Therapy response correlates with ALDH activity in ALDH low-positive childhood acute lymphoblastic leukemias.

The malignant cells of childhood acute lymphoblastic leukemia (ALL) do not form a homogenous entity but a collection of differently maturated blasts. The most immature leukemia cells may be more resistant to therapy than the bulk of more differentiated blasts. We studied 42 patients with childhood ALL treated according to the ALL-BFM 2000 protocol. At diagnosis, we determined the immunophenotype and the aldehyde dehydrogenase (ALDH) activity of the leukemic cells. Additionally, we investigated the expression of CD34, CD38 and CD45 to define a population of immunophenotypically immature cells (CD34(+)/CD38(-)/CD45(-/low)). We then studied levels of minimal residual disease (MRD) after induction therapy (day 33) to determine therapy response. Including all cases (n = 42), there was no correlation between ALDH positive cells, CD34(+)/CD38(-)/CD45(-/low) cells and MRD levels. A subset of 18 ALLs displayed a more mature phenotype with low-ALDH positivity (< 1%). Analyzing this cohort, ALDH positive blasts overlapped with the CD34(+)/CD38(-)/CD45(-/low) population. The initial rate of ALDH positivity correlated with MRD levels at day 33 of therapy (r = 0.61, P < .01). We conclude that in pediatric ALL, ALDH positivity as a marker of immaturity and stemness has prognostic significance only in phenotypically mature cases when the ALDH activity is not a property of the majority of the leukemic blasts. In case of an immature ALL phenotype, ALDH activity might be an inherent characteristic of the whole leukemia and is not limited to a more immature subpopulation that could confer to resistance and increased MRD-levels during therapy.

High proportion of leukemic stem cells at diagnosis is correlated with unfavorable prognosis in childhood acute myeloid leukemia.

In acute myeloid leukemia (AML), the leukemia-initiating cell is found within the CD34(+)/CD38(-) cell compartment. Over the last years evidence grew that AML is initiated and propagated by leukemic stem cells (LSCs). Conceivably, these most immature leukemia cells are more resistant to therapy and subsequently initiate relapse. The authors studied 17 patients with childhood AML treated according to the AML-BFM 98/04 protocol. At diagnosis, the authors determined the characteristic immunophenotype of the leukemic cells by flow cytometry and investigated the expression of CD34, CD38, and CD45 to define a population of immunophenotypically immature cells (CD34(+)/CD38(-)/CD45(-/low)) enriched for LSCs in many cases of AML. The authors compared the fraction of this population of all myeloid cells at diagnosis with event-free survival. Kaplan-Meier analysis revealed significant higher event free survival of patients with low CD34(+)/CD38(-)/CD45(-/low) cell proportion (<0.68%) compared to patients with high burden of this population (>0.83%; log-rank P < .04). This correlation was not found for the total number of CD34(+) cells. This is the first study to show that a higher proportion of immature CD34(+)/CD38(-)/CD45(-/low) blasts at diagnosis correlates with unfavorable prognosis in childhood AML. The results suggest that a large CD34(+)/CD38(-)/CD45(-/low) population reflects a higher fraction of LSCs, leading to increased chemotherapy resistance and elevated relapse rate. Thus the initial frequency of CD34(+)/CD38(-)/CD45(-/low) cells may serve as a prognostic marker in pediatric AML. Future treatment in childhood AML should specifically target this immature population as well as the mature blast population.

High frequency of immature cells at diagnosis predicts high minimal residual disease level in childhood acute lymphoblastic leukemia.

Prognosis for children with acute lymphoblastic leukemia (ALL) has considerably improved, yet relapse still occurs in a significant proportion of patients. Conceivably, the most immature leukemia cells may be more resistant to therapy and initiate relapse. We studied 42 patients with childhood ALL treated according to the ALL-BFM 2000 protocol. At diagnosis, we determined the characteristic immunophenotype of the leukemic cells by flow cytometry and also investigated the expression of CD34 and CD38 to define a population of immunophenotypically immature cells (CD34(+)/CD38(-)). We then studied levels of minimal residual disease (MRD) after induction therapy (day 33) and after consolidation therapy (week 12). We found a significant, increasing correlation between the prevalence of CD34(+)/CD38(-) cells at diagnosis and MRD levels at day 33 and week 12. Our results suggest that the initial frequency of CD34(+)/CD38(-) cells may serve as a prognostic marker in pediatric ALL.