Anne Auvrignon

Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study

Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23- or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (+/- 5%), with large differences across subgroups (11% +/- 5% to 92% +/- 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio [HR] = 0.1, P = .004); t(6;11)(q27;q23) (HR = 2.2, P < .001); t(10;11)(p12;q23) (HR = 1.5, P = .005); and t(10;11)(p11.2;q23) (HR = 2.5, P = .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis.

Outcome in Children With Relapsed Acute Myeloid Leukemia After Initial Treatment With the French Leucémie Aiquë Myéloïde Enfant (LAME) 89/91 Protocol of the French Society of Pediatric Hematology and Immunology

PURPOSE After present first-line therapies for childhood acute myeloid leukemia (AML), nearly 40% of patients still relapse. The goals of this retrospective study were to determine whether these children could be treated successfully with a salvage regimen and to establish the optimal therapeutic strategy. PATIENTS AND METHODS In the multicentric, prospective, Leucémie Aiquë Myéloïde Enfant 89/91 protocol, 106 of the 308 children enrolled between 1988 and 1998 relapsed. Initial treatment after the first complete remission (CR1) had been allogenic HLA-identical bone marrow transplantation (BMT; n = 21) or chemotherapy (n = 85). Treatment procedures were scheduled according to the choice of each participating institution. RESULTS When reinduction therapy was attempted, second complete remission (CR2) was obtained in 71% of patients (68 of 96 patients). BMT was performed in 53 (78%) of these 68 patients (autograft, mainly harvested in CR1, n = 25; matched sibling-donor BMT, n = 12; or alternative-donor BMT, n = 16). The 5-year overall survival (OS) rate for all 106 patients was 33%, and the disease-free survival (DFS) rate for children in CR2 was 45%. Multivariate analysis of re-treated children showed that the 5-year OS was higher if the CR1 had been longer than 12 months compared with less than 12 months (54% v 24%, respectively; P =.001) and lower if maintenance therapy had been given after CR1 compared with chemotherapy without maintenance therapy or HLA-identical BMT (12% v 40% v 52%, respectively; P =.002). For patients attaining CR2, the 5-year DFS rate was not significantly different for matched sibling-donor BMT (60%), autograft (47%), or alternative-donor BMT (44%). CONCLUSION After aggressive first-line therapy, one third of unselected, relapsing AML children could be cured. Further prospective trials are warranted to define the optimal reinduction regimen and megadose chemotherapy and to evaluate the late effects of these therapies.

Impact of Addition of Maintenance Therapy to Intensive Induction and Consolidation Chemotherapy for Childhood Acute Myeloblastic Leukemia: Results of a Prospective Randomized Trial, LAME 89/91

PURPOSE To determine whether the use of maintenance therapy (MT) delivered after intensive induction and consolidation therapy confers any advantage in childhood acute myeloid leukemia (AML). PATIENTS AND METHODS A total of 268 children with AML were registered in the Leucámie Aiquë Myéloïde Enfant (LAME) 89/91 protocol. This regimen included an intensive induction phase (mitoxantrone plus cytarabine) and, for patients without allograft, two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase, and amsacrine. In the LAME 89 pilot study, patients were given an additional MT consisting of mercaptopurine and cytarabine for 18 months. In the LAME 91 trial, patients were randomized to receive or not receive MT. RESULTS A total of 241 (90%) of 268 patients achieved a complete remission. The overall survival and event-free survival at 6 years were 60% +/- 6% and 48% +/- 6%, respectively. For the complete responders after consolidation therapy, the 5-year disease-free survival was not significantly different in MT-negative and in MT-positive randomized patients (respectively, 60% +/- 19% v 50% +/- 15%; P =.25), whereas the 5-year overall survival was significantly better in MT-negative randomized patients (81% +/- 13% v 58% +/- 15%; P =.04) due to a higher salvage rate after relapse. CONCLUSION More than 50% of patients can be cured of AML in childhood. Either drug intensity or each of the induction and postremission phases may have contributed to the outstanding improvement in outcome. Low-dose MT is not recommended. Exposure to this low-dose MT may contribute to clinical drug resistance and treatment failure in patients who experience relapse.

l‐asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: results of the GRASPALL 2005‐01 randomized trial

l‐asparaginase encapsulated within erythrocytes (GRASPA®) should allow serum asparagine depletion over a longer period than the native form of the enzyme, using lower doses and allowing better tolerance. The GRASPALL 2005‐01 study, a multicentre randomized controlled trial, investigated three doses of GRASPA® for the duration of asparagine depletion in a phase I/II study in adults and children with acute lymphoblastic leukaemia (ALL) in first relapse. Between February 2006 and April 2008, 18 patients received GRASPA® (50 iu/kg: n = 6, 100 iu/kg: n = 6, 150 iu/kg: n = 6) after randomization, and six patients were assigned to the Escherichia coli native l‐asparaginase (E. colil‐ASNase) control group. GRASPA® was effective at depleting l‐asparagine. One single injection of 150 iu/kg of GRASPA® provided similar results to 8 × 10 000 iu/m2 intravenous injections of E. colil‐ASNase. The safety profile of GRASPA® showed a reduction in the number and severity of allergic reactions and a trend towards less coagulation disorders. Other expected adverse events were comparable to those observed with E. colil‐ASNase and there was also no difference between the three doses of GRASPA®.

Use of Recombinant Human Granulocyte Colony-Stimulating Factor to Increase Chemotherapy Dose-Intensity: A Randomized Trial in Very High-Risk Childhood Acute Lymphoblastic Leukemia

PURPOSE To determine whether the use of a recombinant human granulocyte colony-stimulating factor ([G-CSF] lenogastrim) can increase the chemotherapy dose-intensity (CDI) delivered during consolidation chemotherapy of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Sixty-seven children with very high-risk ALL were randomized (slow early response to therapy, 55 patients; translocation t(9;22) or t(4;11), 12 patients). Consolidation consisted of six courses of chemotherapy; the first, third, and fifth courses were a combination of high-dose cytarabine, etoposide, and dexamethasone (R3), whereas the second, fourth, and sixth courses included vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate (COPADM). G-CSF was given after each course, and the next scheduled course was started as soon as neutrophil count was > 1 x 10(9)/L and platelet count was > 100 x 10(9)/L. CDI was calculated using the interval from day 1 of the first course to hematologic recovery after the fifth course (100% CDI = 105-day interval). RESULTS CDI was significantly increased in the G-CSF group compared with the non-G-CSF group (mean +/- 95% confidence interval, 105 +/- 5% v 91 +/- 4%; P <.001). This higher intensity was a result of shorter post-R3 intervals in the G-CSF group, whereas the post-COPADM intervals were not statistically reduced. After the R3 courses, the number of days with fever and intravenous antibiotics and duration of hospitalization were significantly decreased by G-CSF, whereas reductions observed after COPADM were not statistically significant. Duration of granulocytopenia was reduced in the G-CSF group, but thrombocytopenia was prolonged, and the number of platelet transfusions was increased. Finally, the 3-year probability of event-free survival was not different between the two groups. CONCLUSION G-CSF can increase CDI in high-risk childhood ALL. Its effects depend on the chemotherapy regimen given before G-CSF administration. In our study, a higher CDI did not improve disease control.

Parental comprehension and satisfaction in informed consent in paediatric clinical trials: a prospective study on childhood leukaemia

Objective To evaluate the extent to which parents are satisfied with and understand the information they are given when their consent is sought for their child to participate in a phase III randomised clinical trial and the reasons for their decision. Patients and method The authors carried out a prospective study. The authors included all parents whose consent was sought for their child to participate in the FRALLE 2000A protocol (acute lymphoblastic leukaemia) at two centres. The parents were questioned twice by a qualified psychologist using a semidirected interview, 1 and 6 months after consent was sought. Results 43 first interviews were carried out. All the parents declared they were satisfied with the explanations provided by the physician. 35 (81%) parents felt that the information provided with the request for consent was appropriate. Eight (19%) parents did not realise that their child had been included in a research protocol. 16 (39%) parents did not understand the concept of randomisation. Half the parents could explain neither the aim of the clinical trial nor the potential benefit of inclusion to their child. Only one third of the parents were aware that they had an alternative. The principal factor underlying their decision, as stated by 29 parents (67%), was confidence in the medical team. Conclusions The parents signed consent forms without having fully understood all the elements specific to the experimental protocol. Rather, the parents based their decision on their confidence in the medical team, even when their childs life was at risk.

Interaction between methotrexate and ciprofloxacin.

High-dose methotrexate is used in malignant hemopathies and solid tumors in children. Methotrexate serum concentrations must be monitored because of the possible toxicity of drug elimination delay. Several drugs (e.g., penicillin, probenecid) can alter the elimination of methotrexate. The authors report two cases of delayed elimination of methotrexate in patients receiving ciprofloxacin, with severe toxicity.

Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients: Results of an international study

We previously demonstrated that outcome of pediatric 11q23/MLL-rearranged AML depends on the translocation partner (TP). In this multicenter international study on 733 children with 11q23/MLL-rearranged AML, we further analyzed which additional cytogenetic aberrations (ACA) had prognostic significance. ACAs occurred in 344 (47%) of 733 and were associated with unfavorable outcome (5-year overall survival [OS] 47% vs 62%, P < .001). Trisomy 8, the most frequent specific ACA (n = 130/344, 38%), independently predicted favorable outcome within the ACAs group (OS 61% vs 39%, P = .003; Cox model for OS hazard ratio (HR) 0.54, P = .03), on the basis of reduced relapse rate (26% vs 49%, P < .001). Trisomy 19 (n = 37/344, 11%) independently predicted poor prognosis in ACAs cases, which was partly caused by refractory disease (remission rate 74% vs 89%, P = .04; OS 24% vs 50%, P < .001; HR 1.77, P = .01). Structural ACAs had independent adverse prognostic value for event-free survival (HR 1.36, P = .01). Complex karyotype, defined as ≥ 3 abnormalities, was present in 26% (n = 192/733) and showed worse outcome than those without complex karyotype (OS 45% vs 59%, P = .003) in univariate analysis only. In conclusion, like TP, specific ACAs have independent prognostic significance in pediatric 11q23/MLL-rearranged AML, and the mechanism underlying these prognostic differences should be studied.

Multicenter randomized trial of chewing gum for preventing oral mucositis in children receiving chemotherapy.

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.

t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients.

Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and eight as having myelodysplastic syndrome. The t(6;9)/DEK-NUP214 was associated with relatively late onset (median age 10.4 years), male predominance (sex ratio 1.7), French-American-British M2 classification (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplantation in first complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% versus 18%; P<0.01) but not the overall survival (68% versus 54%; P=0.48). The presence of FLT3-ITD had a non-significant negative effect on 5-year overall survival compared with non-mutated cases (22% versus 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6;9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with a high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature.