An international phase 2 study combining cladribine and cytarabine (Ara-C) was initiated for patients with refractory, risk-organ–positive Langerhans cell histiocytosis (LCH) in 2005. The protocol, ...comprising at least two 5-day courses of Ara-C (1 g/m2 per day) plus cladribine (9 mg/m2 per day) followed by maintenance therapy, was administered to 27 patients (median age at diagnosis, 0.7 years; median follow-up, 5.3 years). At inclusion, all patients were refractory after at least 1 course of vinblastine (VBL) plus corticosteroid, all had liver and spleen involvement, and 25 patients had hematologic cytopenia. After 2 courses, disease status was nonactive (n = 2), better (n = 23), or stable (n = 2), with an overall response rate of 92%. Median disease activity scores decreased from 12 at the start of therapy to 3 after 2 courses (P < .0001). During maintenance therapy, 4 patients experienced reactivation in risk organs. There were 4 deaths; 2 were related to therapy toxicity and 2 were related to reactivation. All patients experienced severe toxicity, with World Health Organization grade 4 hematologic toxicity and 6 documented severe infections. The overall 5-year survival rate was 85% (95% confidence interval, 65.2%-94.2%). Thus, the combination of cladribine/Ara-C is effective therapy for refractory multisystem LCH but is associated with high toxicity.
•Patients with LCH, risk organs, refractory to standard VBL-steroid regimen have a poor survival, ∼30%.•In a phase 2 study, with 5 years' median follow-up, cladribine and Ara-C was shown to improve the survival up to 85% for this group.
Refractory chronic immune thrombocytopenia (r‐cITP) is one of the most challenging situations in chronic immune thrombocytopenia (cITP). Pediatric r‐cITP is inconsistently defined in literature, ...contributing to the scarcity of data. Moreover, no evidence is available to guide the choice of treatment. We compared seven definitions of r‐cITP including five pediatric definitions in 886 patients with cITP (median min‐max follow‐up 5.3 1.0–29.3 years). The pediatric definitions identified overlapping groups of various sizes (4%–20%) but with similar characteristics (higher proportion of immunopathological manifestations IM and systemic lupus erythematosus SLE), suggesting that they adequately captured the population of interest. Based on the 79 patients with r‐cITP (median follow‐up 3.1 0–18.2 years) according to the CEREVANCE definition (≥3 second‐line treatments), we showed that r‐cITP occurred at a rate of 1.15% new patients per year and did not plateau over time. In multivariate analysis, older age was associated with r‐cITP. One patient (1%) experienced two grade five bleeding events after meeting r‐cITP criteria and while not receiving second‐line treatment. The cumulative incidence of continuous complete remission (CCR) at 2 years after r‐cITP diagnosis was 9%. In this analysis, splenectomy was associated with a higher cumulative incidence of CCR (hazard ratio: 5.43, 95% confidence interval: 1.48–19.84, p = 7.8 × 10−4). In sum, children with cITP may be diagnosed with r‐cITP at any time point of the follow‐up and are at increased risk of IM and SLE. Second‐line treatments seem to be effective for preventing grade 5 bleeding. Splenectomy may be considered to achieve CCR.
Pediatric chronic immune thrombocytopenia (cITP) is a heterogeneous condition in terms of bleeding severity, second‐line treatment use, association with clinical and/or biological immunopathological ...manifestations (IMs), and progression to systemic lupus erythematosus (SLE). No risk factors for these outcomes are known. Specifically, whether age at ITP diagnosis, sex, or IMs impact cITP outcomes is unknown. We report the outcomes of patients with pediatric cITP from the French nationwide prospective cohort OBS'CEREVANCE. We used multivariate analyses to investigate the effect of age at ITP diagnosis, sex, and IMs on cITP outcomes. We included 886 patients with a median (min‐max) follow‐up duration of 5.3 (1.0–29.3) years. We identified an age cutoff that dichotomized the risk of the outcomes and defined two risk groups: patients with ITP diagnosed <10 years (children) and ≥ 10 years (adolescents). Adolescents had a two to four‐fold higher risk of grade ≥3 bleeding, second‐line treatment use, clinical and biological IMs, and SLE diagnosis. Moreover, female sex and biological IMs were independently associated with higher risks of biological IMs and SLE diagnosis, second‐line treatment use, and SLE diagnosis, respectively. The combination of these three risk factors defined outcome‐specific risk groups. Finally, we showed that patients clustered in mild and severe phenotypes, more frequent in children and adolescents, respectively. In conclusion, we identified that age at ITP diagnosis, sex, and biological IMs impacted the long‐term outcomes of pediatric cITP. We defined risk groups for each outcome, which will help clinical management and further studies.
Objectives
Nationwide prospective cohort study exploring (i) the factors associated with treatment initiation (vs. watchful waiting) in children with primary immune thrombocytopenia (ITP) followed in ...routine clinical practice and (ii) the predictors of chronicity at 12 months.
Procedure
Between 2008 and 2013, 23 centers throughout France consecutively included 257 children aged 6 months–18 years and diagnosed with primary ITP over a 5‐year period. Data on ITP clinical features along with medical management were collected at baseline and 12 months. Multivariate logistic regressions were used to determine (i) and (ii) as defined above, providing odds ratio (OR) with 95% confidence interval (95% CI).
Results
One hundred thirty‐seven (53%) children were males, median age was 4.6 years, median platelet count was 7 × 109/l, and 214 (81%) patients initiated medication. Factors independently associated with treatment initiation included platelet counts <10 × 109/l (P < 0.0001) and mucocutaneous bleeding symptoms at baseline (P < 0.001). At 12 months, data were available for 211 (82%) children, of whom 160 (74%) had recovered. Predictors of chronicity included female gender (OR = 2.2; 95% CI = 1.0–4.8), age ≥10 years (OR = 2.6; 95% CI = 1.1–6.0), and platelet counts ≥10 × 109/l (OR = 3.2; 95% CI = 1.5–6.9).
Conclusions
In routine clinical practice, the decision to apply a watchful waiting strategy seems to be driven by platelet counts even in the absence of bleeding symptoms, resulting in treatment being initiated in more than 80% of the children surveyed. Overall, younger children with ITP showed good prognosis, with lower platelet counts and, to a lesser extent, male gender predicting more favorable outcomes.
To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing data from 13 037 individuals enrolled in the National Institute for ...Health Research (NIHR) BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor-encoding gene IKZF5 and thrombocytopenia. We report 5 causal missense variants in or near IKZF5 zinc fingers, of which 2 occurred de novo and 3 co-segregated in 3 pedigrees. A canonical DNA-zinc finger binding model predicts that 3 of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared with wild-type IKZF5, and electron microscopy revealed a reduced quantity of α granules in normally sized platelets. Proplatelet formation was reduced in megakaryocytes from 7 cases relative to 6 controls. Comparison of RNA-sequencing data from platelets, monocytes, neutrophils, and CD4+ T cells from 3 cases and 14 healthy controls showed 1194 differentially expressed genes in platelets but only 4 differentially expressed genes in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.
•Mutations in the transcription factor IKZF5 cause autosomal dominant thrombocytopenia and a paucity of α granules.•Although IKZF5 is expressed across hematopoietic lineages, misregulation in IKZF5 cases is restricted to the megakaryocytic lineage.
Display omitted
Pediatric-onset Evans syndrome (pES) is defined by both immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years. There have been no comprehensive ...long-term studies of this rare disease, which can be associated to various immunopathological manifestations (IM). We report outcomes of the 151 patients with pES and more than 5 years of follow-up from the nationwide French prospective OBS'CEREVANCE cohort. Median age at final follow-up was 18.5 years (range, 6.8-50.0 years) and the median follow-up period was 11.3 years (range, 5.1-38.0 years). At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IM increased with age: at the age of 20 years, 74% had at least one clinical IM (cIM). A wide range of cIM occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IM. The number of cIM was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio 1.4, 95% Confidence Interval: 1.15-1.60, P=0.0002, Cox proportional hazards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 years (range, 1.7-31.5 years), and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, long-term outcomes of pES showed remission of cytopenias but frequent IM linked to high second-line treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.
Summary
Childhood autoimmune haemolytic anaemia (AIHA) requires second‐line immunosuppressive therapy in 30–50% of cases. It appears that rituximab is indicated in such circumstances. This ...prospective national study reports the practice, efficacy and tolerance of rituximab in children with isolated AIHA and AIHA in the setting of Evans syndrome (ES). Sixty‐one children were given rituximab between 2000 and 2014. The median interval from diagnosis to rituximab was 9·9 interquartile range (IQR) 1·6–28·5 months. Forty‐six patients responded (75%) and the 6‐year relapse‐free survival (RFS) was 48%. Twenty patients relapsed at a median interval of 10·8 (IQR 3·9–18·7) months, rituximab allowed steroid withdrawal in 44/61 (72%) of children. In isolated AIHA, complete response and 6‐year RFS were significantly higher than in ES (P < 0·05). Ten out of 61 patients were infants, seven of who responded with a 6‐year RFS of 71%. Among patients without immunoglobulin substitution before rituximab, 4 are still receiving substitutions. Five patients died, including one potentially attributable to rituximab. This large observational series of childhood AIHA established the rituximab benefit‐risk ratio, allowing steroid withdrawal, with 37% of long‐term responders, mainly in isolated AIHA. All subgroups of patients drew benefit. Our long‐term results indicate the baseline to be challenged by new treatment approaches.
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.
PDF
