Characteristics and treatment of acute myeloid neoplasms with cutaneous involvement in infants up to 6 months of age: A retrospective study.

BACKGROUND: Myeloid neoplasms account for 50% of cases of pediatric leukemias in infants. Approximately 25%-50% of patients with newborn leukemia have cutaneous extramedullary disease (EMD). In less than 10% of patients, aleukemic leukemia cutis or isolated extramedullary disease with cutaneous involvement (cEMD) occurs when skin lesions appear prior to bone marrow involvement and systemic symptoms. Interestingly, in acute myeloid leukemia with cutaneous EMD (AML-cEMD) and cEMD, spontaneous remissions have been reported. METHOD: This is a multicentric retrospective cohort study aiming to describe characteristics, treatment, and outcome of infants with either cEMD or presence of cutaneous disease with involvement of the bone marrow (AML-cEMD). This study included patients born between 1990 and 2018 from Italy, the Netherlands, Switzerland, and the United States, diagnosed between 0 and 6 months of life with cEMD or AML-cEMD. Descriptive statistics, Fisher's exact test, Kaplan-Meier method, and log rank test were applied. RESULTS: The cohort consisted of n = 50 patients, including 42 AML-cEMD and eight cEMD patients. The most common genetic mutation found was a KMT2A rearrangement (n = 26, 52%). Overall 5-year event-free survival (EFS) and overall survival (OS) were 66% [confidence interval (CI): 51-78] and 75% [CI: 60-85], respectively. In two patients, complete spontaneous remission occurred without any therapy. Central nervous system (CNS) involvement was found in 25% of cEMD patients. No difference in outcomes was observed between the AML-cEMD and cEMD groups, but none of the latter patients included in the study died. KMT2A rearrangements were not associated with poorer prognosis. CONCLUSION: In the largest cohort to date, our study describes the characteristics of infants with cutaneous involvement of myeloid neoplasms including cytomolecular findings and survival rates. Further prospective biologic and clinical studies of these infants with myeloid neoplasms will be required to individualize therapy for this rare patient population.

INSPIRED Symposium Part 4B: Chimeric Antigen Receptor T Cell Correlative Studies-Established Findings and Future Priorities.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of B cell malignancies, with multiple CAR T cell products approved for numerous indications by regulatory agencies worldwide. However, significant work remains to be done to enhance these treatments. In March 2023, a group of experts in CAR T cell therapy assembled at the National Institutes of Health in Bethesda, Maryland at the Insights in Pediatric CAR T Cell Immunotherapy: Recent Advances and Future Directions (INSPIRED) Symposium to identify key areas for research for the coming years. In session 4B, correlative studies to be incorporated into future clinical trials and real-world settings were discussed. Active areas of research identified included (1) optimizing CAR T cell product manufacturing; (2) ensuring adequate lymphodepletion prior to CAR T cell administration; (3) overcoming immunoregulatory cells and tumor stroma present in the tumor microenvironment, particularly in solid tumors; (4) understanding tumor intrinsic properties that lead to CAR T cell immunotherapy resistance; and (5) uncovering biomarkers predictive of treatment resistance, treatment durability, or immune-related adverse events. Here we review the results of previously published clinical trials and real-world studies to summarize what is currently known about each of these topics. We then outline priorities for future research that we believe will be important for improving our understanding of CAR T cell therapy and ultimately leading to better outcomes for patients.

Differentiation between rebound thymic hyperplasia and thymic relapse after chemotherapy in pediatric Hodgkin lymphoma.

BACKGROUND: Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum. METHODS: After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated. RESULTS: After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth. CONCLUSION: Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.

Response-adapted omission of radiotherapy in children and adolescents with early-stage classical Hodgkin lymphoma and an adequate response to vincristine, etoposide, prednisone, and doxorubicin (EuroNet-PHL-C1): a titration study.

BACKGROUND: Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. METHODS: The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1-5; prednisone 60 mg/m2 orally on days 1-15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006-000995-33) and is completed. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1-69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3-89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8-92·5), for which the 95% CI included the 90% target rate. The most common grade 3-4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths. INTERPRETATION: On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

[Precision medicine in the treatment of pediatric cancers]. / Médecine de précision dans le traitement des cancers pédiatriques.

Despite the progress in cure rates for pediatric cancers, several challenges remain, such as the management of diseases with poor prognosis. The efficacy of intensified chemotherapies is also accompanied by increased risks of severe acute and chronic toxicities. Thus, therapies specifically targeting tumor cells, or inhibiting oncogenic molecular aberrations, could provide more effective and less toxic treatments for pediatric cancers. Personalization of chemotherapies through pharmacogenetics and precision dosing could also improve the efficacy and toxicity of chemotherapies. In this review, we describe precision medicine strategies implemented or undergoing clinical evaluation in the treatment of pediatric cancers.

Malgré les progrès sur les taux de guérison des cancers pédiatriques, plusieurs défis restent à relever, comme la prise en charge des maladies à mauvais pronostic. L'efficacité des chimiothérapies intensives s'accompagne aussi de risques accrus de toxicités aiguës et chroniques graves. Ainsi, les thérapies ciblant spécifiquement les cellules tumorales, ou inhibant les aberrations moléculaires oncogéniques, pourraient offrir des traitements plus efficaces et moins toxiques pour les cancers pédiatriques. La personnalisation des chimiothérapies grâce à la pharmacogénétique et au dosage de précision pourrait également améliorer l'efficacité et la toxicité des chimiothérapies. Dans cet article de revue, nous décrivons les stratégies de médecine de précision implémentées ou en cours d'évaluation clinique dans le traitement des cancers pédiatriques.

How should childhood acute lymphoblastic leukemia relapses in low-income and middle-income countries be managed: The AHOPCA-ALL study group experience.

BACKGROUND: Children with relapsed acute lymphoblastic leukemia (ALL) in low-income and middle-income countries rarely survive. The Pediatric Hematology-Oncology Association of Central America (AHOPCA) developed the AHOPCA-ALL REC 2014 protocol to improve outcomes in resource-constrained settings without access to stem cell transplantation. METHODS: The AHOPCA-ALL REC 2014 protocol was based on a modified frontline induction phase 1A, a consolidation therapy with six modified R-blocks derived from the ALL-Berlin-Frankfurt-Munster REZ 2002 protocol and intermittent maintenance therapy. Children with B-lineage ALL were eligible after a late medullary relapse, an early or late combined relapse, or any extramedullary relapses. Those with T-lineage ALL were eligible after early and late extramedullary relapses, as were those with both B-lineage and T-lineage relapses occurring at least 3 months after therapy abandonment. RESULTS: The study population included 190 patients with T-lineage (n = 3) and B-lineage (n = 187) ALL. Of those with B-lineage ALL, 25 patients had a very early extramedullary relapse, 40 had an early relapse (32 extramedullary and 8 combined), and 125 had a late relapse (34 extramedullary, 19 combined, and 72 medullary). The main cause of treatment failure was second relapse (52.1%). The 3-year event-free survival rate (± standard error) was 25.9% ± 3.5%, and the 3-year overall survival rate was 36.7% ± 3.8%. The 3-year event-free survival rate was 47.2% ± 4.7% for late relapses. The most frequently reported toxicity was grade 3 or 4 infection. Mortality during treatment occurred in 17 patients (8.9%), in most cases because of infectious complications. CONCLUSIONS: Selected children with relapsed ALL in Central America can be cured with second-line regimens even without access to consolidation with stem cell transplantation. Children in low-income and middle-income countries who have lower risk relapses of ALL should be treated with curative intent.

Cancer medicines on the WHO Model List of Essential Medicines: processes, challenges, and a way forward.

The selection of cancer medicines for national procurement requires deliberate evaluation of population benefit, budget impact, sustainability, and health system capacity. However, this process is complicated by numerous challenges, including the large volume and rapid pace of newly developed therapies offering marginal gains at prohibitively high prices. The WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc) have undergone a series of evidence-based updates to ensure recommended cancer medicines offer meaningful clinical benefit. This Health Policy paper describes how cancer medicines are listed on the EML and EMLc, including two updated WHO processes: (1) the formation of the Cancer Medicines Working Group, and (2) additional selection principles for recommending cancer medicines, including a minimum overall survival benefit of 4-6 months with improvement to quality of life compared with standard treatment. These updates, along with proposals to include formal price considerations, additional selection criteria, and multisectoral collaboration (eg, voluntary licensing) promote procurement of high-value essential cancer medicines on national formularies in the context of supporting sustainable health systems to achieve universal health coverage.

Near-tetraploid T-cell acute lymphoblastic leukaemia in childhood: Results of the AIEOP-BFM ALL studies.

BACKGROUND: Near-tetraploidy-defined by DNA index 1.79-2.28 or 81-103 chromosomes-is a rare cytogenetic abnormality observed both in children and adults with T-cell acute lymphoblastic leukaemia (T-ALL) and its prognostic value is not yet determined. PATIENTS AND METHODS: We report a retrospective study conducted in paediatric patients with newly diagnosed T-ALL treated in AIEOP-BFM ALL 2000 and 2009 studies. 31 near-tetraploid T-ALL patients (1.4%) are compared to T-ALL patients without near-tetraploidy. RESULTS: Near-tetraploid karyotype was associated with lower frequency of high-risk features: white blood cells count at diagnosis ≥100,000/µL (19.3% versus 41.0%, p-value < 0.001), PPR (13.3% versus 35.8%, p-value = 0.01) and minimal residual disease high-risk at the end of consolidation phase Induction B (4.03% versus 14.6%, p-value = 0.001). Complete remission was achieved at the end of induction phase (day 33) in 100% near-tetraploid T-ALL patients, compared to 93.2% T-ALL without near-tetraploidy. CONCLUSION: Overall, we found that near-tetraploid T-ALL in newly diagnosed paediatric patients is associated with low-risk presenting features, with favourable treatment response and outcome.

Modified Manufacturing Process Modulates CD19CAR T-cell Engraftment Fitness and Leukemia-Free Survival in Pediatric and Young Adult Subjects.

T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). The durability of remission is related to the length of time the CAR T cells persist. Efforts to understand differences in persistence have focused on the CAR construct, in particular the costimulatory signaling module of the chimeric receptor. We previously reported a robust intent-to-treat product manufacturing success rate and remission induction rate in children and young adults with recurrent/refractory B-ALL using the SCRI-CAR19v1 product, a second-generation CD19-specific CAR with 4-1BB costimulation coexpressed with the EGFRt cell-surface tag (NCT02028455). Following completion of the phase I study, two changes to CAR T-cell manufacturing were introduced: switching the T-cell activation reagent and omitting midculture EGFRt immunomagnetic selection. We tested the modified manufacturing process and resulting product, designated SCRI-CAR19v2, in a cohort of 21 subjects on the phase II arm of the trial. Here, we describe the unanticipated enhancement in product performance resulting in prolonged persistence and B-cell aplasia and improved leukemia-free survival with SCRI-CAR19v2 as compared with SCRI-CAR19v1.

Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T cells.

Chimeric antigen receptor (CAR) T-cell toxicities resembling hemophagocytic lymphohistiocytosis (HLH) occur in a subset of patients with cytokine release syndrome (CRS). As a variant of conventional CRS, a comprehensive characterization of CAR T-cell-associated HLH (carHLH) and investigations into associated risk factors are lacking. In the context of 59 patients infused with CD22 CAR T cells where a substantial proportion developed carHLH, we comprehensively describe the manifestations and timing of carHLH as a CRS variant and explore factors associated with this clinical profile. Among 52 subjects with CRS, 21 (40.4%) developed carHLH. Clinical features of carHLH included hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hepatic transaminitis, hyperbilirubinemia, severe neutropenia, elevated lactate dehydrogenase, and occasionally hemophagocytosis. Development of carHLH was associated with preinfusion natural killer(NK) cell lymphopenia and higher bone marrow T-cell:NK cell ratio, which was further amplified with CAR T-cell expansion. Following CRS, more robust CAR T-cell and CD8 T-cell expansion in concert with pronounced NK cell lymphopenia amplified preinfusion differences in those with carHLH without evidence for defects in NK cell mediated cytotoxicity. CarHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH. In the setting of CAR T-cell mediated expansion, clinical manifestations and immunophenotypic profiling in those with carHLH overlap with features of secondary HLH, prompting consideration of an alternative framework for identification and management of this toxicity profile to optimize outcomes following CAR T-cell infusion.

Utilizing the prognostic impact of minimal residual disease in treatment decisions for pediatric acute lymphoblastic leukemia.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the first pediatric cancer where the assessment of early response to therapy by minimal residual disease (MRD) monitoring has demonstrated its importance to improve risk-based treatment approaches. The most standardized tools to study MRD in ALL are multiparametric flow cytometry and realtime-quantitative polymerase chain reaction amplification-based methods. In recent years, MRD measurement has reached greater levels of sensitivity and standardization through international laboratory networks collaboration. AREAS COVERED: We herewith describe how to assess and apply the prognostic impact of MRD in treatment decisions, with specific focus on pediatric ALL. We also highlight the role of MRD monitoring in the context of genetically homogeneous subgroups of pediatric ALL. However, some queries remain to be addressed and emerging technologies hold the promise of improving MRD detection in ALL patients. EXPERT OPINION: Emerging technologies, like next generation flow cytometry, droplet digital PCR, and next generation sequencing appear to be important methods for assessing MRD in pediatric ALL. These more specific and/or sensitive MRD monitoring methods may help to predict relapse with greater accuracy, and are currently being used in clinical trials to improve pediatric ALL outcome by optimizing patient stratification and earlier MRD-based interventional therapy.

Spontaneous Partial Remission in a Child With B-Lineage Acute Lymphoblastic Leukemia and Chickenpox: A Role For Acyclovir?

A 2.5-year-old boy presented to his pediatrician with progressive pallor, asthenia, fever, splenomegaly, and hematomas. Leukemia was suspected, and a bone marrow aspirate confirmed acute lymphoblastic leukemia. Before chemotherapy induction, the child developed a vesicular rash and was diagnosed clinically with chickenpox. Acyclovir treatment was initiated immediately, whereas induction chemotherapy was postponed by 10 days. At the time of chickenpox resolution, a spontaneous partial recovery of his blood counts and a 50% decrease of blastic bone marrow infiltration were noted. After a brief nonsystematic review, we discuss the potential beneficial effect of acyclovir and chickenpox infection in children with leukemia.

Assessment of Waldeyer's ring in pediatric and adolescent Hodgkin lymphoma patients-Importance of multimodality imaging: Results from the EuroNet-PHL-C1 trial.

BACKGROUND: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging. PATIENTS, MATERIALS, AND METHODS: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from 18 F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment. RESULTS: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient. CONCLUSIONS: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.

Comparison of Interim PET Response to Second-Line Versus First-Line Treatment in Classic Hodgkin Lymphoma: Contribution to the Development of Response Criteria for Relapsed or Progressive Disease.

In first-line treatment of Hodgkin lymphoma (HL), Deauville scores 1-3 define complete metabolic remission. Interim 18F-FDG PET is also used for relapse-treatment adaptation; however, PET response criteria are not validated for relapse treatment. Methods: We performed a pairwise comparative analysis of early response to first- and second-line treatments in 127 patients with classic HL who experienced relapse. The patients participated in the prospective, multicenter EuroNet-PHL-C1 study. Residual uptake was measured retrospectively using the qPET method, a validated semiautomatic quantitative extension of the Deauville score. Empiric cumulative distribution functions of the qPET values were used to systematically analyze the response to first- and second-line treatments. Results: Individual patients responded variably to first- and second-line treatments. However, the empiric cumulative distribution functions of the qPET values from all patients were nearly superimposable. Conclusion: The findings support that first- and second-line treatments in HL do not require different response criteria.

Second malignant neoplasms after treatment of non-Hodgkin's lymphoma-a retrospective multinational study of 189 children and adolescents.

Data on the spectrum of second malignant neoplasms (SMNs) after primary childhood non-Hodgkin's lymphoma (NHL) are scarce. One-hundred-and-eighty-nine NHL patients diagnosed in a 30 years period of 1980-2010 developing an SMN were retrieved from 19 members of the European Intergroup for Childhood NHL and/or the international Berlin-Frankfurt-Münster Study Group. Five subgroups of SMNs were identified: (1) myeloid neoplasms (n = 43; 23%), (2) lymphoid neoplasms (n = 51; 27%), (3) carcinomas (n = 48; 25%), (4) central nervous system (CNS) tumors (n = 19; 10%), and (5) "other" SMNs (n = 28; 15%). In 37 patients (20%) preexisting disorders were reported with 90% having any kind of cancer predisposition syndrome (CPS). For the 189 primary NHL patients, 5-year overall survival (OS) after diagnosis of an SMN was 56 ± 4%, being worst for patients with preexisting disorders at 28 ± 8%. Five-year OS rates were 38 ± 8%, 59 ± 7%, 79 ± 8%, 34 ± 12%, and 62 ± 11%, respectively, for patients with myeloid and lymphoid neoplasms, carcinomas, CNS tumors, and "other" SMNs (p < 0.0001). Patients with SMNs after childhood NHL having a reported CPS, mostly mismatch repair disorders, carried a very poor prognosis. Moreover, although outcome was favorable in some subtypes of SMNs after childhood NHL (carcinomas, lymphoid neoplasms), other SMNs such as myeloid neoplasms and CNS tumors had a dismal prognosis.

Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy.

Immunotherapy with the adoptive transfer of T cells redirected with CD19-specific chimeric antigen receptors (CARs) for B-lineage acute lymphoblastic leukemia (ALL) can salvage >80% of patients having relapsed/refractory disease. The therapeutic index of this emerging modality is attenuated by the occurrence of immunologic toxicity syndromes that occur upon CAR T-cell engraftment. Here, we report on the low incidence of severe cytokine release syndrome (CRS) in a subject treated with a CAR T-cell product composed of a defined ratio CD4:CD8 T-cell composition with a 4-1BB:zeta CAR targeting CD19 who also recieved early intervention treatment. We report that early intervention with tocilizumab and/or corticosteroids may reduce the frequency at which subjects transition from mild CRS to severe CRS. Although early intervention doubled the numbers of subjects dosed with tocilizumab and/or corticosteroids, there was no apparent detrimental effect on minimal residual disease-negative complete remission rates or subsequent persistence of functional CAR T cells compared with subjects who did not receive intervention. Moreover, early intervention therapy did not increase the proportion of subjects who experience neurotoxicity or place subjects at risk for infectious sequelae. These data support the contention that early intervention with tocilizumab and/or corticosteroids in subjects with early signs of CRS is without negative impact on the antitumor potency of CD19 CAR T cells. This intervention serves to enhance the therapeutic index in relapsed/refractory patients and provides the rationale to apply CAR T-cell therapy more broadly in ALL therapy. This trial was registered at www.clinicaltrials.gov as #NCT020284.

Chimeric Antigen Receptor T Cells for B-Cell Acute Lymphoblastic Leukemia.

Chimeric antigen receptor (CAR) T-cell therapy is transforming the landscape for treatment of B-lineage acute lymphoblastic leukemia (B-ALL). Chimeric antigen receptor T-cell therapy makes use of T cells that have been modified to target a cancer-specific cell surface antigen. There is currently 1 Food and Drug Administration-approved CD19-directed CAR T-cell therapy for relapsed/refractory B-ALL with numerous other CAR T-cell products under clinical investigation. This review covers the development of CAR T cells for B-ALL, citing the remarkable efficacy of inducing remissions in a very high-risk population of patients. However, following the first round of CAR T-cell trials targeting CD19 in B-ALL, it has been found that approximately 50% of patients who initially respond will ultimately recur. Current efforts in the field are focusing on the identification of targets beyond CD19 as well as advancing strategies to promote more durable remissions as work is ongoing to move this therapy upfront.

[Recent advances and future directions in CAR-T cell therapy in pediatric oncology]. / Progrès récents et orientations futures de la thérapie avec cellules CAR-T en oncologie pédiatrique.

Fighting leukemia using the immune system (antibodies, lymphocytes) is an old idea, which has already been fulfilled in allogeneic bone marrow transplantation. Indeed, the effectiveness of the transplant depends on the action of the donor lymphocytes. To limit the adverse effects on bystander organs (graft-versus-host disease), autologous T cells can be engineered to express synthetic chimeric antigen receptors (CARs) with artificially redirected antigen specificity. Autologous T cells engineered to express a CAR targeting CD19 have shown unprecedented efficacy in clinical trials for relapsed/refractory B-cell leukemias and lymphomas. In this review article, we describe the therapeutic strategies, clinical trial results, side effects and future direction of CAR T cell therapy in B cell acute lymphoblastic leukemia and other pediatric cancers and its future role in the Swiss setting.

Combattre la leucémie en utilisant les armes immunologiques, via les anticorps et les lymphocytes, est une idée ancienne, qui a déjà connu un accomplissement dans la greffe de moelle osseuse. Pour limiter les effets néfastes sur d'autres organes (maladie du greffon contre l'hôte), des cellules T autologues peuvent être modifiées pour exprimer des récepteurs d'antigènes chimères synthétiques (CAR) avec spécificité antigénique. Dans le cadre d'essais cliniques, les cellules CAR-T anti-CD19 ont montré une efficacité importante dans les leucémies et les lymphomes B en rechute ou réfractaires. Dans cet article, nous décrivons les approches proposées, les résultats des essais cliniques, les effets secondaires et l'orientation future de ces thérapies dans les leucémies et d'autres cancers pédiatriques ainsi que leurs perspectives dans le contexte suisse.

Genetic risk factors for VIPN in childhood acute lymphoblastic leukemia patients identified using whole-exome sequencing.

AIM: To identify genetic markers associated with vincristine-induced peripheral neuropathy (VIPN) in childhood acute lymphoblastic leukemia. PATIENTS & METHODS: Whole-exome sequencing data were combined with exome-wide association study to identify predicted-functional germline variants associated with high-grade VIPN. Genotyping was then performed for top-ranked signals (n = 237), followed by validation in independent replication group (n = 405). RESULTS: Minor alleles of rs2781377/SYNE2 (p = 0.01) and rs10513762/MRPL47 (p = 0.01) showed increased risk, whereas that of rs3803357/BAHD1 had a protective effect (p = 0.007). Using a genetic model based on weighted genetic risk scores, an additive effect of combining these loci was observed (p = 0.003). The addition of rs1135989/ACTG1 further enhanced model performance (p = 0.0001). CONCLUSION: Variants in SYNE2, MRPL47 and BAHD1 genes are putative new risk factors for VIPN in childhood acute lymphoblastic leukemia.