Non-Hodgkin lymphoma is the fourth most common malignancy in children, has an even higher incidence in adolescents, and is primarily represented by only a few histologic subtypes. Dramatic progress ...has been achieved, with survival rates exceeding 80%, in large part because of a better understanding of the biology of the different subtypes and national and international collaborations. Most patients with Burkitt lymphoma and diffuse large B-cell lymphoma are cured with short intensive pulse chemotherapy containing cyclophosphamide, cytarabine, and high-dose methotrexate. The benefit of the addition of rituximab has not been established except in the case of primary mediastinal B-cell lymphoma. Lymphoblastic lymphoma is treated with intensive, semi-continuous, longer leukemia-derived protocols. Relapses in B-cell and lymphoblastic lymphomas are rare and infrequently curable, even with intensive approaches. Event-free survival rates of approximately 75% have been achieved in anaplastic large-cell lymphomas with various regimens that generally include a short intensive B-like regimen. Immunity seems to play an important role in prognosis and needs further exploration to determine its therapeutic application. ALK inhibitor therapeutic approaches are currently under investigation. For all pediatric lymphomas, the intensity of induction/consolidation therapy correlates with acute toxicities, but because of low cumulative doses of anthracyclines and alkylating agents, minimal or no long-term toxicity is expected. Challenges that remain include defining the value of prognostic factors, such as early response on positron emission tomography/computed tomography and minimal disseminated and residual disease, using new biologic technologies to improve risk stratification, and developing innovative therapies, both in the first-line setting and for relapse.
Infantile myofibromatosis is one of the most prevalent soft tissue tumors of infancy and childhood. Multifocal nodules with visceral lesions are associated with a poor prognosis. A few familial cases ...have been linked to mutations in various genes including PDGFRB. In this study, we sequenced PDGFRB, which encodes a receptor tyrosine kinase, in 16 cases of myofibromatosis or solitary myofibroma. Mutations in the coding sequence of PDGFRB were identified in 6 out of 8 patients with the sporadic multicentric form of the disease and in 1 out of 8 patients with isolated myofibroma. Two patients had the same mutation in multiple separated lesions. By contrast, a third patient had three different PDGFRB mutations in the three nodules analyzed. Mutations were located in the transmembrane, juxtamembrane and kinase domains of the receptor. We showed that these mutations activated receptor signaling in the absence of ligand and transformed fibroblasts. In one case, a weakly-activating germline variant was associated with a stronger somatic mutation, suggesting a two-hit model for familial myofibromatosis. Furthermore, the mutant receptors were sensitive to the tyrosine kinase inhibitor imatinib, except D850V, which was inhibited by dasatinib and ponatinib, suggesting a targeted therapy for severe myofibromatosis. In conclusion, we identified gain-of-function PDGFRB mutations in the majority of multifocal infantile myofibromatosis cases, shedding light on the mechanism of disease development, which is reminiscent of multifocal venous malformations induced by TIE2 mutations. Our results provide a genetic test to facilitate diagnosis, and preclinical data for development of molecular therapies.
•The B1MG project aims to build a federated network of genomic data in Europe.•As one of the B1MG piloting countries, Belgium assessed its maturity level.•This paper discusses the results of 49 ...indicators spanning eight domains.
Genomic medicine has great potential to offer insights into how humans’ genetic variation can affect their health, prevention options and treatment responses. The Beyond 1 Million Genomes (B1MG) project was kicked off in 2020 with the aim of building a federated network of genomic data in Europe, in which Belgium took part as a piloting country. B1MG developed a framework to enable all interested countries to self-evaluate the level of maturity of national genomic medicine practices following a common matrix, called Maturity Level Model (MLM), that contained 49 indicators across eight domains: I. Governance and strategy; II. Investment and economic model; III. Ethics, legislation and policy; IV. Public awareness and acceptance; V. Workforce skills and organisation; VI. Clinical organisation, infrastructure and tools; VII. Clinical genomics guidelines and infrastructure; and VIII. Data management, standards and infrastructure. The ongoing Genomic Data Infrastructure (GDI) project aims to capitalise on the experience of B1MG piloting countries and their MLM results. In this paper, we present the qualitative and quantitative outcomes of B1MG MLM assessment in Belgium and discuss their relevance to GDI. The insights gained from this study can be helpful for steering future policy directions and interventions on genomics in Belgium and beyond.
We determined first- and second-line regimens, including hematopoietic stem cell transplantations, in all diffuse large B cell lymphoma (DLBCL) patients aged ≥20 yr (n = 1,888), registered at the ...Belgian Cancer Registry (2013-2015). Treatments were inferred from reimbursed drugs, and procedures registered in national health insurance databases. This real-world population-based study allows to assess patients usually excluded from clinical trials such as those with comorbidities, other malignancies (12%), and advanced age (28% are ≥80 yr old). Our data show that the majority of older patients are still started on first-line regimens with curative intent and a substantial proportion of them benefit from this approach. First-line treatments included full R-CHOP (44%), "incomplete" (R-)CHOP (18%), other anthracycline (14%), non-anthracycline (9%), only radiotherapy (3%), and no chemo-/radiotherapy (13%), with significant variation between age groups. The 5-year overall survival (OS) of all patients was 56% with a clear influence of age (78% 20-59 yr versus 16% ≥85 yr) and of the type of first-line treatments: full R-CHOP (72%), other anthracycline (58%), "incomplete" (R-)CHOP (47%), non-anthracycline (30%), only radiotherapy (30%), and no chemo-/radiotherapy (9%). Second-line therapy, presumed for refractory (7%) or relapsed disease (9%), was initiated in 252 patients (16%) and was predominantly (71%) platinum-based. The 5-year OS after second-line treatment without autologous stem cell transplantation (ASCT) was generally poor (11% in ≥70 yr versus 17% in <70 yr). An ASCT was performed in 5% of treated patients (n = 82). The 5-year OS after first- or second-line ASCT was similar (69% versus 66%). After adjustment, multivariable OS analyses indicated a significant hazard ratio (HR) for, among others, age (HR 1.81 to 5.95 for increasing age), performance status (PS) (HR 4.56 for PS >1 within 3 months from incidence), subsequent malignancies (HR 2.50), prior malignancies (HR 1.34), respiratory and diabetic comorbidity (HR 1.41 and 1.24), gender (HR 1.25 for males), and first-line treatment with full R-CHOP (HR 0.41) or other anthracycline-containing regimens (HR 0.72). Despite inherent limitations, patterns of care in DLBCL could be determined using an innovative approach based on Belgian health insurance data.
(1) Background: Haematological malignancies (HMs) represent a heterogeneous group of mostly rare cancers that differ in pathophysiology, incidence, and outcome. (2) Methods: Our study aims to ...understand the epidemiological situation and trends of 24 main types of HMs in Belgium over a 15-year period, with a focus on the impact of age. Age-standardised incidence, average annual percentage change (AAPC), 5- and 10-year relative survival (RS) and RS trends were estimated for all HMs (N = 94,415) diagnosed between 2004 and 2018. (3) Results: Incidence rates of HM increased, mainly in the 70+ age group (AAPC: 3%). RS varied by age and HM type. For each HM type, outcome decreased with age. The greatest decrease with age in 5-year RS is observed for aggressive HM, acute myeloid leukaemia (AML), acute lymphoblastic leukaemia, and Burkitt lymphoma, from 67%, 90%, and 97% below 20 years, to 2%, 12%, and 16% above 80 years of age, respectively. The moderate improvement in 5-year RS over the 2004–2018 period for all HMs, of +5 percentage point (pp), masks highly heterogenous outcomes by HM type and age group. The most impressive improvements are observed in the 80+ group: +45, +33, +28, and +16 pp for Hodgkin lymphoma, immunoproliferative disorders, follicular lymphoma, and chronic myeloid leukaemia, respectively. (4) Conclusions: The increasing incidence and survival over the 2004–2018 period are likely explained by diagnostic and therapeutic innovations, which have spread to populations not targeted by clinical trials, especially older adults. This real-world population-based study highlights entities that need significant improvement, such as AML.
Congenital neutropenia is a group of genetic disorders that involve chronic neutropenia and susceptibility to infections. These neutropenias may be isolated or associated with immunologic defects or ...extra-hematopoietic manifestations. Complications may occur as infectious diseases, but also less frequently as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, the transcription factor GATA2 has been identified as a new predisposing gene for familial AML/MDS. In the present study, we describe the initial identification by exome sequencing of a GATA2 R396Q mutation in a family with a history of chronic mild neutropenia evolving to AML and/or MDS. The subsequent analysis of the French Severe Chronic Neutropenia Registry allowed the identification of 6 additional pedigrees and 10 patients with 6 different and not previously reported GATA2 mutations (R204X, E224X, R330X, A372T, M388V, and a complete deletion of the GATA2 locus). The frequent evolution to MDS and AML in these patients reveals the importance of screening GATA2 in chronic neutropenia associated with monocytopenia because of the frequent hematopoietic transformation, variable clinical expression at onset, and the need for aggressive therapy in patients with poor clinical outcome.
•Mutations of key transcription factor in myeloid malignancies.
JAK2 constitutive activation/overexpression is common in classical Hodgkin lymphoma, and several cytokines stimulate Hodgkin lymphoma cells by recognizing JAK1-/JAK2-bound receptors. JAK blockade may ...thus be therapeutically beneficial in Hodgkin lymphoma. In this phase II study we assessed the safety and efficacy of ruxolitinib, an oral JAK1/2 inhibitor, in patients with relapsed/refractory Hodgkin lymphoma. The primary objective was overall response rate according to the International Harmonization Project 2007 criteria. Thirty-three patients with advanced disease (median number of prior lines of treatment: 5; refractory: 82%) were included; nine (27.3%) received at least six cycles of ruxolitinib and six (18.2%) received more than six cycles. The overall response rate after six cycles was 9.4% (3/32 patients). All three responders had partial responses; another 11 patients had transient stable disease. Best overall response rate was 18.8% (6/32 patients). Rapid alleviation of B-symptoms was common. The median duration of response was 7.7 months, median progression-free survival 3.5 months (95% CI: 1.9-4.6), and the median overall survival 27.1 months (95% CI: 14.4-27.1). Forty adverse events were reported in 14/33 patients (42.4%). One event led to treatment discontinuation, while 87.5% of patients recovered without sequelae. Twenty-five adverse events were grade 3 or higher. These events were mostly anemia (n=11), all considered related to ruxolitinib. Other main causes of grade 3 or higher adverse events included lymphopenia and infections. Of note, no cases of grade 4 neutropenia or thrombocytopenia were observed. Ruxolitinib shows signs of activity, albeit short-lived, beyond a simple anti-inflammatory effect. Its limited toxicity suggests that it has the potential to be combined with other therapeutic modalities.
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Long bone nonunion in the context of congenital pseudarthrosis or carcinologic resection (with intercalary bone allograft implantation) is one of the most challenging pathologies in pediatric ...orthopedics. Autologous cancellous bone remains the gold standard in this context of long bone nonunion reconstruction, but with several clinical limitations. We then assessed the feasibility and safety of human autologous scaffold-free osteogenic 3-dimensional (3D) graft (derived from autologous adipose-derived stem cells ASCs) to cure a bone nonunion in extreme clinical and pathophysiological conditions. Human ASCs (obtained from subcutaneous adipose tissue of 6 patients and expanded up to passage 4) were incubated in osteogenic media and supplemented with demineralized bone matrix to obtain the scaffold-free 3D osteogenic structure as confirmed in vitro by histomorphometry for osteogenesis and mineralization. The 3D "bone-like" structure was finally transplanted for 3 patients with bone tumor and 3 patients with bone pseudarthrosis (2 congenital, 1 acquired) to assess the clinical feasibility, safety, and efficacy. Although minor clones with structural aberrations (aneuploidies, such as tri or tetraploidies or clonal trisomy 7 in 6%-20% of cells) were detected in the undifferentiated ASCs at passage 4, the osteogenic differentiation significantly reduced these clonal anomalies. The final osteogenic product was stable, did not rupture with forceps manipulation, did not induce donor site morbidity, and was easily implanted directly into the bone defect. No acute (<3 mo) side effects, such as impaired wound healing, pain, inflammatory reaction, and infection, or long-term side effects, such as tumor development, were associated with the graft up to 4 years after transplantation. We report for the first time that autologous ASC can be fully differentiated into a 3D osteogenic-like implant without any scaffold. We demonstrated that this engineered tissue can safely promote osteogenesis in extreme conditions of bone nonunions with minor donor site morbidity and no oncological side effects.
Heterozygous germline
mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients ...in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.
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