New markers for minimal residual disease detection in acute lymphoblastic leukemia.

To identify new markers for minimal residual disease (MRD) detection in acute lymphoblastic leukemia (ALL), we compared genome-wide gene expression of lymphoblasts from 270 patients with newly diagnosed childhood ALL to that of normal CD19⁺CD10⁺ B-cell progenitors (n = 4). Expression of 30 genes differentially expressed by ≥ 3-fold in at least 25% of cases of ALL (or 40% of ALL subtypes) was tested by flow cytometry in 200 B-lineage ALL and 61 nonleukemic BM samples, including samples containing hematogones. Of the 30 markers, 22 (CD44, BCL2, HSPB1, CD73, CD24, CD123, CD72, CD86, CD200, CD79b, CD164, CD304, CD97, CD102, CD99, CD300a, CD130, PBX1, CTNNA1, ITGB7, CD69, CD49f) were differentially expressed in up to 81.4% of ALL cases; expression of some markers was associated with the presence of genetic abnormalities. Results of MRD detection by flow cytometry with these markers correlated well with those of molecular testing (52 follow-up samples from 18 patients); sequential studies during treatment and diagnosis-relapse comparisons documented their stability. When incorporated in 6-marker combinations, the new markers afforded the detection of 1 leukemic cell among 10(5) BM cells. These new markers should allow MRD studies in all B-lineage ALL patients, and substantially improve their sensitivity.

Assessing Trial-to-Trial Variability in Auditory ERPs in Autism and Schizophrenia.

Sensory abnormalities are characteristic of autism and schizophrenia. In autism, greater trial-to-trial variability (TTV) in sensory neural responses suggest that the system is more unstable. However, these findings have only been identified in the amplitude and not in the timing of neural responses, and have not been fully explored in schizophrenia. TTV in event-related potential amplitudes and inter-trial coherence (ITC) were assessed in the auditory mismatch negativity (MMN) in autism, schizophrenia, and controls. MMN was largest in autism and smallest in schizophrenia, and TTV was greater in autism and schizophrenia compared to controls. There were no differences in ITC. Greater TTV appears to be characteristic of both autism and schizophrenia, implicating several neural mechanisms that could underlie sensory instability.

CBFA2T3::GLIS2-positive acute leukemia with RAM and mixed T/megakaryocytic phenotype.

Herein, we present a rare case of acute myeloid leukemia (AML) with CBFA2T3-rearrangement and the expression of megakaryocytic and lymphoid markers, highlighting the need for a high suspicion index in differential diagnosis and applying adequate workup to avoid misdiagnosing this entity. CBFA2T3::GLIS2-positive AML is primarily found in infants with non-down syndrome acute megakaryoblastic leukemia (non-DSAMKL). Flow cytometry immunophenotyping plays an important role in recognizing the unique immunophenotype of bright CD56 expression with dim/negative expression of HLA-DR, CD38, and CD45 termed the RAM immunophenotype in this entity. Still, CBFA2T3::GLIS2-positive acute leukemia with T/megakaryocytic markers could be misdiagnosed as T-lymphoblastic leukemia/lymphoma, early T-cell precursor acute lymphoblastic leukemia/lymphoma, NK lymphoblastic leukemia, AML with minimal differentiation, or AML with myelodysplasia-related changes.

Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia.

Minimal residual disease (MRD) at the end of remission-induction therapy predicts relapse in acute lymphoblastic leukemia (ALL). We examined the clinical significance of levels below the usual threshold value for MRD positivity (0.01%) in 455 children with B-lineage ALL, using polymerase chain reaction amplification of antigen-receptor genes capable of detecting at least 1 leukemic cell per 100 000 normal mononucleated cells (0.001%). Of the 455 clinical samples studied on day 46 of therapy, 139 (30.5%) had MRD 0.001% or more with 63 of these (45.3%) showing levels of 0.001% to less than 0.01%, whereas 316 (69.5%) had levels that were either less than 0.001% or undetectable. MRD measurements of 0.001% to less than 0.01% were not significantly related to presenting characteristics but were associated with a poorer leukemia cell clearance on day 19 of remission induction therapy. Patients with this low level of MRD had a 12.7% (+/- 5.1%; SE) cumulative risk of relapse at 5 years, compared with 5.0% (+/- 1.5%) for those with lower or undetectable MRD (P < .047). Thus, low levels of MRD (0.001%-< 0.01%) at the end of remission induction therapy have prognostic significance in childhood ALL, suggesting that patients with this finding should be monitored closely for adverse events.