correlates with a higher rate of cancer progression and poor prognosis (Shipitsin et al, 2007;Schatton et al, 2008).…”