Summary Background Trials of imatinib have provided evidence of activity in adults with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (ALL), but the drug's role when given with ...multidrug chemotherapy to children is unknown. This study assesses the safety and efficacy of oral imatinib in association with a Berlin–Frankfurt–Munster intensive chemotherapy regimen and allogeneic stem-cell transplantation for paediatric patients with Philadelphia-chromosome-positive ALL. Methods Patients aged 1–18 years recruited to national trials of front-line treatment for ALL were eligible if they had t(9;22)(q34;q11). Patients with abnormal renal or hepatic function, or an active systemic infection, were ineligible. Patients were enrolled by ten study groups between 2004 and 2009, and were classified as good risk or poor risk according to early response to induction treatment. Good-risk patients were randomly assigned by a web-based system with permuted blocks (size four) to receive post-induction imatinib with chemotherapy or chemotherapy only in a 1:1 ratio, while all poor-risk patients received post-induction imatinib with chemotherapy. Patients were stratified by study group. The chemotherapy regimen was modelled on a Berlin–Frankfurt–Munster high-risk backbone; all received four post-induction blocks of chemotherapy after which they became eligible for stem-cell transplantation. The primary endpoints were disease-free survival at 4 years in the good-risk group and event-free survival at 4 years in the poor-risk group, analysed by intention to treat and a secondary analysis of patients as treated. The trial is registered with EudraCT (2004-001647-30) and ClinicalTrials.gov , number NCT00287105. Findings Between Jan 1, 2004, and Dec 31, 2009, we screened 229 patients and enrolled 178: 108 were good risk and 70 poor risk. 46 good-risk patients were assigned to receive imatinib and 44 to receive no imatinib. Median follow-up was 3·1 years (IQR 2·0–4·6). 4-year disease-free survival was 72·9% (95% CI 56·1–84·1) in the good-risk, imatinib group versus 61·7% (45·0–74·7) in the good-risk, no imatinib group (p=0·24). The hazard ratio (HR) for failure, adjusted for minimal residual disease, was 0·63 (0·28–1·41; p=0·26). The as-treated analysis showed 4-year disease-free survival was 75·2% (61·0–84·9) for good-risk patients receiving imatinib and 55·9% (36·1–71·7) for those who did not receive imatinib (p=0·06). 4-year event-free survival for poor-risk patients was 53·5% (40·4–65·0). Serious adverse events were much the same in the good-risk groups, with infections caused by myelosuppression the most common. 16 patients in the good-risk imatinib group versus ten in the good-risk, no imatinib group (p=0·64), and 24 in the poor-risk group, had a serious adverse event. Interpretation Our results suggests that imatinib in conjunction with intensive chemotherapy is well tolerated and might be beneficial for treatment of children with Philadelphia-chromosome-positive ALL. Funding Projet Hospitalier de Recherche Clinique-Cancer (France), Fondazione Tettamanti-De Marchi and Associazione Italiana per la Ricerca sul Cancro (Italy), Novartis Germany, Cancer Research UK, Leukaemia Lymphoma Research, and Central Manchester University Hospitals Foundation Trust.
Summary Background Acute lymphoblastic leukaemia in infants younger than 1 year is rare, and infants with the disease have worse outcomes than do older children. We initiated an international study ...to investigate the effects of a new hybrid treatment protocol with elements designed to treat both acute lymphoblastic leukaemia and acute myeloid leukaemia, and to identify any prognostic factors for outcome in infants. We also did a randomised trial to establish the value of a late intensification course. Methods Patients aged 0–12 months were enrolled by 17 study groups in 22 countries between 1999 and 2005. Eligible patients were stratified for risk according to their peripheral blood response to a 7-day prednisone prophase, and then given a hybrid regimen based on the standard protocol for acute lymphoblastic leukaemia, with some elements designed for treatment of acute myeloid leukaemia. Before the maintenance phase, a subset of patients in complete remission were randomly assigned to receive either standard treatment or a more intensive chemotherapy course with high-dose cytarabine and methotrexate. The primary outcomes were event-free survival (EFS) for the initial cohort of patients and disease-free survival (DFS) for the patients randomly assigned to a treatment group. Data were analysed on an intention-to-treat basis. This trial was registered with ClinicalTrials.gov , number NCT 00015873 , and at controlled-trials.com , number ISRCTN24251487. Findings In the 482 enrolled patients who underwent hybrid treatment, 260 (58%) were in complete remission at a median follow-up of 38 (range 1–78) months, and EFS at 4 years was 47·0% (SE 2·6, 95% CI 41·9–52·1). Of 445 patients in complete remission after 5 weeks of induction treatment, 191 were randomised: 95 patients to receive a late intensification course, and 96 to a control group. At a median follow-up of 42 (range 1–73) months, 60 patients in the treatment group and 57 controls were disease-free. DFS at 4 years did not differ between the two groups (60·9% SE 5·2 for treatment group vs 57·0% 5·5 for controls; p=0·81). During the intensification phase, of 71 patients randomly assigned to the treatment group, and for whom toxicity data were available, 35 (49%) had infections, 21 (30%) patients had mucositis, 22 (31%) patients had toxic effects on the liver, and 2 (3%) had neurotoxicity. All types of rearrangements in the (mixed lineage leukaemia) MLL gene, very high white blood cell count, age of younger than 6 months, and a poor response to the prednisone prophase were independently associated with inferior outcomes. Interpretation Patients treated with our hybrid protocol, and especially those who responded poorly to prednisone, had higher EFS than most reported outcomes for treatment of infant ALL. Delayed intensification of chemotherapy did not benefit patients.
The inherited bone marrow failure (BMF) syndromes are characterized by impaired hematopoiesis and cancer predisposition. Most inherited BMF syndromes are also associated with a range of congenital ...anomalies. Progress in improving the outcomes for children with inherited BMF syndromes has been limited by the rarity of these disorders, as well as disease-specific genetic, molecular, cellular, and clinical characteristics that increase the risks of complications associated with hematopoietic stem cell transplantation (HSCT). As a result, the ability to develop innovative transplant approaches to circumvent these problems has been limited. Recent progress has been made, as best evidenced in studies adding fludarabine to the preparative regimen for children undergoing unrelated donor HSCT for Fanconi anemia. The rarity of these diseases coupled with the far more likely incremental improvements that will result from ongoing research will require prospective international clinical trials to improve the outcome for these children.
Since the beginning of COVID-19 pandemic, it is known that the severe course of the disease occurs mostly among the elderly, whereas it is rare among children and young adults. Comorbidities, in ...particular, diabetes and hypertension, clearly associated with age, besides obesity and smoke, are strongly associated with the need for intensive treatment and a dismal outcome. A weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. Thus, there is concern that children treated for cancer may allso be at risk for an unfavourable course of infection. Along the same line, anecdotal information from Wuhan, China, mentioned a severe course of COVID-19 in a child treated for leukaemia.
We made a flash survey on COVID-19 incidence and severity among children on anticancer treatment. Respondents were asked by email to fill in a short Web-based survey.
We received reports from 25 countries, where approximately 10,000 patients at risk are followed up. At the time of the survey, more than 200 of these children were tested, nine of whom were positive for COVID-19. Eight of the nine cases had asymptomatic to mild disease, and one was just diagnosed with COVID-19. We also discuss preventive measures that are in place or should be taken and treatment options in immunocompromised children with COVID-19.
Thus, even children receiving anticancer chemotherapy may have a mild or asymptomatic course of COVID-19. While we should not underestimate the risk of developing a more severe course of COVID-19 than that observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment.
•Flash survey was used to get data on COVID-19 incidence and severity.•Paediatric haematology/oncology departments of 25 countries responded.•COVID-19 may have a mild course in these immunocompromised children.•Precautions should be taken to prevent any infections including COVID-19.•Malignancy is a primary danger; preventive measures should not hinder its treatment.
Summary Background Studies in the 1970s and 1980s suggested that the outcome of childhood acute lymphoblastic leukaemia (ALL) could be improved by intensification of conventional continuation ...chemotherapy with pulses of vincristine sulfate and steroids. We aimed to investigate the efficacy and toxic effects of vincristine-dexamethasone pulses as an addition to the continuation-therapy phase in a large cohort of children with intermediate-risk disease who were treated with the Berlin-Frankfurt-Münster (BFM) treatment strategy. Methods 3109 children, diagnosed with ALL and intermediate-risk features, were enrolled by eight participating organisations in eleven countries. All were treated with very similar protocols based on the BFM treatment strategy, which included induction, consolidation, reinduction, and continuation-therapy phases. At the beginning of the continuation-therapy phase, those patients in complete remission were randomly assigned to either a treatment or a control group. Control patients were given conventional mercaptopurine and methotrexate chemotherapy only. Patients in the treatment arm were also given pulses of vincristine (1·5 mg/m2 weekly for 2 weeks) and dexamethasone (6 mg/m2 daily for 7 days) every 10 weeks for six cycles. The primary outcome measure was disease-free survival. Analysis was by intention to treat. The study is registered at http://www.clinicaltrials.gov with the identifier NCT00411541. Findings 174 patients (5·6%) relapsed or died in complete remission before randomisation. Of the remaining 2935 patients, 2618 (89·2%) were randomly assigned: 1325 to the treatment group and 1293 to the control group. With median follow-up of 4·8 years, 240 children in the treatment group and 241 in the control group had relapses; 15 in the treatment group and 14 controls died in complete remission or developed second malignant neoplasms. The 5-year and 7-year disease-free survival estimates were 79·8% (SE 1·2) and 77·5% (1·5) in the treatment group and 79·2% (1·2) and 78·4% (1·3) in the control group, respectively. Treatment with pulses of vincristine and dexamethasone was associated with a non-significant 3% relative-risk reduction (hazard ratio 0·97; 95% CI 0·81–1·15; p=0·70). Interpretation Children with intermediate-risk ALL who received intensive chemotherapy based on BFM protocols did not benefit from intensification of the continuation-therapy phase with a schedule of pulses of vincristine and dexamethasone.
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