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.
Off-label use of vemurafenib (VMF) to treat
mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated.
Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They ...were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events version 4.3) and therapeutic responses according to Disease Activity Score.
LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (
< .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood
allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment;
< .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the
clone.
VMF seemed safe and effective in children with refractory
-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.
Langerhans cell histiocytosis (LCH) represents a disorder characterised by an abnormal accumulation of histiocytes in miscellaneous tissues. The bone is commonly affected, especially the flat bones, ...the spine and the long bones. Some lesions in children such as a “
vertebra plana
” or a solitary lytic lesion of the skull may be suggestive for LCH, whereas others can be confused with a malignant tumour or osteomyelitis. This pictorial essay presents the main usual and unusual skeletal manifestations observed in LCH.
Teaching points
• Osseous involvement in children with LCH is very similar to that seen in multiple myeloma.
• A solitary lytic lesion of the cranial vault is a typical radiographic finding of LCH.
• A
vertebra plana
appearance in the spine is another typical radiographic finding.
• Extensive signal intensity changes within bone marrow on MRI are a helpful sign for the diagnosis.
• In long bones, endosteal scalloping may be responsible for a “budding appearance”.
Summary
High cure rates are possible in children with localized mature B‐cell lymphoma (B NHL) using a variety of chemotherapeutic strategies. To reduce late sequelae, the duration and intensity of ...chemotherapy has been progressively reduced. The Lymphome Malins de Burkitt (LMB) 89 study reported long‐term survival in almost all children with localized resected disease treated with two courses of COPAD (cyclophosphamide, vincristine, prednisolone and doxorubicin). This study was designed to confirm the effectiveness of this approach in a larger number of patients in a multinational co‐operative study. The patient cohort was part of an international study (French‐American‐British LMB 96), which included all disease stages and involved three national groups. Patients in this part of the study had resected stage I or completely resected abdominal stage II disease. Following surgery, two courses of COPAD were given, without intrathecal (IT) chemotherapy. One hundred and thirty‐two children were evaluable. Two of 264 (0·9%) courses were associated with grade IV toxicity (one stomatitis and one infection). With a median follow up of 50·5 months, the 4 year event‐free survival is 98·3% and overall survival is 99·2%. Children with resected localized B‐NHL can be cured with minimal toxicity following two courses of low intensity treatment without IT chemotherapy.
Abstract▪2227▪This icon denotes a clinically relevant abstract
While splenectomy is the gold standard treatment for adult's refractory primary immune thrombocytopenia (ITP), its place remains debated ...in children. The Rare Disease Plan gave us the opportunity to conduct a French collaborative work aiming to study efficiency, tolerance and prognostic factors associated with success of this procedure in childhood ITP.
A retrospective study was conducted in France, of less than 18 years old children and adolescents who underwent a splenectomy for ITP during a 9-year period (2000–2009). Data from both the CEREVANCE national cohort and systematic requests to 30 paediatric units were reviewed. Medical data and procedures were checked from patients’ medical records. Complete remission (CR) was defined by platelet count of more than 100 G/L, continuous complete remission (CCR) was defined as CR with no relapse or treatment for at least one year (Aladjidi et al, Haematologica 2011). Relapse-free survival was assessed by Kaplan Meier method.
For 78 children in 16 units, the median ages at diagnosis of ITP and at splenectomy were respectively 9.6 (0.8–16.5) and 12.4 (3.5–17.4) years. The median duration of ITP before splenectomy was 24 months (1–162), 62 children had chronic ITP of more than 12 months duration. The surgical procedure was laparoscopy in 81% of children. Four patients experienced post-operative complications: 1 severe intra-abdominal hemorrhage requiring open surgery twelve hours after laparoscopy, 1 pleural and peritoneal hemorrhage after laparotomy, 1 mesenteric and splenic thrombosis and 1 pulmonary atelectasia. With a median follow up of 41 months (1–109), CR and CCR were achieved respectively for 83% and 75% of 62 children with chronic ITP. No overwhelming sepsis was reported during the follow-up. Isotopic platelet studies were available in 10 of the 16 units and assessed in 30 of the 44 concerned children. CR was obtained in 77% of 26 cases with predominant splenic destruction, and in 0% of 2 cases with non splenic destruction. Five-year relapse-free survival was 35% in children of less than 10 years old and 81% in children of more than 10 years old at initial diagnosis of ITP (p=0.0002).
This collaborative national study confirms the excellent benefit-risk ratio of splenectomy for refractory chronic ITP, especially in older children. Even if our own results are limited by the small number of patients, prior isotopic platelet studies is useful when locally available. Long term respect of anti-infectious measures is recommended.
Acknoledgements to the Association Française pour le Syndrome d’Evans (AFSE), the GIS - Institut des Maladies Rares - INSERM, and the French Health Ministry (Programme Hospitalier de Recherche Clinique 2005, Rare Diseases Plan 2007).
No relevant conflicts of interest to declare.
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