Patients with extreme p53 IHC expression have a worse OS than those with NE expression. Accounting for EN as well as EP expression improves the prognostic impact. Extreme expression positively correlates with nodal stage and histological grade, and negatively with hormone receptor status. Extreme expression may relate to specific mutational status.
Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.
Inherited bone marrow failure syndromes (IBMFSs) are a group of congenital rare diseases characterized by bone marrow failure, congenital anomalies, high genetic heterogeneity, and predisposition to cancer. Appropriate treatment and cancer surveillance ideally depend on the identification of the mutated gene. A next-generation sequencing (NGS) panel of genes could be 1 initial genetic screening test to be carried out in a comprehensive study of IBMFSs, allowing molecular detection in affected patients. We designed 2 NGS panels of IBMFS genes: version 1 included 129 genes and version 2 involved 145 genes. The cohort included a total of 204 patients with suspected IBMFSs without molecular diagnosis. Capture-based targeted sequencing covered > 99% of the target regions of 145 genes, with more than 20 independent reads. No differences were seen between the 2 versions of the panel. The NGS tool allowed a total of 91 patients to be diagnosed, with an overall molecular diagnostic rate of 44%. Among the 167 patients with classified IBMFSs, 81 patients (48%) were diagnosed. Unclassified IBMFSs involved a total of 37 patients, of whom 9 patients (24%) were diagnosed. The preexisting diagnosis of 6 clinically classified patients (6%) was amended, implying a change of therapy for some of them. Our NGS IBMFS gene panel assay is a useful tool in the molecular diagnosis of IBMFSs and a reasonable option as the first tier genetic test in these disorders.
We prospectively analyzed outcomes of haploidentical hematopoietic stem cell transplantation using αβ+ T-cell receptor/CD19+ depleted grafts. Sixty-three transplantations were performed in 60 patients. Twenty-eight patients were diagnosed with acute lymphoblastic leukemia (ALL), 27 patients were diagnosed with acute myelogenous leukemia, and in eight other hematological malignancies were diagnosed. Twenty-three were in first complete remission (CR), 20 in second CR, 20 beyond second CR. Four patients developed graft failure. Median time to neutrophil and platelet recovery was 14 (range 9–25) and 10 days (range 7–30), respectively. The probability of non-relapse mortality (NRM) by day +100 after transplantation was 10 ± 4%. With a median follow-up of 28 months, the probability of relapse was 32 ± 6% and disease-free survival was 52 ± 6%. Immune reconstitution was leaded by NK cells. As such, a high CD56dim/CD56bright NK cell ratio early after transplantation was associated with better disease-free survival (DFS) (≥3.5; 77 ± 8% vs. <3.5; 28 ± 5%; p = 0.001) due to lower relapse incidence (≥3.5; 15 ± 7% vs. <3.5; 37 ± 9%; p = 0.04). T-cell reconstitution was delayed and associated with severe infections after transplant. Viral reactivation/disease and presence of venooclusive disease of liver in the non-caucasian population had a significant impact on NRM. αβ+ T-cell receptor/CD19+ cell-depleted haploidentical transplant is associated with good outcomes especially in patients in early phase of disease. A rapid expansion of “mature” natural killer cells early after transplantation resulted on lower probability of relapse, suggesting a graft vs. leukemia effect independent from graft-vs.-host reactions.
BackgroundT-cell depleted (TCD) haploidentical transplantation using CD3+/CD19+ and TCRαβ+/CD19+ depletion techniques has been increasingly used in children with hematological malignancies. We present a retrospective study aimed to compare transplant outcomes in children with leukemia receiving a TCD haploidentical transplant using either CD3+/CD19+ or TCRαβ+/CD19+ platforms.MethodsA total of 159 children with leukemia (ALL=80) (AML=79) that received a TCD haploidentical transplantation using either CD3+/CD19+ (n=79) or TCRαβ+/CD19+ (n=80) platforms between 2005 and 2020 were included. Median age was 9 years in both groups. There were no differences in patient, donor, and transplant characteristics between groups except for donor KIR B genotype more frequent in the TCRαβ+/CD19+ group (91%) than in the CD3+/CD19+ group (76%) (p=0.009) and a high number of NK+ cells and lower CD19+ cells infused in the TCRαβ+/CD19+ group (35.32x106/kg and 0.06 x106/Kg) than in the CD3+/CD19 group (24.6x106/Kg and 0.25 x106/Kg) (p=0.04 and p=0.0001), respectively. Conditioning was based on TBF. Median follow-up for survivors was 11 years (range; 8-16 y) in CD3+/CD19+ group and 5 years (range; 2-9 y) in the TCRαβ+/CD19+ group.ResultsEngraftment kinetics were similar in both groups (13 days for neutrophils and 10 days for platelets). There was no difference in the incidence of acute GvHD II-IV (29 ± 5% in the CD3+/CD19+ group vs 38 ± 5% in the TCRαβ+/CD19+ group) and chronic GvHD (32 ± 5% vs 23 ± 4%, respectively). NRM was 23 ± 5% in the CD3+/CD19+group vs 21 ± 4% in the TCRαβ+/CD19+group. Relapse incidence was also similar, 32 ± 5% vs 34 ± 6%, respectively. DFS and OS were not different (45 ± 5% vs 45 ± 6% and 53 ± 6% vs 58 ± 6% respectively). As there were no differences on transplant outcomes between groups, we further analyzed all patients together for risk factors associated with transplant outcomes. On multivariate analysis, we identified that early disease status at transplant (HR: 0.16; 95%CI (0.07-0.35) (p=0.0001), presence of cGvHD (HR: 0.38; 95%CI (0.20-0.70) (p= 0.002), and donor KIR-B genotype (HR: 0.50; 95%CI (0.32-0.90) (p=0.04) were associated with better DFS.ConclusionsOur data suggest that there are no advantages in transplant outcomes between TCD platforms. Risk factors for survival are dependent on disease characteristic, donor KIR genotype, and chronic GvHD rather than the TCD platform used.
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