Imatinib is the standard of care in adults with chronic myeloid leukemia (CML) in chronic phase (CP). Only a few studies to assess efficacy in children have been performed. We report on the results ...of the French prospective trial (ClinicalTrials.gov identifier NCT00845221) conducted in children and adolescents with newly diagnosed CML in CP.
A total of 44 patients from age 10 months to 17 years with newly diagnosed CML in CP received daily imatinib 260 mg/m(2). Progression-free survival, responses, and tolerance were evaluated.
With a median follow-up times of 31 months (range, 11 to 64 months), the estimated progression-free survival rate at 36 months was 98% (95% CI, 85% to 100%). A complete hematologic response was achieved in 98% of the patients. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were 61% and 31% at 12 months, respectively. During follow-up, CCyR and MMR were achieved in 36 children (77%) and 25 children (57%), respectively. Overall, 30% of the patients discontinued imatinib, mainly because of unsatisfactory response. The most common adverse events were neutropenia and musculoskeletal events.
Imatinib is effective in children with CML in CP with response rates similar to rates reported in adults. The adverse effects are acceptable, but longer follow-up studies are required to fully assess the long-term impact.
The safety and efficacy of rituximab have been retrospectively assessed in 17 children with Evans syndrome. Patients received 4 or 3 weekly doses of rituximab (375 mg/m(2) per dose) associated with ...prednisone, alone (14 patients) or associated with other immunosuppressive drugs. Complete or partial remission of at least one cytopenia was achieved in 13 out of the 17 patients (76%), and lasted in 11 of them with a mean follow-up of 2.4 years (range 0.5-7 years). Steroid therapy was stopped or tapered at 50-100% of the baseline dosage in all long-term responders. Moderate side effects and infection occurred only in 4 and 1 children respectively.
To describe neurologic, radiologic and laboratory features in children with central nervous system (CNS) inflammatory disease complicating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ...infection.
We focused on CNS inflammatory diseases in children referred from 12 hospitals in the Paris area to Necker-Sick Children Reference Centre.
We identified 19 children who had a history of SARS-CoV-2 infection and manifest a variety of CNS inflammatory diseases: encephalopathy, cerebellar ataxia, acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, or optic neuritis. All patients had a history of SARS-CoV-2 exposure, and all tested positive for circulating antibodies against SARS-CoV-2. At the onset of the neurologic disease, SARS-CoV-2 PCR results (nasopharyngeal swabs) were positive in 8 children. Cerebrospinal fluid was abnormal in 58% (11/19) and magnetic resonance imaging was abnormal in 74% (14/19). We identified an autoantibody co-trigger in 4 children (myelin-oligodendrocyte and aquaporin 4 antibodies), representing 21% of the cases. No autoantibody was found in the 6 children whose CNS inflammation was accompanied by a multisystem inflammatory syndrome in children. Overall, 89% of patients (17/19) received anti-inflammatory treatment, primarily high-pulse methylprednisolone. All patients had a complete long-term recovery and, to date, no patient with autoantibodies presented with a relapse.
SARS2-CoV-2 represents a new trigger of postinfectious CNS inflammatory diseases in children.
Abstract Purpose The aim is to study statural growth in a large cohort of children with chronic myeloid leukaemia (CML) treated with front-line imatinib. Methods Retrospective data from 81 children ...less than 18 years of age with CML identified in the French pediatric registry were analysed. Height was expressed as standard deviation score (SDS). Results A gradual decrease in height SDS was observed over time since starting imatinib. The height SDS was significantly lower 12 months and 24 months after the start of imatinib overall ( p < 10−4 ) irrespective of gender and pubertal age. The height SDS was significantly ( p < 10−4 ) lower 12 months after the start of imatinib in boys and girls, and in the prepubertal age group as well as in the postpubertal age group, respectively. A similar finding was observed in the subgroups of boys and girls starting imatinib at a prepubertal or postpubertal age. Loss in height SDS 12 months after the start of imatinib was of the same range in boys when compared to girls and in patients who started imatinib at a prepubertal age compared to those who started at a postpubertal age. Conclusion Growth velocity was altered during the first years of imatinib treatment in boys as well as in girls and in prepubertal age patients as well as in adolescents.
Here we report a retrospective analysis based on BCR-ABL transcript level at 3 months after the start of imatinib assessing its impact on subsequent response and outcome in children and adolescents ...with chronic myeloid leukemia (CML) enrolled in the French prospective trial Glivec Phase 4 (Millot F et al, JCO 2011).
44 children were enrolled in the Glivec Phase 4 Study. The median age was 11.5 years (range: 10 months-17 years). The median follow-up was 49 months (range: 16 to 83). We retrospectively analyzed the rates of complete cytogenetic responses (CCR) and major molecular response (MMR) 1 year after the start of imatinib, the progression free survival (PFS) and the overall survival (OS).
At 3 months after the start of imatinib, 40/44 (91%) patients were evaluable for molecular response. BCR-ABL transcripts levels were: BCR-ABL> 10% in 15 (37%) pts and BCR-ABL<10% in 25 (63%) pts. Children and adolescents with BCR-ABL >10% at 3 months had similar Sokal score distribution but a larger spleen size and a higher leukocyte count at diagnosis compared with patients with BCR-ABL <10%. The median dose of imatinib administered within the first 3 months of treatment was similar in patients with BCR-ABL >10% and those with <10% at 3 months. Two patients progressed to blastic phase 25 and 42 months after the start of imatinib and 1 died. Both of them had a BCR-ABL transcript level of more than 10% at 3 months after the start of imatinib. A transcript level <10% correlated with a better PFS (Table 1). Patients with a BCR-ABL transcript level <10% 3 months after the start of imatinib had a higher rate of CCR and MMR 12 months after the start of imatinib compared to those with a BCR-ABL transcript level >10% (Table 1). However the difference is statistically significant only for the molecular response.
Table 1BCR-ABL/ABL at 3 monthsN (%)CCyR at 12 monthsMMR at 12 monthsPFS at 36 months< 10%25 (63%)18 (72%)12 (92%)100%> 10%15 (37%)7 (28%)1 (8%)92%p=0.177p=0.0128p=0.034
The children and adolescents with >10% of BCR-ABL at 3 months after the start of imatinib are characterized by a higher propensity to fail the treatment and to progress. The value of a cut-off of 10% of BCR-ABL 3 months after the start of imatinib as a reliable surrogate marker of response at 1 year and outcome remains to be determined in a larger cohort of children and adolescents.
No relevant conflicts of interest to declare.
The French pediatric CML working group conducted a retrospective study analysing the growth of patients under 18 years with CML treated with imatinib front-line.
Data from 78 patients receiving ...imatinib (260 mg/m2) for newly diagnosed CML in chronic phase between July 2001 and August 2012 were collected. Height was expressed as standard deviation score (SDS). Height SDS was calculated using French growth standard, as patient height minus mean height for age and sex, divided by standard deviation of height for age and sex. Pre-pubertal age was defined as being younger than 9 years for girls or 11 years for boys.
A gradual decrease in the median of the height SDS score is observed over time since the start of imatinib. Sixty three patients were assessable for paired analysis at onset of imatinib and 12 months later. The median height-SDS in this group of patients was significantly lower (p < 10-4) 12 months after the start of imatinib. Variance analysis was performed in 36 children at onset of imatinib, 12 months and 24 months later. The median height-Z score in this group of patients was significantly lower 12 months and 24 months after the start of imatinib (p < 10-4) compared to initial diagnosis. The 63 patients assessable for paired data analysis at onset of imatinib and 12 months later were classified by sex and pubertal status. The median height Z score in boys and girls was significantly (p < 10-4) lower 12 months after the start of imatinib. When the patients were analysed according to the pubertal status at onset of imatinib, the median height SDS score was significantly (p < 10-4) lower 12 months after the start of imatinib in the prepurbertal group as well as in the postpubertal group. A similar finding was observed in the subgroups of boys and girls starting imatinib at a prebubertal or postpubertal age. No significant difference was observed when the median M12 height SDS score in patients who started imatinib at a prepubertal stage or a pospubertal stage were compared. Moreover, no significant difference was observed when the median M12 height-Z score in boys and girls were compared.
This retrospective analysis revealed a statistically significant deceleration in growth during the first 2 years of imatinib treatment in children and adolescents with CML and an absence of influence of sex and pubertal status on the depth of growth deceleration.
No relevant conflicts of interest to declare.
Inborn errors of cobalamin (Cbl, vitamin B12) absorption include hereditary intrinsic factor deficiency (HIFD) and Imerslund–Gräsbeck disease (IGD). HIFD is secondary to mutations in the HIF gene ...while IGD is due to mutations in one of the 2 subunits of the intrinsic factor receptor that is cubilin (CUBN) or amnionless (AMN). These disorders lead to intracellular Cbl depletion which in turn causes megaloblastic bone marrow failure, accumulation of homocysteine and methylmalonic acid (MMA), and methionine depletion. The clinical presentation reflects Cbl deficiency, with gastrointestinal symptoms, pancytopenia, and megaloblastic anemia. Mixed proteinuria, when it is present is strongly suggestive of IGD. Accurate diagnosis is always an emergency because early detection and treatment with life-long parenteral pharmacological doses of hydroxocobalamin are life saving and prevent further deterioration. However, the optimal frequency for cobalamin injections as a maintenance therapy is poorly reported. In order to evaluate the optimal maintenance schedule of cobalamin injections, we retrospectively collected clinical, biological, molecular and treatment data on 7 patients affected with congenital Cbl malabsorption. Unlike previous recommendations, we showed that a maintenance dosage of 1mg cobalamin twice a year was enough to ensure a normal clinical status and keep the hematological and metabolic parameters in the normal range. These data suggest that patients affected with inborn errors of cobalamin absorption may be safely long-term treated with cobalamin injections every 6months with careful follow-up of hematological and metabolic parameters. This maintenance regime is beneficial because the patients’ quality of life improves.
► Inborn errors of vitamin B12 absorption are a treatable cause of pancytopenia. ► These include Imerslund–Gräsbeck disease and hereditary intrinsic factor deficiency. ► Life-long parenteral cobalamin (Cbl) injections are life saving. ► Such a treatment easily corrects hematological and metabolic abnormalities. ► Our data on 7 patients suggest that 1mg of IM Cbl bi-annually is sufficient.
Abstract 2571
In our previous EORTC 58881 trial in childhood ALL, we have shown the prognostic impact of the MRD, quantitated by polymerase chain reaction assay. Patients with TP1 MRD ≥10–2 (D35), ...had a higher risk of relapse than those with TP1 MRD<10-2 (Cavé et al, NEJM, 1998). For these patients hematopoietic stem cell transplantation (HSCT) with an HLA matched donor was recommended in our subsequent EORTC 58951 trial. Here we report on the patients with MRD ≥10-2 (TP1) in the 58951 trial.
Between December 1998 and July 2008, 1955 children (1y-18y) with ALL were enrolled in the 58951 trial, 1459 being evaluable for the MRD (TP1) by PCR (rearrangements of the T-cell receptor and immunoglobulin heavy chain genes). Seventy-nine patients with Phi-negative ALL had a TP1 MRD ≥10-2, and 69 of them achieved a complete hematological remission after induction. Here we report on the outcome of these 69 patients.
At a median follow-up of 7.6 years, the overall 5-years EFS and OS rates for the 69 patients were 56.1% (SE 6.0%) and 62.0% (SE 5.9%) respectively. Prephase good responders (PGR) (<1000 blasts/mm3 D8) (N=40) had a better OS rate as compared to prephase poor responders (PPR) (N=29): 72.2% (SE 7.1%) vs 48.0% (SE 9.3%) (hazard ratio=0.43, p = 0. 002). In B-lineage ALL patients the OS was similar between PGR (N=32) and PPR (N=6) subgroups, whereas in T-ALL patients there was a better OS for PGR (N=8) than for PPR (N=23) subgroup. Of note, all the patients with hyperdiploidy > 51 chromosomes were PGR.
TP2 MRD (after consolidation) was assessed in 59 pts. All patients but one (1/13) with TP2 MRD ≥10-2 died. In PGR patients, those with TP2 MRD < 10-3 (N=18) had a significant better OS rate at 5 years than those with TP2 MRD ≥10-3 (N=17): 88.9% (SE 7.4%) vs 52.3 % (SE 12.3%), hazard ratio=0.17, p=0.009. We observed no relapses among patients with hyperdiploidy > 51 chromosomes and TP2 <10-3. PPR patients had a poor 5-year OS, independent of TP2 level (MRD <10-3 (N=8) or MRD ≥10-3 (N=16)).
The prognosis of children ALL with TP1 MRD ≥10-2 has improved with early intensification of the treatment as compared to the one observed in our previous 58881 study. However the outcome of these patients was still heterogeneous and the prephase response was still of prognostic importance. Patients with GPR and TP2 <10-3 had a favourable prognosis and for those patients HSCT is not mandatory.
For other patients with PPR and/or TP2 ≥10-3 the prognosis was worse and these patients may benefit from alternative therapy and/or intensification with HSCT.
No relevant conflicts of interest to declare.
The purpose of this study was to determine the clinical and biological characteristics at diagnosis in children and adolescents with chronic myelogenous leukemia (CML) in contemporary practice.
...Analysis was conducted on data from 3 prospective trials conducted in children and adolescents with CML. Forty pediatric patients were evaluated in 16 French pediatric oncology units between 1991 and 2003.
The disease predominately affected children who were older than 10 years (67% of the patients), with a higher prevalence in boys than girls (gender ratio: 1.5). Approximately 20% of cases were diagnosed incidentally. The main presenting symptoms were asthenia, weight loss, and complaints related to splenomegaly. Occasional patients presented with signs evocative of leukostasis. Symptoms were more common in patients with splenic enlargement, which was present in 70% of patients, and higher leukocyte counts. Markedly raised leukocyte counts were common (median white blood cell count: 242 x 10(9)/L). The age and the gender of the patients had no effect on the leukocyte count, the hemoglobin level, or the platelet count. A predominance of b3a2 transcript was observed in the 16 children who were studied for the type of chimeric BCR-ABL mRNA.
This is largest reported series of CML at diagnosis in children and adolescents. It shows that the characteristics of CML seem to differ in children compared with previously published adult series; in particular, the presenting leukocyte counts are often higher in children.
PDF
