Distinct molecular profile of IRF4-rearranged large B-cell lymphoma.

Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma-related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.

First-in-Human, First-in-Child Trial of Autologous MSCs Carrying the Oncolytic Virus Icovir-5 in Patients with Advanced Tumors.

We present here the results of a first-in-human, first-in-child trial for patients with relapsed/refractory solid tumors using Celyvir, an advanced therapy medicine that combines autologous mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus. Celyvir was manufactured from a bone marrow aspirate and then given intravenously. Patients received weekly infusions for 6 weeks at a dose of 2 × 106 cells/kg (children) or 0.5-1 × 106 cells/kg (adults), 2 × 104 viral particles per cell. Fifteen pediatric and 19 adult patients were recruited, but 18 were screen failures, mainly because rapid disease progression before Celyvir was available. No grade 2-5 toxicities were reported. Adenoviral replication detected by PCR was found in all but 2 pediatric patient and in none of the adult ones. Absolute numbers of circulating leukocytes suffered minor changes along therapy, but some subsets showed differences comparing the pediatric versus the adult cohorts. Two patients with neuroblastoma showed disease stabilization, and one of them continued on treatment for up to 6 additional weeks. Celyvir, the combination of MSCs and oncolytic adenovirus, is safe and warrants further evaluation in a phase 2 setting. The use of MSCs may be a strategy to increase the amount of oncolytic virus administered to patients, minimizing toxicities and avoiding direct tumor injections.

Old drugs still work! Oral etoposide in a relapsed medulloblastoma.

Medulloblastoma is the most common malignant brain tumor in children. Approximately 30% of children with medulloblastoma will progress or relapse despite being treated. New therapies have been proposed in recent years, including high-dose chemotherapy, immunotherapy, and targeted therapy. However, the best treatment for these patients remains unclear, and in this situation prognosis is poor. Oral etoposide has been used as a single agent or in combination for treating relapsed brain tumors since the 1990s. We report an 8-year-old patient with recurrent metastatic medulloblastoma who had an excellent response after treatment with oral etoposide, maintaining a great quality of life. As clinicians, we must always try to include our patients in clinical trials; however, when this is not possible, we should not forget that "old drugs" such as oral etoposide may work in some patients, with a good response of the tumor, and what is most important, providing the patient with a good quality of life.

Safety and outcome of children, adolescents and young adults participating in phase I/II clinical oncology trials: a 9-year center experience.

Introduction: Enrolling children with cancer in early phase trials is crucial to access innovative treatments, contributing to advancing pediatric oncology research and providing tailored therapeutic options. Our objective is to analyze the impact of these trials on patient outcomes and safety, and to examine the evolution and feasibility of trials in pediatric cancer over the past decade. Methods: All patients recruited in pediatric anticancer phase I/II clinical trials from January 2014 to December 2022 were included. Clinical records and trial protocols were analyzed. Results: A total of 215 patients (median age 11.2 years, range 1-29.5) were included in 52 trials (258 inclusions). Patients with extracranial solid tumors (67%), central nervous system (CNS) tumors (24%), and leukemia (9%) were included. The most common investigational drugs were small molecules (28.3%) and antibodies (20.5%). Serious adverse events were experienced by 41% of patients, 4.4% discontinued treatment because of toxicity and two had toxic deaths. Median event-free survival was 3.7 months (95%CI: 2.8-4.5), longer in phase II trials than in phase I (2 vs. 6.3 months; p ≤ 0.001). Median overall survival was 12 months (95%CI: 9-15), higher in target-specific vs. non-target-specific trials (14 vs. 6 months; p ≤ 0.001). Discussion: A significant and increasing number of patients have been included in early clinical trials, suggesting that both oncologists and families consider it valuable to be referred to specialized Units to access new therapies. Moreover, our data suggests that participation in early clinical trials, although not without potential toxicities, might have a positive impact on individual outcomes.

Very late isolated CNS relapse of acute myeloid leukemia.

Isolated central nervous system (CNS) relapse in acute myeloid leukemia (AML) rarely occurs later than 2 years after remission. We present a child diagnosed with AML (FAB M5) without CNS involvement at diagnosis who was treated with chemotherapy and consolidated with autologous hematopoietic stem cell transplantation. He was in complete remission for >6 years until he had an isolated CNS relapse. He was treated with only intrathecal chemotherapy and achieved a second complete remission, but relapsed in the bone marrow 5 months after the CNS relapse. Treatment of late isolated CNS relapse of AML is discussed.

Allogeneic hematopoietic transplantation using haploidentical donor vs. unrelated cord blood donor in pediatric patients: a single-center retrospective study.

We retrospectively analyzed outcomes in 67 children with acute leukemia who received hematopoietic stem cell transplantation from alternative allogeneic donors: 29 received a haploidentical family donor and 38, an unrelated cord blood donor. All transplantations were performed from 1996 through 2010 in our center. Neutrophil and platelet engraftment were significantly delayed after cord blood transplantation. The median times to neutrophil and platelet recovery were 13 d (7-34) and 11 d (5-70) after haploidentical transplant and 20 d (9-125) and 56 d (12-200) after cord blood (P < 0.001). All supportive care measures included red blood cell, and platelet transfusions were significantly increased in cord blood transplantation group.Transplant-related mortality rates was lower with haplo donors (25 ± 9%) than with cord blood donors (47 ± 9%) (P < 0.05). Acute graft-versus-host disease (GVHD) more than grade II was also lower in haploidentical transplants (19 ± 7%) than in cord blood transplants (44 ± 10%) (P < 0.03). Relapse and chronic GVHD incidence were not significantly different in the two groups. Leukemia-free survival was higher after haploidentical transplants (44 ± 10%) than after cord blood transplants (33 ± 7%) (P < 0.03). Main differences were observed in patients diagnosed with acute lymphoblastic leukemia: haplo, 41 ± 13%; cord blood, 26 ± 9% (P < 0.03) and in advanced phase of disease: haplo, 37 ± 14%; cord blood, 21 ± 8% (P < 0.05). In conclusion, haploidentical transplants are a good and promising alternative option for patients with childhood leukemia who lack an human leukocyte antigen-matched donor (sibling or unrelated donor).

High-dose busulfan and cyclophosphamide as a conditioning regimen for autologous peripheral blood stem cell transplantation in childhood non-Hodgkin lymphoma patients: a long-term follow-up study.

We analyzed the outcome in 22 children with refractory or relapsed non-Hodgkin lymphoma who underwent autologous peripheral blood progenitor cell transplantation between 1994 and 2009. The conditioning regimen used in all patients consisted of busulfan and cyclophosphamide. Median age was 6 years (range 2 to 16 y). The most common histologic subtype was Burkitt lymphoma. Ten patients were in complete remission and 12 in partial remission at the time of transplant. The median dose of CD34+ cells that was infused was 4.6 × 10/kg (range 2.1 to 58.7 × 10/kg). All the patients were engrafted, with a median time for neutrophils and platelets recovery of 11 (range, 8 to 15 d) and 14 (range, 9 to 60 d) days, respectively. Nonhematologic treatment-related toxicity included severe mucositis in 3 patients and hepatic sinusoidal obstruction syndrome in 1 patient. There were no transplant-related mortalities. With a median follow-up of 60 months (range, 4 to 180 d) the disease-free survival was 90 ± 6.5% for the whole group. This retrospective study shows a high long-term survival using busulfan/cyclophosphamide as conditioning regimen in children with refractory or relapsed non-Hodgkin lymphoma.

High-dose busulfan and melphalan as conditioning regimen for autologous peripheral blood progenitor cell transplantation in high-risk neuroblastoma patients.

The aim of this retrospective study was to analyze the outcome and identify risk factors associated with progression-free survival (PFS) in 36 children with high-risk neuroblastoma who underwent autologous peripheral blood progenitor cell (PBPC) transplantation between 1994 and 2010. The conditioning regimen used in all cases consisted of high-dose of busulfan and melphalan. Median age at transplantation was 3 years (range: 0.7-14 years). The median times to neutrophil and platelet engraftment were 11 days (range: 9.16 days) and 13 days (range: 9.33), respectively. Twenty-one patients developed nonhematologic toxicity: 15 patients had mucositis, 4 patients developed an engraftment syndrome, and there were 2 cases of liver toxicity. No toxic deaths were observed. There were 15 patients who relapsed. The median time to relapse was 6 months after the transplant (range: 3-13 months). With a median follow-up of 55 months (range: 4-180 months), the PFS was 57% ± 8.5% for the whole group. In multivariate analysis, age below 3 years (P < .005), complete remission (CR) pretransplantation (P < .07) and 1p germline status (P < .01) were variables associated with better outcomes. Patients who were or achieved early CR following transplantation (3 months posttransplantation) had a probability of PFS of 91% ± 6% as compared to patients who did not (PFS 9% ± 8%) (P < .0001). This retrospective study shows that high dose of busulfan and melphalan as conditioning regimen in children with high-risk neuroblastoma is associated with very low morbidity and no mortality in the authors' hands. Younger patients with no 1p deletions and in first CR at transplantation had the better outcome.