A case-control study was conducted to investigate the role of a familial history of cancer in the etiology of childhood acute leukemia. The history of cancer in the relatives of 472 cases was ...compared with that of 567 population-based controls. Recruitment was frequency matched on age, sex and region. The familial history of cancer in each child's relatives was reported by the mother in response to a standardized self-administered questionnaire. A familial history of solid tumor in first or second-degree relatives was associated with an increased risk of acute lymphoblastic leukemia (odds ratio (OR)=1.6 95% confidence interval, 1.2-2.1), while a familial history of hematopoietic malignancies in first or second-degree relatives was associated with an increased risk of acute myeloid leukemia (OR=4.3 1.4-13). The ORs for the histories of cancer increased with the number of relatives with cancer (OR=1.5 1.1-2.0 for one relative and OR=2.3 1.3-3.8 for two relatives or more; Ptrend < 0.0001). Significant associations between childhood acute leukemia and familial history of genital cancers and brain tumor were also observed (OR=2.7 1.2-5.8 and OR=10.7 1.3-86, respectively). This study supports the hypothesis that a familial history of cancer may play a role in the etiology of childhood acute leukemia. It also evidences some specific associations that require further investigation.
Valacyclovir was administered to 28 immunocompromised children (ages 5–12 years) to obtain preliminary pharmacokinetic and safety information. Patients were randomized to valacyclovir regimens of 250 ...mg (9.4–13.3 mg/kg) or 500 mg (13.9–27.0 mg/kg) twice daily or 500 mg (13.2–21.7 mg/kg) 3 times a day. Acyclovir pharmacokinetics were evaluated at steady state. Valacyclovir was rapidly absorbed and converted to acyclovir. Mean (±SD) acyclovir peak concentrations from 250 mg and 500 mg valacyclovir were 4.11±1.41 and 5.19±1.96 μg/mL, respectively. Corresponding single dose area-under-curve values were 12.14±6.60 and 14.49±4.69h×μg/mL. By using historical data for intravenous acyclovir as reference, the overall estimate of acyclovir bioavailability from valacyclovir was 48%, 2- to 4-fold greater than for oral acyclovir. In general, adverse events were not attributable to valacyclovir and were consistent with disease-related expectations and concomitant therapies. Dosage options for using valacyclovir in children are discussed
From January 2000 to July 2006, 580 BCR-ABL negative patients with HR/VHR-ALL (200 T-ALL and 380 BCP-ALL (age≥10 or WBC≥50 or CNS+ or MLL-R) were included in the FRALLE 2000-BT trials. Induction ...regimen is prednisone (PRED) prephase + IT MTX, VCR, L-Aspa, DNR 120mg/m2 cumulated dose or DNR 160mg/m2 + cyclophosphamide 1g/m2 (T-ALL and D21 M2M3 marrow or MLL-R BCP-ALL). MRD at EOI is quantitatively determined by DNA-based PCR for Ig/TCR rearrangements either competitive PCR with GeneScan analysis or RQ-PCR with clone specific primers (sensitivity ranges 0.5×10−3–10−3, and 10−3–10−5, respectively). MRD status at EOI are available for 425 out of 552 CR (77%). MRD results are reported as negative, positive <10−3, highly positive (10−3≤MRD<10−2), very highly positive (≥10−2). Patients with EOI MRD ≥10−2 were to receive an intensified treatment.
Results:
1.30% (89/293) of HR/VHR BCP-ALL and 34% (45/132) T-ALL have detectable MRD at EOI, NS. A high or very high MRD is encountered in 16% (47/293) of BCP-ALL and 21% (27/132) of T-ALL (NS).2.Surprisingly 57% (20/35) of the pts with BCP-ALL and D8 poor PRED response (PPR) and 71% (36/51) of the pts with D8 PPR T-ALL have a negative or slightly positive MRD (<10−3) at EOI, NS. 30% (7/23) of the pts with D21 M2M3 BCP-ALL and 46% (6/13) of the pts with D21 M2M3 T-ALL have also a negative or slightly positive MRD (<10−3) at EOI. By contrast, 11% of good early responders (D8 good PRED response and D21 M1) with BCP-ALL or T-ALL (27/245 and 11/74, respectively) have a high or very high positive MRD.3.Overall, 20 out of 449 (4.5%) HR/VHR pts in CR have received an intensified treatment due to a very high MRD only.4.3y DFS for pts with a highly positive or very highly positive MRD are 65±7% (BCP-ALL) and 64±9% (T-ALL), NS. 3y DFS for pts with a negative or slightly positive MRD (<10−3) are 94±2% (BCP-ALL) and 87±4% (T-ALL), p=.04.5.There is a statistically significant difference in term of DFS between pts with MRD≥10−3 and MRD < 10−3, p=.001 and p =.05 for BCP- and T-ALL, respectively.
Conclusions:
1.the incidence of high and very high MRD at EOI is identical in children with HR/VHR-BCP- and T-ALL.2.High and very high MRD levels are found in good early responders defined by morphology. Conversely, excellent molecular responses can be found in bad early responders.3.High or very high MRD values are associated to a comparable prognosis between BCP- and T-ALLs.
After LMT81 and SFOP LMT89 protocols (both modified LSA2L2), the SFOP LMT96 was designed according to BFM 86 back bone (Reiter and al, J Clin Oncol , 13:359. 1995). The aim of LMT96 protocol was to ...increase chemotherapy intensity early (day 8) and late (after the intensification phase). From February 1997 to December 2003, 83 unselected patients (pts) with newly diagnosed TLL were included in LMT96 protocol: classic corticosteroid prephase (d1 to d7); induction phase with Cyclophosphamide(CPM: 1g/m2) and high dose methotrexate (HDMTX: 3g/m2 infusion over 3h) at d8, followed by Vincristine, Daunorubicin (40mg/m2) d15, 22, 29; 8 injections of Asparaginase, 2 intrathecal injection MTX at d8 and d15 and prednisone for 4 weeks; two consolidation phases with HDMTX, Cyclophosphamide (CPM), Cytarabine and Asparaginase; one interphase with HDMTX and; an intensification phase similar to a phase II BFM study, a maintenance phase with Mercaptopurine/MTX including initially six intensified monthly pulse phases alternating either HDMTX/Asparaginase, or Cytarabine/prednisone. The total duration of treatment was 18 months for stage I, II and III and 24 months for stage IV. Cranial radiotherapy (18Gy) was only performed in pts with CNS disease. 66% were boys, median age was 10.5 y 1.9 – 17.2 and 88% had a mediastinal involvement. According to St Jude classification, 5 had a stage I or II (6%); 47 had a stage III (57%); 24 had a stage IV (63%), 18 bone marrow (BM) involvement, 4 CSF+ and 2 both. 7 pts received corticosteroid before diagnosis and were classified as stage X and treated as stage IV. After induction phase and consolidation (d 65), the complete remission rate was 95%. 1 pt had a progressive disease and died and 2 pts in partial remission are alive after salvage treatment with local radiotherapy or intensification. Up to now, 8 pts relapsed between 3.7 months and 18 months (median=10.5 months) and 1 pt who developed a glioblastoma before relapsing at 69.2 months. All relapses were mediastinal, 3 were combined with BM and 1 with BM and CSF. The median of FU is 4 years. Five-year EFS is 87% CI95%: 79–94 and OS is 89% CI95%: 82–96. In conclusion these results are as high as those of BFM experience. The intensified monthly pulse courses for 6 months did not seem decrease the relapses on therapy. Early intensification at d8 (with CPM and HDMTX) is feasible with a BFM regimen. Omission of prophylactic cranial irradiation while using a short duration (3 hours) of HDMTX infusion did not jeopardize the outcome. We suggest that our early intensification might be combined with a classic BFM regimen.
TLS is a metabolic complication of haematological malignancies, which can translate in renal impairment. As previously described (Goldman S.C. et al, Blood 2001; 972998–3003 and Pui C.H.et al., ...J.Clin.Oncol. 2001; 19,697–704), some patients are at High Risk (HR) of developing TLS. Rasburicase (R) a recombinant urate oxidase which transforms uric acid into a highly soluble compound, allantoin, more easily excreted by the kidneys, is highly effective in the prevention and treatment of TLS. SFCE has made recommendations for the management of TLS in children and developed a prospective survey in order to validate these recommendations.
Patients and Methods: HR pts were defined as: Acute Lymphoblastic (ALL) or Myeloblastic (AML) Leukaemia with initial leucocytes counts of at least 50x109/L, B cell ALL, Stage III and IV T or B Non Hodgkin Lymphoma (NHL), any leukaemia or NHL with a plasma uric acid concentration (U) of at least 300mmoles/L if ≤ 10 years old or 350mmoles/L if ≥ 10 years old, or any disease with serum creatinine (C) or lactate deshydrogenase concentration (LDH) exceeding twice the upper limit of normal (N), hyperphosphatemia (P)≥ 2 mmoles/L. These pts received hydration (3L/m2) ± alkalinization and R 0,20 mg/kg/d x 5 days. If C >1,5 N or P> 3mmoles/L or U ≥ 200mmoles/l, R administration is prolonged until normalization. Low risk (LR) pts, defined as not HR, received hydration 3L/m2 and R 0,20 mg/kg/for only one day. R could be prolonged according to the same criteria as HR pts.
Results: Between May and December 2004, 174 patients including 91 boys and 83 girls (median age 5 years) were treated according to these recommendations, in 8 centers in France. Initial diagnosis was LA in141 and NHL in 33. 143 patients (82%) were classified HR and 31 LR (18%). In the HR group, the patients received a median of 5 days of treatment with R (1–12) and in the LR group a median of 1 day (0–5). 25% of HR patients required treatment prolongation, while the LR group treatment prolongation was needed for 1 patient (3%). No complication of TLS was observed.
Conclusions: these results show that the risk classification as established by the SFCE was accurate and that the treatment guidelines was effective for the control of hyperuricemia and TLS.
We report on the case of a girl with type 1 Gaucher's disease, treated from age 9 to 15 with high-dose enzyme replacement therapy. This treatment did not avert the development of an extensive ...mutilating hepatic fibrosis warranting a liver transplantation, which was followed by death. In some cases of Gaucher's disease, alternative strategies such as fractionated or further increased ERT, gene therapy, or glucosyltransferase inhibitor should be explored.
We determined the proportion of survival variability explained by the usual prognostic factors in childhood acute lymphoblastic leukaemia (ALL) during a prognostic study of 1552 patients enrolled in ...three consecutive Fralle group protocols (Fralle 83, Fralle 87 and Fralle 89). The event‐free survival rates at 5 years were 54.8% (SD 1.9), 43.1% (SD 2.7) and 55.6% (SD 2.2), respectively. In the univariate analysis the following variables were predictive of poor outcome: male gender, elevated leucocytosis (> 50 × 109/l), circulating blastosis, haemoglobin >12 g/dl, platelet count <100 × 109/l, age under 1 year or over 9 years, enlarged mediastinum, nodes, spleen and liver, T phenotype, absence of CD10+ cells; testicular and meningeal involvement, poor response to induction therapy (CCSG M3), and LDH >400 U/l. Among the cytogenetic features, hyperdiploidy had a protective effect, whereas hypodiploidy, translocation and other structural abnormalities had a negative influence, particularly in cases of t(9;22) or t(4;11). Multivariate analysis summarized the prognostic information in terms of four variables: age, gender, leucocytosis and cytogenetic features. Missing data had little influence on the results. However, despite their significance in the multivariate analysis, these four variables each had very low predictive power (1.1% for gender, 2.0% for age, 3.5% for leucocytosis, and 1.6% for cytogenetic features). Thus, the most significant prognostic factors in childhood ALL each explain no more than 4% of the variability in prognosis. This may explain the disappointing practical value of these factors and underlines the need for prognostic tools in childhood ALL.
Adolescence has been claimed since the seventies to be associated to a a bad prognosis in childhood ALL. Out of 4658 patients with ALL, 258 adolescents (15–20 year old)(5.5%) were treated in the ...successive FRALLE 83, FRALLE 87–89, FRALLE 92 (pilot phase), FRALLE 93 and FRALLE 2000 protocols. The main characteristics were: a sex ratio of 1.8 (M/F), a B-lineage in 71% of the cases vs T lineage in 29%, and a median WBC of 12 G/L (9–1000). Translocation and fusion transcripts were searched for in 120 evaluable BCP-ALL: t(9;22)/BCR-ABL, 8 pts (6%); t(1;19)/E2A-PBX1, 12 pts (10%); t(4;11)/MLL-AF4, 4 pts (3%). Out of 75 evaluable pts t(12;21)/TEL-AML1 was found in only 4 pts (3%). 242 out of 258 adolescents were in CR at the end of induction therapy(EOI)(94%) without any significant difference according to the era. Nevertheless a major difference in the 3y and 5y EFS was found:
Number of ptsCR at EOI (%)3y EFS (%)5y EFS (%)10y EFS (%)Eighties (F83, F87–89)1009342 +/− 535 +/− 535 +/− 5Nineties (F92, F93)849371 +/−5*67 +/− 5**67 +/− 52000– (F2000)749686 +/−5*86 +/− 10**NYA*: p=.04; **: p=.04
The main modification introduced in the nineties was the adoption of a double delayed intensification for the good early responders. Autologous BMT or allogenic BMT were indicated in bad early responders (D8 poor prednisone response, D21 marrow M3 response) and/or unfavourable cytogenetics. The better results of the 2000 protocol can mainly be explained by the further intensification of chemotherapy between induction and delayed Intensification 1 and before delayed Intensification 2. These better results were obtained despite decreasing the indications of BMT (6 performed vs 20 in the nineties) and of CNS irradiation (100% in the nineties vs 35% in the current era, including the TBI for BMTs).
Conclusions:excellent results can now be achieved in adolescents with ALLthis study emphasizes again the need to treat adolescents with ALL according to pediatric intensive protocols and not “adult-type” protocols, as we recently suggested (Boissel et al, J Clin Oncol 2003).Whether this could also be applied to young adults remains to be demonstrated but seems appealing.
The clinical value of metaiodobenzylguanidine (mIBG) scintigraphy in patients with disseminated neuroblastoma (NB) at the time of diagnosis and after induction chemotherapy was evaluated.
The medical ...records and imaging studies of 30 patients with stage 4 NB who underwent mIBG scintigraphy and 99mTc hydroxy methylene diphosphonate bone scintigraphy at the time of diagnosis were reviewed. Scores were calculated for the mIBG and bone scintigrams, and outcome according to the initial and follow-up imaging studies was determined.
Discrepancies between bone scintigraphy and mIBG osteomedullary localization were seen in six patients. For the entire cohort, 2-year event-free survival did not significantly differ for the group of patients with initial mIBG or bone scintigraphy scores > or = 10 compared to those with scores < 10 (P = 0.23 and 0.61, respectively). However, for patients older than 1 year, a trend associating worse outcome with mIBG scores > or = 10 at diagnosis was seen (P = 0.08). A trend correlating abnormal mIBG scintigraphy after induction therapy and poor outcome was also observed (P = 0.09). Outcome did not correlate with the results of the bone scintigram studies performed after induction chemotherapy (P = 0.68).
Because a discordance between mIBG and bone scintigraphy results were seen in a subset of stage 4 NB patients, both imaging studies should be performed at the time of diagnosis. mIBG imaging studies performed at the time of diagnosis and after induction chemotherapy may be of prognostic value, particularly in stage 4 patients older than 1 year.
The FRALLE 93A protocol aimed to identify a very low-risk ALL subgroup, to limit treatment morbidity and to investigate the value of intermediate dose methotrexate. Inclusion criteria were : B-cell ...precursor ALL, age 2-7 years, leukocyte count <10G/l ; patients with CNS or testicular leukemia, bulky disease, t(9;22), t(4;11), t(1;19) or hypodiploïdy (<44 chromosomes) were not included.
181 children were included (13.5% of all the ALL included in the FRALLE 93 protocol) between June 1993 and Dec 1999. After a predisone prophase and induction phase (4-week daily prednisone, 4 weekly vincristine, thrice weekly 10,000 units of E coli asparaginase for 6 doses), during the 12-week antimetabolite consolidation therapy, patients were randomized to receive either low-dose methotrexate (25 mg/m2 p.o.) (lmtx) or 6 doses of intermediate dose methotrexate (IMTX) at 1500 mg/m2 by 24 hours infusion. Further therapy included a CCG type delayed intensification (dexamethasone, weekly vindesine, 3 doses of weekly doxorubicin and asparaginase, cytarabine) but without cyclophosphamide and a two years maintenance treatment. All pts received 16 triple intrathecal injections. The complete remission rate was 99.5%. The overall survival and event-free survival at 5 years were 93 % ± 4 % and 82 % ± 6 % (point date : 01.01.04). Only 1pt was considered prednisone-resistant (0.5%) D21 M1 marrow response is associated to a better 5 y EFS (86 + 5% vs 44 + 21% for M2/M3 pts (18 pts); p=0.001). Among 158 randomized patients, 9 testicular/meningeal relapses (6 isolated, 3 combined) occurred in the lmtx arm versus 1 in the IMTX arm (p=0.03) ; six BM relapses occurred in the lmtx group vs 9 in the IMTX group (p= NS). The 5-year DFS is not different 83% ± 8% and 85% ± 8% (p=0.47).
Conclusion: a high cure rate could be achieved in low-risk ALL without cranial radiation, alkylating agents or epipodophyllotoxin and with a low cumulative dose of anthracyclins (75 mg/m2). Prednisone response is of no help in this subgroup of BCP-ALL. D21 marrow response allows to identify a very low-risk subgroup in addition to initial criteria. IMTX proved superior to lmtx in preventing testicular or meningeal relapse in low-risk ALL.
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