In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).

We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function.

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PURPOSE Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129 ). RESULTS Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.

Background:MicroRNAs (miRNAs) regulate expression of many cancer-related genes through posttranscriptional repression of their mRNAs. In this study we investigate the proto-oncogene MYCN as a target for miRNA regulation.Methods:A luciferase reporter assay was used to investigate software-predicted miRNA target sites in the 3′-untranslated region (3′UTR) of MYCN. The miRNAs were overexpressed in cell lines by transfection of miRNA mimics or miRNA-expressing plasmids. Mutation of the target sites was used to validate MYCN 3′UTR as a direct target of several miRNAs. To measure miRNA-mediated suppression of endogenous N-myc protein, inhibition of proliferation and inhibition of clonogenic growth, miRNAs were overexpressed in a MYCN-amplified neuroblastoma cell line.Results:The results from this study show that MYCN is targeted by several miRNAs. In addition to the previously shown mir-34a/c, we experimentally validate mir-449, mir-19a/b, mir-29a/b/c, mir-101 and let-7e/mir-202 as direct MYCN-targeting miRNAs. These miRNAs were able to suppress endogenous N-myc protein in a MYCN-amplified neuroblastoma cell line. The let-7e and mir-202 were strong negative regulators of MYCN expression. The mir-101 and the let-7 family miRNAs let-7e and mir-202 inhibited proliferation and clonogenic growth when overexpressed in Kelly cells.Conclusion:The tumour-suppressor miRNAs let-7 and mir-101 target MYCN and inhibit proliferation and clonogenic growth of MYCN-amplified neuroblastoma cells.

Sterile alpha motif domain protein 9 (SAMD9) and its paralogue SAMD9-like (SAMD9L) are cytoplasmic proteins encoded by two juxtaposed single-exon genes on chromosome 7q21. They share a 60% amino acid sequence identity and likely originated from a duplication of a common ancestral gene 1 . Their function remains enigmatic; they have been linked to tumor suppression 2 , inflammation 3 , stress response 4 , development 4 , endosomal fusion 5,6 and protein translation 7,8 . Both proteins were also shown to function as restriction factors forming a cross-species barrier for poxvirus infection [9][10][11][12] . Structural analysis of these large proteins has been limited to homology modeling, which predicted identical domains in either protein (SAM, ALBA2, SIR2, P-loop/ NTPase and OB-fold) 13 . Moreover, these genes exhibit tight regulation during embryonic development and transition to ubiquitous expression levels in adult tissues 14,15 .Notably, Samd9l-haploinsufficient mice develop myeloid neoplasia mimicking human MDS with monosomy 7 5 . Several groups reported germline SAMD9 or SAMD9L mutations (SAMD9/9L mut ) underlying new human syndromes with a propensity for cytopenia, bone marrow failure (BMF) and MDS with non-random monosomy 7 or deletion of 7q 6,16-28 . SAMD9 mutations (SAMD9 mut ) were initially linked to a fatal, early-onset MIRAGE syndrome (myelodysplasia, infections, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy) 6,29 . In contrast, SAMD9L mutations (SAMD9L mut ) were originally described in families with a progressive neurological phenotype, multi-lineage cytopenia and bone marrow hypoplasia (ataxia-pancytopenia syndrome) 16,17 . Recent reports broadened this spectrum and found missense SAMD9/9L mut in non-syndromic familial MDS [30][31][32][33] , truncating SAMD9L mut in children with autoinflammatory panniculitis resembling CANDLE

RIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.

The inability to generate mesenchymal stromal cells (MSCs) of consistent potency likely is responsible for inconsistent clinical outcomes of patients with aGvHD receiving MSC products. We developed a novel MSC manufacturing protocol characterized by high in vitro potency and near-identity of individual doses, referred to as “MSC-Frankfurt am Main (MSC-FFM)”. Herein, we report outcomes of the 69 patients who have received MSC-FFM. These were 51 children and 18 adults with refractory aGvHD grade II (4%), III (36%) or IV (59%). Patients were refractory either to frontline therapy (steroids) (29%) or to steroids and 1–5 additional lines of immunosuppressants (71%) were given infusions in four weekly intervals. The day 28 overall response rate was 83%; at the last follow-up, 61% and 25% of patients were in complete or partial remission. The median follow-up was 8.1 months. Six-month estimate for cumulative incidence of non-relapse mortality was 27% (range, 16–38); leukemia relapse mortality was 2% (range, 0–5). This was associated with a superior six-month overall survival (OS) probability rate of 71% (range, 61–83), compared to the outcome of patients not treated with MSC-FFM. This novel product was effective in children and adults, suggesting that MSC-FFM represents a promising therapy for steroid refractory aGvHD.