Speed of blast clearance is an indicator of outcome in childhood acute lymphoblastic leukemia (ALL). Availability of measurement of minimal residual disease (MRD) at an early time point with a ...reduced-cost method is of clinical relevance. In the AIEOP-BFM-ALL (Associazione Italiana Ematologia Oncologia Pediatrica and Berlin-Frankfurt-Münster Study Group) 2000 trial, patients were stratified by levels of polymerase chain reaction (PCR) MRD at day +33 and +78. AIEOP studied the prognostic impact of MRD measured by flow cytometry (FCM) at day 15 of induction therapy.
Bone marrow samples from 830 Italian patients were collected on day 15, after 14 days of steroids, and one dose of intrathecal methotrexate, vincristine, daunorubicine, and asparaginase. Cells were analyzed by four-color FCM for detection of leukemia-associated immunophenotypes.
Three patient risk groups were identified by FCM: standard (< 0.1% blast cells; 42% of the total), intermediate (0.1 to < 10%; 47%), and high (> or = 10%; 11%). Their 5-year cumulative incidences of relapse were 7.5% (SE, 1.5), 17.5% (SE, 2.1), and 47.2% (SE, 5.9), respectively. In multivariate analysis, FCM was the most important prognostic factor among those available by day 15, with two-fold and five-fold increase in the risk of relapse compared with patients with less than 0.1%. PCR MRD, when added to the model, had significant prognostic impact; yet high levels of FCM MRD retained an independent ability to detect a significantly higher risk of relapse.
Measurement of FCM MRD in day 15 bone marrow was the most powerful early predictor of relapse, applicable to virtually all patients; it may complement PCR MRD-based stratification including later time points, thus allowing additional treatment tailoring.
Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune ...dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.
Bone marrow mesenchymal cells (MSCs) can protect leukemic cells from chemotherapy, thus increasing their survival rate. We studied the potential molecular mechanisms underlying this effect in acute ...lymphoblastic leukemia (ALL) cells. Coculture of ALL cells with MSCs induced on the lymphoblast plasma membrane the expression of a signaling complex formed by hERG1 (human ether-à-go-go-related gene 1) channels, the β1-integrin subunit, and the chemokine receptor CXC chemokine receptor-4. The assembly of such a protein complex activated both the extracellular signal-related kinase 1/2 (ERK1/2) and the phosphoinositide 3-kinase (PI3K)/Akt prosurvival signaling pathways. At the same time, ALL cells became markedly resistant to chemotherapy-induced apoptosis. hERG1 channel function appeared to be important for both the initiation of prosurvival signals and the development of drug resistance, because specific channel blockers decreased the protective effect of MSCs. NOD/SCID mice engrafted with ALL cells and treated with channel blockers showed reduced leukemic infiltration and had higher survival rates. Moreover, hERG1 blockade enhanced the therapeutic effect produced by corticosteroids. Our findings provide a rationale for clinical testing of hERG1 blockers in the context of antileukemic therapy for patients with ALL.
Platelet-derived growth factor receptor B (
PDGFRB
) gene rearrangements define a unique subgroup of myeloid and lymphoid neoplasms frequently associated with eosinophilia and characterized by high ...sensitivity to tyrosine kinase inhibition. To date, various
PDGFRB/
5q32 rearrangements, involving at least 40 fusion partners, have been reported. However, information on genomic and clinical features accompanying rearrangements of
PDGFRB
is still scarce. Here, we characterized a series of 14 cases with a myeloid neoplasm using cytogenetic, single nucleotide polymorphism array, and next-generation sequencing. We identified nine
PDGFRB
translocation partners, including the
KAZN
gene at 1p36.21 as a novel partner in a previously undescribed t(1;5)(p36;q33) chromosome change. In all cases, the
PDGFRB
recombination was the sole cytogenetic abnormality underlying the phenotype. Acquired somatic variants were mainly found in clinically aggressive diseases and involved epigenetic genes (
TET2
,
DNMT3A
,
ASXL1
), transcription factors (
RUNX1
and
CEBPA
), and signaling modulators (
HRAS
). By using both cytogenetic and nested PCR monitoring to evaluate response to imatinib, we found that, in non-AML cases, a low dosage (100–200 mg) is sufficient to induce and maintain longstanding hematological, cytogenetic, and molecular remissions.
Introduction
ε
γδβ
thalassemia is a rare form of β-thalassemia mostly described in children originating from Northern Europe. Only anecdotic cases from the Mediterranean area are reported. The ...diagnosis is challenging, considering the rarity of the disease and its heterogeneous clinical presentation. Most patients have neonatal microcytic anemia, sometimes requiring in
utero
and/or neonatal transfusions, and typically improving with age.
Case Description
We report on an Italian newborn presenting with severe neonatal anemia that required red blood cell transfusion. After the first months of life, hemoglobin levels improved with residual very low mean corpuscular volume. β and α thalassemia, IRIDA syndrome, and sideroblastic anemia were excluded. Finally, a diagnosis of ε
γδβ
thalassemia was made after microarray analysis of single nucleotide polymorphisms revealed a 26 kb single copy loss of chromosome 11p15.4, including the
HBD, HBBP1, HBG1, and HBB
genes.
Conclusions
Despite its rarity, the diagnosis of ε
γδβ
thalassemia should be considered in newborns with severe neonatal anemia requiring in
utero
and/or neonatal transfusions, but also in older infants with microcytic anemia, after excluding more prevalent red blood cell disorders.
...because of the onset of MDS, at age 9 years, he underwent hematopoietic stem cell transplant from his HLA-matched (GATA2 wild-type) brother. Cytogenetic data were described according to ...International System for Human Cytogenetic Nomenclature 2009.E3 Clinical symptoms Laboratory findings Differential diagnosis HSCT indication UTI Mild leukopenia and neutropenia Congenital/autoimmune neutropenia Chromosome 7 monosomy Aphthous stomatitis Absent monocytes and DCsLow B cells/NK cells Rheumatological diseases (ie, SLE) Â Warts Bone marrow hypocellurarity with mild dysmyelopoiesis ALPS Â Fever and reactive arthritis (Parvovirus B19 infection) Normal immunoglobulin valuesNegative autoimmune screening Bone marrow failure (TERC/TINF2) Â Localized alopecia areata Negative viral PCRs Unspecified antibody defects (but normal serum immunoglobulin levels) Â Table E1 Summary of clinical and laboratory findings, possible differential diagnosis, and indication for performing HSCT See text for more details.ALPS, Autoimmune lymphoproliferative syndrome; SLE, systemic lupus erythematosus, UTI, upper respiratory tract infection.
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