The properties of saliva led us to hypothesize that the salivary flow increase induced by gum chewing might protect the oral mucosa from lesions due to cancer chemotherapy. We conducted a multicenter ...randomized trial to evaluate the efficacy of chewing gum in preventing oral mucositis in 145 children receiving chemotherapy regimens expected to induce WHO grade 3-4 oral mucositis in at least 30% of patients. Patients were allocated at random to standard oral care with or without 5 gum pieces per day. No overall reduction in severe oral mucositis occurred in the gum arm (51%) compared with the standard arm (44%). VIDE, COPADM, and multidrug intensive chemotherapy caused severe oral mucositis in 75% of patients in both arms. In patients receiving less toxic regimens, a decrease in WHO grade 1-4 oral mucositis was noted in the gum arm compared with the standard arm (49% vs. 72%, P=0.03). In the multivariate analysis, the risk of oral mucositis was related only to the type of chemotherapy regimen, suggesting that further strategies for preventing oral mucositis could be mainly based on these criteria.
The thrombocytopenia and absent radii (TAR) syndrome is a rare disease associating bilateral radial agenesis and congenital thrombocytopenia. Here, we investigated in vitro megakaryocyte (MK) ...differentiation and expression of c-mpl in 6 patients. Using blood or marrow CD34+ cells, the colony-forming unit (CFU)-MK number was markedly reduced. CD34+ cells were also cultured in liquid medium in the presence of a combination of 3 cytokines (stem cell factor, interleukin-3, and interleukin-6) or megakaryocyte growth and development factor (PEG-rHuMGDF) with or without SCF. In the presence of PEG-rHuMGDF, the majority of mature megakaryocytes (CD41 high, CD42 high) underwent apoptosis. This phenomenon was also observed in cultures stimulated by three cytokines. However, this last combination of cytokines allowed a more complete terminal MK differentiation. Surprisingly, a homogeneous population of CD34-CD41+CD42- cells accumulated during the cultures. This population was unable to differentiate along the myeloid pathways. This result suggests that a fraction of MK cells is unable to differentiate in the TAR syndrome. We subsequently investigated whether this could be related to an abnormality in c-mpl. No mutation or rearrangement in the c-mpl gene was found by Southern blots or by sequencing of the c-mpl coding region and its promoter in any of the patients. Using Western blot analysis, a decreased level of Mpl was found in patient platelets. A decreased level of c-mpl messenger RNA in TAR platelets was also detected with a lower c-mpl-P to c-mpl-K ratio in comparison to adult platelets. Altogether, these results demonstrate that the thrombocytopenia of the TAR syndrome is associated with a dysmegakaryocytopoiesis characterized by cells blocked at an early stage of differentiation.
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.
Background: Cranial irradiation (XRT) in combination with intrathecal chemotherapy has markedly reduced the incidence of meningeal relapse in childhood acute lymphoblastic leukemia (ALL), and is ...still recommended for patients (pts) at high risk of relapse within the CNS. Because of late adverse effects of XRT, the previous CLG trial (EORTC 58881, 1989–1996) deleted XRT from the treatment regimen of all ALL patients. Nevertheless, the results (5-year event-free survival (EFS) rates) of 58881 trial were good in CNS-1 (72.1%), dubious CNS-2 (62.2%), surreptitious CNS-2 (64.6%) and particularly good in pts with CNS leukemia involvement (70.3%, SE 6.2%), emphasizing the importance of systemic chemotherapy in such pts, of whom, 50% were treated according to a very high risk group protocol (ASH, 2006). In order to validate this therapeutic strategy, we evaluate the prognostic significance of CNS status at diagnosis in ALL children enrolled from 12/1998 to 2/2008 in the EORTC CLG 58951 randomized phase III trial.
Methods: Treatment design was according to BFM. Three randomizations were programmed:
R1) the value of Dexamethasone (DEX) vs Prednisolone (PRED) during induction (all pts);R2) the value of prolonged (24 injections) vs conventional (12 injections) duration of L-asparaginase courses during consolidation and late intensification (all except very high risk pts);R3) the value of 6 (DEX or PRED + vincristine) pulses every 10 weeks in maintenance therapy (average risk pts).
CNS-directed therapy consisted in i.v. methotrexate (MTX) (5 g/sqm over 24 hours) in 4 to 10 courses, according to the degree of initial CNS involvement, and intrathecal MTX. No radiotherapy was used. According to CNS status, pts were classified in 4 groups:
CNS-1: no blasts and WBC<6/μl, RBC<100/μl;dubious CNS-2: presence of blasts, RBC □100/μl;surreptitious CNS-2: presence of blasts, WBC<6/μl, RBC<100/μl;CNS-3: presence of blasts, WBC>5/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=38) did eventually receive 10 courses as well.
Results: Between 12/1998 and 2/2008, a total of 1853 ALL pts were registered in 58951 trial. On 2/2008 a total of 1686 were evaluable for EFS; the distribution according to initial CNS status was: CNS-1 (n=1494, 88.6%), dubious CNS- 2 (n=100, 5.9%), surreptitious CNS-2 (n=59, 3.5%) and CNS-3 (n=33, 2%). The higher the degree of CNS involvement, the higher the incidence of unfavourable features: initial WBC□100000/μl, T-lineage, NCI high risk; very high risk (VHR) initial features (peripheral blasts ≥1000/μl post prephase, high-risk cytogenetics). In CNS-3 group, 10/33 (30%) pts were treated according to VHR protocol. Median follow-up was 4 years.
CNS-1Dubious CNS-2Surrept. CNS-2CNS-3No CR17 (1.1%)0 (0%)0 (0%)1 (3.0%)CCR1286 (86.1%)84 (84.0%)50 (84.7%)22 (66.7%)Isolated CNS rel.17 (1.1%)3 (3.0%)1 (1.7%)2 (6.1%)Combined CNS r.23 (1.5%)1 (1.0%)2 (3.4%)2 (6.1%)Non-CNS relapse20 (13.4%)2 (2.0%)1 (1.7%)5 (15.2%)Death in CR31 (2.1%)2 (2.0%)1 (1.7%)1 (3.0%)4-yr EFS (%, SE)84.0% (1.1%)88.2% (3.5%)82.4% (5.4%)55.1% (10.8%)4-yr OS (%, SE)90.7% (0.9%)92.0% (2.9%)88.0% (4.6%)63.4% (12.8%)
Conclusion: In comparison with previous EORTC 58881 trial, and according to CNS status, EFS, OS, and isolated and combined CNS relapses rates improved in 58951 trial, except for CNS-3 pts. These “disappointing” results in CNS-3 pts (representing 2% of the entire population), less heavily treated in 58951 than in 58881, confirm the importance of systemic chemotherapy in such pts.
Background: An overview of trials dating back to the ‘70s and ‘80s has shown that addition of vincristine (VCR)+prednisone/prednisolone pulses to continuation therapy of childhood ALL, i.e. ...6-mercaptopurine (6-MP) + methotrexate (MTX), improved disease-free survival (DFS) (Lancet, 1996). However, a recent randomized intergroup trial (IGT) has shown that, when given to intermediate risk (age<1 or >=6 yrs or WBC>20×109/L) patients (pts) treated according to the BFM protocol, VCR+dexamethasone (DEX) pulses in continuation therapy failed to improve DFS and overall survival (Lancet, 2007).
Methods: In 12/1998, EORTC CLG started the randomized phase III 58951 trial addressing 3 questions:
R1) the value of DEX vs PRED in induction;R2) the value of prolonged (24 injections) vs conventional (12 injections) duration of L-asparaginase (ASPA) courses during consolidation and late intensification;R3) for average risk (AR) pts only: the value of 6 (VCR+corticosteroid) pulses every 10 weeks during continuation therapy.
The corticoid of the pulses was that assigned to the patient at R1: DEX (6 mg/sm/d) or prednisolone (PRED) (60 mg/sm/d) during 7 days. AR pts were defined by being neither low risk (hyperploidy > 50 or DNI>1.16, and WBC<10×109/L and no extramedullary involvement) nor very high risk (Leukemia 2000). A total of 81 pts from the EORTC 58951 trial were included in the IGT study. Randomization was done centrally, and the main endpoint was DFS; secondary endpoints were OS and toxicity. Intent-to-treat analysis was used.
Results: Between 6.1999 and 11.2004, 411 pts, ALL (N=384) and NHL (N=27), were randomized for the pulse question. In the Pulses group, 101 vs 101 pts were randomized for PRED vs DEX. At a median follow-up of 6.3 years, there were 19 vs 34 DFS events for the Pulses vs No Pulses comparison: BM (10 vs 16), CNS only (1 vs 4), other isolated (2 vs 3), BM+CNS (2 vs 5), BM+other (4 vs 4), death in CR (0 vs 2). The 6-year DFS rate from randomization was 90.6% (SE 2.1%) in the Pulses group and 82.8% (SE 2.8%) in the No Pulses group (hazard ratio (HR) = 0.54, 95% CI 0.32–0.94, 2-sided logrank p=0.027). The impact of pulses on DFS was similar in the PRED group (HR=0.56) and the DEX group (HR=0.59). In girls the treatment difference seemed to be more pronounced (HR=0.25, 99% CI 0.04–1.25; p=0.015) than in boys (HR=0.71, 99% CI 0.30–1.66; p=0.30), and also in those having been randomized to receive conventional duration of ASPA courses (HR=0.46, 99% CI 0.18–1.19; p=0.03) than in prolonged ASPA arm (HR=0.87, 99% CI 0.23–3.29; p=0.78). Grade 3–4 hepatic toxicity was lower in the Pulses group (30% vs 40%); incidence of grade 2–3 osteonecrosis was 4.4% (Pulses) vs 2% (No Pulses) and pancreatitis rate was 4.9% (Pulses) vs 2.9% (No Pulses).
Conclusion: VCR+corticosteroid pulses, at long follow-up (median=6.3 yrs), significantly improved the DFS, particularly in pts having received conventional duration of ASPA. Pulses did not increase toxic effects. In future, for AR pts treated according to the BFM protocol, pulses should become a standard component of therapy.
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.
The use of Gemtuzumab-Ozogamicin (GO), an anti-CD33 monoclonal antibody, is associated to a 20–30% response rate in refractory/relapsed AML. We have reviewed the efficacy and the tolerance of a ...combination of GO plus cytarabine (GOCYT) given to children with refractory/relapsed AML in order to improve the response rate. This retrospective analysis includes 17 children (9M, 8F) who received the same induction schedule on a compassionate-use basis between may 2004 and june 2006: GO 3 mg/m2/d D1, D4, D7 plus cytarabine 100 mg/m2/d CIV for 7 days. In addition, 6 patients received a consolidation course with GO 3 mg/m2 D1 plus cytarabine 100 mg/m2/d D1 to D7 and 1 patient received GO 3 mg/m2 monthly for 4 doses. Median age at diagnosis of AML is 4.5 y (0.4–16.7). The patient distribution is: de novo AML: 13; biclonal (T and myeloid) acute leukemia: 1; erythremia: 1; t-AML: 2. Initial caryotype was unfavourable in 6 cases, intermediate in 9 and favourable in 2. Patient's status at GOCYT start were as follows: 2 pts refractory to 1st line therapy (t-AML: 1, M7: 1); 8 pts in refractory first relapse (median time to relapse: 7.25 m, 5–19); 6 pts in relapse after BMT (median time to relapse: 13.5 m, 10.5–111); 1 untreated pt (del(5q) t-AML). CD33 expression was positive in all cases. The median time between initial diagnosis and GOCYT administration is 11.5 m (3–116). MFU is 5 months (1–21). Ten responses were obtained after GOCYT induction (59%): CR: 2, CRp: 4 and PR: 4. Noteworthy, 3 of 7 responders who received a consolidation course with GO improved their response (PR to CR: 2, PR to CRp: 1). Lastly, a subsequent BMT could be performed in 7 responders. Six pts were in leukemic failure and 1 pt died from invasive aspergillosis without bone marrow evaluation. Grade 3 and 4 side effects were: hematologic (17, 100%); documented infections (5): invasive aspergillosis (2 including one responder), pulmonary reactivation of aspergillosis (1), streptococcus oralis septicemia (1), candida kefyr septicemia (1); fever and neutropenia without documented infection (6); hyperbilirubinemia (1); hypertransaminasemia (1); sinusoidal obstruction syndrome SOS (0). Among the 7 patients alive at point date, 6 were responders to GOCYT.
Conclusion: a high response rate (59%) was objectived in children with heavily pre-treated refractory/relapsed AML allowing a subsequent BMT in 7. A consolidation course improved the quality of the response in some cases. Despite the limitations of this study, the response rate seems higher than the one observed in phase I–II or compassionate-use pediatric studies using GO alone. No unexpected toxicity was seen. Remarkably, no SOS was observed despite previous BMT in 8 out of the 17 children and a second BMT was feasible in responding pts. GOCYT should be tested prospectively in a largest pediatric AML population.
Clofarabine alone or in combination with cyclophosphamide and etoposide has shown a good efficacy and a tolerable toxicity profile in previous studies of children with relapsed or refractory ...leukaemia. This report describes a retrospective study of 38 French patients who received clofarabine as a monotherapy or in combination for relapsed or refractory acute lymphoblastic leukaemia (ALL) outside of clinical trials after marketing authorization.
We retrospectively analysed data for 38 patients, up to 21 years old, attending 17 French centres. Thirty patients received clofarabine alone or in combination for a bone marrow relapse of acute lymphoblastic leukaemia (ALL) or refractory disease and eight patients for a high level of minimal residual disease (MRD). Survival and response durations were estimated by the Kaplan-Meier method.
For the 30 patients who received clofarabine for a bone marrow relapse of ALL (number of relapse, 1-3; median, 1), the overall remission rate (ORR) was 37%: eight complete remission (CR) and three complete remission without platelet recovery (CRp). Ten of the 11 responding patients subsequently underwent haematopoietic stem cell transplantation (HSCT).Only four of the eight patients who received clofarabine while in remission for a high level of MRD, showed a moderate improvement of MRD. Seven of these eight patients received HSCT and six of them were alive at the end of the study. One other patient was alive without receiving HSCT.However, clofarabine treatment was associated with a high risk of infection and hepatotoxicity. Febrile neutropenia grade ≥ 3 was reported in 79% of patients and documented infections grade ≥ 3 occurred in nine patients (24%). Hepatotoxicity grade 3 was reported in nine patients (24%). We observed four deaths related to treatment.
In our experience, the efficacy of clofarabine is poorer than previously reported. Its toxicity is high and can be life threatening. Prospective studies on clofarabine used during earlier phases of the disease may help to define how best this new drug can be exploited for childhood and adolescent ALL.
Data on secondary acute lymphoblastic leukaemia (sALL) following ALL treatment are very rare. To our knowledge only 8 such cases have been described so far - 6 and 2 with late developing t(9;22) and ...t(4;11), respectively. Recently, the extensive examination of immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements for the purposes of residual disease monitoring brought a new tool that can help in discrimination between real relapse and sALL clonally unrelated to the original disease. In our study we analysed 276 relapses of patients treated according to BFM-based protocols and examined in 3 centres (Prague, Berlin, Paris). We found 5 cases where the second malignancy is highly suspicious of being sALL rather than relapse. Our basal criteria for selection of the patients were (A) completely unrelated Ig/TCR rearrangements between presentation and relapse or (B) gain or loss of a leukaemo-specific fusion gene or (C) significant immunophenotypic switch. Basic patients characteristics are summarised in the table below. In two cases an MLL gene rearrangement appeared at the time of “relapse” with MLL/ENL and MAML2/MLL fusion genes, respectively. The MAML2 at 11q21 is a new fusion partner of the MLL gene not described previously. ALL is the most common childhood malignancy and thus it can be supposed that sALL after ALL treatment is more common than reported - sALLs without a significant lineage shift have been probably often automatically diagnosed as relapses. Based on the current knowledge on childhood ALL there are probably 3 types of disease recurrence: (1) genuine relapse from a resistant diagnostic (sub)clone, (2) secondary leukaemia arising from original pre-leukaemic clone (with some clonal markers maintained and some changed) and (3) pure sALL, clonally unrelated to the original leukaemia. In our study at least two patients (number 1 and 5) belong to the third category. This frequency (0,5–1%) is a minimal estimate as in some cases the differences could be subtler. In these “unquestionable” cases the adequate treatment strategy should be considered. Both “pure sALL” and “sALL from the same pre-leukaemic clone” cases should be also considered in discussions regarding an intensity of treatment strategies - some recurrences of ALL might, in fact, occur not because of low intensity of protocol but because of overtreatment. In our study we present a largest cohort of patients with possible sALL after ALL treatment analysed so far and, moreover, we describe a new fusion gene in ALL - MAML2/MLL.
Patients characteristicsPatient12345Age at dg. years5,83,13,05,55,1GendermmmmfImmunophenotype (P/S)BCP/TBCP/BCPpreT/TBCP/BCPBCP/TFusion genes (P/S)TEL-AML1/neg.TEL-AML1/TEL-AML1neg./neg.neg./MLL-ENLneg./MAML2-MLLIg/TCR (P/S)ABCD/EFGHABCD/EFGAB/CA/AABC/DECR years2,22,51,71,72,7P=presentation; S=sALL; CR=remission preceding sALL; Ig/TCR: In each patient different letters stand for different and unrelated rearrangements
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