Background: there is some biologic and clinical evidence that DEX is more efficient than PRED at similarly anti-inflammatory doses in the treatment of childhood ALL. Previous trials have called for ...PRED doses (40 mg/sm/d) lower than those of PRED traditionally used in EORTC trials. In order to check whether the claimed superiority of DEX might be dose-dependent, we conducted a randomized phase III trial comparing DEX (6 mg/sm/d) to PRED (60 mg/sm/d) (conventional dose) in induction therapy.
Methods: the trial was opened in 12/1998 to all newly diagnosed children with ALL up to 18 y. of age. After the opening of the Interfant trial in 1999, children <1 y. old were registered in the latter. Ph1 pts recruited in this 58951 trial were kept in the present analysis because the switch to the EsPhALL was only after induction. The treatment regimen was of BFM type, without CNS radiation even in case of initial CNS leukemia. Randomization was done either on day 1 of the prephase (whenever feasible) or on day 8. In the latter case, PRED was administered before day 8. Non-very high risk pts were further randomized to prolong versus conventional duration of L-asparaginase courses during consolidation and late intensification. Part of average risk pts were also randomized (N=384) for the addition of pulses of VCR + glucocorticoid (same as that assigned for induction) in continuation therapy. Randomization was done centrally, stratification factors being disease, WBC, age, sex, timing of randomization and center. The main endpoint was EFS; secondary endpoints were OS and toxicity. Two interim analyses were foreseen in the protocol. Intent-to-treat analysis was used.
Results: between 12/1998 and 2/2008, a total of 1853 ALL pts were randomized; as of 2/2008, 1703 pts were evaluable for EFS analysis. At a median follow up of 4.3 y., the 5 y. EFS rate was 82.1% (SE 1.5%) for the pts in the DEX arm and 82.4% (SE 1.5%) in the PRED arm (hazard ratio (HR) = 0.99, 98.8% CI 0.72–1.36, p=0.94); the futility boundary was crossed. In precursor-B ALL pts, the 5 y. EFS rate was 84.2% (DEX) vs 84.1% (PRED) (HR=0.95, p=0.75) and in precursor-T ALL the 5y. EFS rate was 70.7% vs 72.0% (HR=1.06, p=0.83). Isolated and combined CNS relapse crude rates were 1.1% each (DEX) vs 1.6% and 2.2% (PRED) respectively (resp.). The 5-y CNS incidence rate was 2.9% (DEX) vs 4.9% (PRED), the non-CNS incidence rate was 10.9% (DEX) vs 9.4% (PRED), and the 5-yr death in CR incidence rate was 2.7% (DEX) vs 2.1% (PRED). During induction the incidence of grade 3–4 infection was very similar in the two arms. During post-induction consolidation (“protocol IB”), it was higher in the DEX arm (23.5% vs 21.1%), in particular in pts randomized to prolonged L-asparaginase arm: 29.1% (DEX) vs 21.8% (PRED).
Conclusion: DEX and PRED, used at the doses of resp. 6 and 60 mg/sm/d during induction, had equal efficacy. DEX decreased by 2.0% the 5-yr CNS incidence rate but increased by 1.5% the non-CNS incidence rate and by 0.6% the death in CR incidence rate. DEX in induction entails a higher infection rate during the consolidation, particularly when L-asparaginase is pursued throughout this phase. The optimal dosage of either glucocorticoid, compatible with acceptable toxicity, remains to be determined.
Objective
Cryopyrin‐associated periodic syndromes (CAPS) are a group of rare autoinflammatory diseases. Neonatal‐onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, ...cutaneous, articular syndrome (CINCA syndrome) is the most severe phenotype, with fever, rash, articular manifestations, and neurologic and neurosensory involvement. CAPS are caused by mutations in CIAS1, the gene encoding NLRP3, which plays a critical role in interleukin‐1 (IL‐1) processing. Anakinra, an IL‐1 receptor antagonist, has been shown to be an effective treatment; however, data on long‐term efficacy and safety have been sparse. This study was undertaken to assess the long‐term efficacy and safety of anakinra treatment in patients with NOMID/CINCA syndrome.
Methods
We retrospectively analyzed the medical records of NOMID/CINCA syndrome patients referred to 2 centers, who had started anakinra treatment before June 2007.
Results
There were 10 patients with NOMID/CINCA syndrome who had been treated with anakinra. The patients' ages at the time anakinra treatment was initiated ranged from 3 months to 20 years. They had been followed up for 26–42 months. Sustained efficacy in the treatment of systemic inflammation and, in some cases, neurologic involvement and growth parameters, was achieved. The dosage of anakinra required for efficacy ranged from 1 to 3 mg/kg/day in the 8 oldest patients and from 6 to 10 mg/kg/day in the 2 youngest. Residual central nervous system inflammation and deafness persisted in some patients, especially if there had been a delay in diagnosis and treatment. Secondary amyloidosis persisted in cases in which it was present at treatment initiation, but no new lesions developed. No effect on overgrowth arthropathy was observed. Adverse events consisted of mild injection‐site reactions.
Conclusion
The present results indicate that anakinra treatment is effective over the long term in NOMID/CINCA syndrome. However, treatment has to be initiated before irreversible lesions develop, and, particularly in very young patients, dosage adjustment is required.
Abstract The EORTC Children's Leukemia Group (CLG) is a spin-off from the EORTC Hemopathies Working Party (adults and children). After a decade of collaboration in the adult-pediatric group it became ...clear that there was not only a large difference in cure rates between children and adults, but many chemotherapeutic-toxic borders were substantially different. During the following decade the CLG was not only a witness of a very exciting battle against childhood leukemia, but it also contributed substantially to better cure rates for these diseases. The main activity of the CLG was concentrated on the field of acute lymphoblastic leukemia (ALL). Fine tuning of treatment elements using the BFM design as a backbone has been done very successfully over the past decades. The CLG has many achievements, and the major ones include: the 58831 trial showing the superfluity of the prophylactic Central Nervous System (CNS) radiotherapy in ALL patients when a adequate systemic and CNS directed chemotherapy is ascertained. The 58881 trial demonstrated that the assessment of minimal residual disease (MRD) at completion of induction in ALL is a key step in the process to categorizing and allocating patients into different risk groups, and that MRD is a powerful and independent prognostic factor. This same 58881 trial showed the clear difference in efficacy of different asparaginases resulting in an optimization of the use these drugs and a revival of interest for the asparaginases in the treatment of ALL. In the near future the CLG will focus mainly on translational research projects and innovative biologically targeted treatment approaches, on collaborations with other children's leukemia groups in intergroup studies, and on the evaluation of the long-term outcome of childhood cancer survivors.
To evaluate the prognostic significance of blasts in the CSF at diagnosis in children with ALL, 2049 patients (pts) enrolled from 1989 to 1996 in EORTC 58881 trial were retrospectively studied. ...Treatment design was according to BFM. Central nervous system (CNS)-directed therapy consisted in i.v. methotrexate (MTX) (5 g/sqm over 4 hours) in 4 to 10 courses, according to grade of initial CNS involvement, and intrathecal MTX. No radiotherapy was used. Three randomizations were programmed: Erwinia vs Medac E.coli asparaginase (all pts); addition or not of i.v. Ara-C to i.v. MTX (for increased-risk pts); addition of monthly courses of i.v. 6-MP in maintenance therapy (all pts). According to CNS status, pts were classified in 4 groups: 1) CNS-1: <6 WBC/μl, RBC<100/μl, no blasts; 2) dubious CNS-2: presence of blasts, RBC>100/μl; 3) surreptitious CNS-2: presence of blasts, <6 WBC/μl, RBC<100/μl; 4) CNS-3: presence of blasts, >5 WBC/μl, RBC<100/μl. Only CNS-3 pts were to receive 10 courses of i.v. MTX, but some of dubious (N=21) and surreptitious CNS-2 pts (N=19) did eventually receive 10 courses as well. Dubious CNS-2 (n=53), surreptitious CNS-2 (n=52), and CNS-3 (n=54) contained a higher rate of pts with unfavourable features than CNS-1 pts: WBC > 100000/μl; T-lineage; NCI high risk; very high risk (VHR) features (≥1000 peripheral blasts/μl post prephase, high-risk cytogenetics). Median follow-up was 7.5 years. The 5-yr overall event-free survival (EFS) and overall survival (OS) rates (SE%) were 71.6 % (1.0 %) and 82.6 % (0.8%) respectively. The 5-yr EFS rate (SE%) was 72.1 % (1.0%) for CNS-1, 62.2 % (6.6%) for dubious CNS-2, 64.7 % (6.7%) for surreptitious CNS-2, and 70.3 % (6.2%) for CNS-3 group. Overall, pts with blasts in the CSF (dubious CNS-2, surreptitious CNS-2 or CNS-3) had a significantly (p=0.02) shorter EFS than those in the CNS-1 group: 5-yr EFS rate 65.6% (3.8%) vs 72.1%. Multivariate analysis indicated that low WBC, Medac E-Coli asparaginase, absence of VHR features, middle age group were, together, predictive for longer EFS, whereas CNS involvement (CNS-2/-3 vs CNS-1) lost its prognostic value (p=0.87). Out of 2018 pts who reached CR, a total of 71 isolated and 78 combined CNS relapses were reported. The 5-yr isolated CNS relapse rate was 3.8%: 3.5% in CNS-1, 6.7% in dubious CNS-2, 10.5% in surreptitious CNS-2 and 7.1% in CNS-3 group. The 5-yr isolated or combined CNS relapse rate was 7.9%; in the 4 CNS-groups it was 7.6%, 11.1%, 14.7% and 9.2% respectively. The 5-yr OS rate (SE%) was 83.5% (0.9%) in CNS-1 vs 72.4% (3.9%) in CNS-2/-3: p=0.0003. Prognostic importance was lost (p=0.23) in multivariate analysis. Conclusion: the presence of blasts in the CSF, with or without pleiocytosis, is associated with unfavorable prognostic features and with worse outcome. Intensification of CNS-directed chemotherapy, without CNS radiation, is an effective treatment of initial meningeal leukemic involvement.
An estimation of the incidence and demographic picture of the major hemoglobinopathies in Belgium has been approached through a confidential inquiry sent to 228 pediatric and adult hematological ...departments. Forty-two percent of responses showed that 417 patients are known in Belgium: 83% with sickle cell disease, 13% with β-thalassemia (β-thal) major, 2% with β-thal intermedia, and 1% with Hb H disease. Twenty-five percent of the sickle cell disease patients and 54% of those suffering from a β-thal major were older than 20 years. Three hospitals ensure the follow-up of 70% of the patients and are situated in Brussels, Belgium; a follow-up of less than 20 patients was reported at 21 centers. These results confirm that sickle cell disease is the major hemoglobinopathy in Belgium; it concerns mostly pediatricians but adult hematologists are also confronted with these pathologies. Therefore, it is necessary to implement integrated programs of prevention and treatment.
The improved cure rate in childhood ALL may be attributed largely to the effective multidrug regimens currently applied in well-designed clinical trials. However, in a minority of patients with ALL, ...chemotherapy failure remains a leading cause of cancer related death, most probably due to cellular drug resistance. The better-known mechanism of such resistance is mediated by P-glycoprotein (P-gp). In a long term prospective study (mean time of follow-up: 65 months) the multidrug efflux pump P-gp was examined immunocytochemically in leukemic cells of 102 protocol-treated children with de novo acute lymphoblastic leukemia (ALL) and of 37 children with relapsed ALL. Fourteen percent expressed P-gp at initial diagnosis and 35% were P-gp positive at relapse. The patients being P-gp positive at initial diagnosis had a higher rate of leukemic relapse than the P-gp negative patients (P =0.02). In the relapsing patients, those who were P-gp positive had a 2.18-fold greater risk for leukemic death than those who were P-gp negative. Paired analysis on diagnostic and relapsed samples from 20 patients did not support the hypothesis of P-gp mediated expression being a chemotherapy induced phenomenon. The cumulative event free survival for de novo ALL patients was significantly higher in the P-gp negative patient group. Multivariate analysis showed that P-gp expression is independent of other known risk factors. In conclusion we strongly advise that tests for P-gp in leukemic blasts should be conducted for every child with ALL, since this parameter selects a subgroup of patients with increased risk for leukemic relapse.
A 10-year-old boy with a history of acute lymphoblastic leukaemia (ALL), but without previous evidence of central nervous system involvement, presented with seizures 3 years after complete remission.
...MRI showed bilateral enlargement of the optic nerves despite normal ophthalmological examination.
Only the third cerebrospinal fluid examination showed 2 % blasts without concomitant bone-marrow infiltration. Enlargement of the optic nerves was consistent with bilateral leukaemic peri-optic nerve infiltration. The appearances returned to normal after chemotherapy.
The optic nerves are a potential site of relapse in patients with systemic and meningeal ALL, even in the absence of ophthalmological signs.
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