Papers by Jean-Marie Leclerc
Journal of Clinical Oncology, May 20, 2019
10006 Background: DFCI ALL Consortium Protocol 11-001 assessed the efficacy and toxicity of Calas... more 10006 Background: DFCI ALL Consortium Protocol 11-001 assessed the efficacy and toxicity of Calaspargase pegol (SC-PEG), a novel pegylated asparaginase (ASP) formulation with longer half-life, compared with standard pegaspargase (SS-PEG). Methods: Patients (pts) aged 1-21 years with newly diagnosed acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) were eligible. At study entry, pts were randomly assigned to receive either intravenous SS-PEG or SC-PEG, 2500 IU/m2/dose. Pts received 1 dose during the first treatment month. Beginning week 7, SS-PEG was administered every 2 weeks for 15 doses, SC-PEG every 3 weeks for 10 doses (30 weeks). Serum asparaginase activity (SAA) (considered therapeutic at ≥ 0.1 IU/mL) was assessed 4, 11, 18, and 25 days after the induction dose and before each post-induction dose. End-induction minimal residual disease (MRD) was assessed in ALL pts by IGH/TCR PCR. Results: Between 2012-2015, 239 eligible pts enrolled (230 ALL, 9 LL); 120 assigned to SS-PEG, 119 to SC-PEG. After dose 1, SAA remained ≥ 0.1 IU/mL in ≥ 95% of pts on both arms through day 18. Median SAA was higher (0.319 IU/mL vs 0.056 IU/mL) and more pts had therapeutic SAA (88% vs 17%, p˂0.001) with SC-PEG vs SS-PEG 25 days after dose 1. Post-induction, median nadir SAA (NSAA) were similar ( > 1.0 IU/mL) for both arms. There was no difference in rates of ASP-allergy, pancreatitis, thrombosis, hyperbilirubinemia, osteonecrosis, or infection. Of 230 evaluable pts, 99% of SS-PEG and 95% of SC-PEG pts achieved complete remission (p = 0.12). For B ALL pts, there was no difference in frequency of high end-induction MRD (10.3% SS-PEG, 9.5% SC-PEG, p = 1.0). With 4-year median follow-up, 4-year event-free survival (EFS) (90% confidence interval) for SS-PEG was 90.2% (84.3, 93.9), 87.7% (81.5, 91.9) for SC-PEG (p = 0.78); overall survival (OS) was 95.6% (91.0, 97.9) for SS-PEG, 94.8% (90.0, 97.3) for SC-PEG (p = 0.74). Conclusions: Every 3-week SC-PEG had similar EFS, OS, safety profile, and NSAA compared with every 2-week SS-PEG. The high NSAA observed for both preparations suggest dosing strategies can be further optimized. These data informed FDA approval of SC-PEG for pediatric pts. Clinical trial information: NCT01574274.
Journal of Clinical Oncology, Nov 1, 2021
PURPOSE Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-00... more PURPOSE Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel pegylated asparaginase formulation with longer half-life, compared with the standard formulation pegaspargase. METHODS Patients age 1 to ≤ 21 years with newly diagnosed ALL or lymphoblastic lymphoma were randomly assigned to intravenous pegaspargase or calaspargase, 2,500 IU/m2/dose. Patients received one induction dose. Beginning week 7, pegaspargase was administered every 2 week for 15 doses and calaspargase every 3 week for 10 doses (30 weeks). Serum asparaginase activity (SAA) (≥ 0.1 IU/mL considered therapeutic) was assessed 4, 11, 18, and 25 days after the induction dose and before each postinduction dose. RESULTS Between 2012 and 2015, 239 eligible patients enrolled (230 ALL, nine lymphoblastic lymphoma); 120 were assigned to pegaspargase and 119 to calaspargase. After the induction dose, SAA was ≥ 0.1 IU/mL in ≥ 95% of patients on both arms 18 days after dosing. At day 25, more patients had SAA ≥ 0.1 IU/mL with calaspargase (88% v 17%; P ˂ .001). Postinduction, median nadir SAAs were similar (≥ 1.0 IU/mL) for both arms. Of 230 evaluable patients, 99% of pegaspargase and 95% of calaspargase patients achieved complete remission ( P = .12), with no difference in frequency of high end-induction minimal residual disease among evaluable patients with B acute lymphoblastic leukemia (B-ALL). There were no differences in frequencies of asparaginase allergy, pancreatitis, thrombosis, or hyperbilirubinemia. With 5.3 years median follow-up, 5-year event-free survival for pegaspargase was 84.9% (SE ± 3.4%) and 88.1% (± SE 3.0%) for calaspargase ( P = .65). CONCLUSION Every 3-week calaspargase had similar nadir SAA, toxicity, and survival outcomes compared with every 2-week pegaspargase. The high nadir SAA observed for both preparations suggest dosing strategies can be further optimized.
Blood, Nov 5, 2020
The application of next-generation sequencing (NGS) approaches to leukemia markedly expanded our ... more The application of next-generation sequencing (NGS) approaches to leukemia markedly expanded our understanding of the molecular landscape of pediatric acute lymphoblastic leukemia (ALL), but NGS integration into clinical care and therapeutic decision making is still limited. The prognostic impact of discovered mutations in uniformly treated patients with newly diagnosed B-ALL is not well characterized, and there is no consensus regarding the clinical significance of many of these findings. We investigated the frequency of mutations affecting common molecular pathways in pediatric B-ALL that are potentially druggable with targeted therapies, to define the prognostic role of these mutations, as measured by end-induction minimal residual disease (MRD) and event-free survival (EFS). We analyzed 159 patients (median age 6 years, range 1-18) with newly diagnosed Ph-negative B-ALL treated between 2005-2015 according to the Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols 05-001 and 11-001. Diagnostic leukemia samples were sequenced using a validated clinical NGS panel. We focused on mutations affecting the following pathways: Ras (NRAS, KRAS, PTPN11, NF1 and BRAF), cell cycle regulation (CCND3, CDKN2A/B and RB1), PI3K signaling (PTEN, PIK3CA, PIK3R1, PIK3C2B, MTOR, TSC1 and TSC2), Polycomb repressive complex 2 (PRC2) (EED, EZH2 and SUZ12), and JAK/STAT signaling (CRLF2, JAK2, JAK3, MPL, SH2B3 and SOCS1). Additionally, we analyzed mutations affecting CREBBP, FLT3, PAX5, SETD2 and TP53. Mutations occurring in the ExAC database at a frequency greater than 0.01% were excluded. A Fisher exact test and Wilcoxon rank sum test were used for categorical and continuous variables. High end-induction MRD, defined as > 10-3, was assessed by an Ig-TCR PCR assay. EFS was estimated using Kaplan and Meier method and tested between groups using a log-rank test. Induction death/failure, relapse or death were considered as events. Overall, 108 of the 159 patients (68%) carried at least one mutation in the studied genes. Most common mutations were in the Ras pathway (47%), CREBBP (9%), JAK pathway (8%), FLT3 (8%), PI3K pathway (5%), PAX5 (4%), SETD2 (4%), TP53 (4%), cell cycle regulation (3%) and PRC2 complex (3%). We investigated the distribution of mutations among common cytogenetic groups: ETV6-RUNX1, high hyperdiploidy (HHD) (51-65 chromosomes), hypodiploidy (<45 chromosomes), KMT2A-rearranged, TCF3-PBX1, and intra-amplification chromosome 21 (iAMP21). There was a strong association between TP53 and hypodiploidy (43% vs 2%; p=0.001). Ras pathway and FLT3 mutations were enriched in HHD (67% vs 39%; p=0.004) and (17% vs 4%; p=0.016), respectively. FLT3 mutations were mutually exclusive with ETV6-RUNX1 (12% vs. 0%, p=0.038), and Ras pathway mutations were rare in this subgroup (p=0.018). PAX5 mutations were enriched in children >10 years of age (p=0.035). There were no associations with sex. Ras pathway mutations were associated with high end-induction MRD (68% vs 42%; p=0.045), and this association was stronger for clonal (variant allele frequency (VAF) >25%) mutations (n=33) (63% vs 19%; p=0.0002). Focusing on HHD, CREBBP mutations frequently co-occurred with clonal Ras pathway mutations (83% vs 17%; p=0.032). Among HHD patients with evaluable MRD (n=33), 7 patients had high MRD, and 3 of these had CREBBP mutations (p=0.052). The analyzed cohort was enriched for higher risk ALL disease (Table 1). The 5-year EFS was 80%±3% among these 159 patients. Overall, no EFS difference was observed based on Ras pathway (p=0.35). Among HHD ALL, the presence of CREBBP or clonal Ras pathway mutations was significantly associated with inferior 5-yr EFS (50%±20% vs 97%±3%; p=0.0006, Figure 1) and (70%±13% vs 100%; p=0.007, Figure 2), respectively. In conclusion, our findings provide insight into the prognostic significance of the most common mutations in pediatric HHD B-ALL in a uniformly treated cohort of patients as part of the DFCI ALL Consortium. The presence of CREBBP and clonal Ras pathway mutations may be associated with upfront chemotherapy resistance as demonstrated by high end-induction MRD. Further analysis of Ras pathway mutations segregated by VAF is warranted. Future trials may integrate these findings into risk stratification of HHD ALL. With prospective continued clinical use of NGS assays, we will further clarify the role of mutations and their contribution to disease outcomes in B-ALL. Disclosures Mar: Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Stegmaier:Novartis: Research Funding; Auron Therapeutics: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board.
Blood, Dec 3, 2015
Background: Pediatric patients receiving induction chemotherapy for newly diagnosed acute lymphob... more Background: Pediatric patients receiving induction chemotherapy for newly diagnosed acute lymphoblastic leukemia (ALL) are at high risk of developing life-threatening infections. We investigated whether uniform antibacterial guidelines, including mandatory antibacterial prophylaxis in afebrile patients during induction, decreases the incidence of microbiologically documented bacteremia. Methods: Between 2012 and 2015, 230 patients with newly diagnosed ALL (aged 1-21) were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 11-001 (DFCI 11-001). Induction therapy, regardless of risk group, included vincristine, prednisone, doxorubicin, methotrexate, and PEG-asparaginase. Afebrile patients received fluoroquinolone prophylaxis at the initiation of induction and those presenting with fever received broad-spectrum antibiotics; antibiotics were continued until blood count recovery. Rates of documented bacteremias and fungal infections on DFCI 11-001 were compared to those on the predecessor protocol (DFCI 05-001), which included the same induction phase without antibiotic prophylaxis guidelines. Results: Sixty-six (28.7%) patients received fluoroquinolone prophylaxis, the remaining patients received broad-spectrum antibiotics. Twenty-four (36.4%) patients on prophylaxis developed fever and seven (10.6%) developed bacteremia. The overall rate of infection during induction on DFCI 11-001 was lower than on DFCl 05-001 (14.3% vs. 26.3%, P < 0.
Clinical Nutrition, Dec 1, 2019
Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Nutrition... more Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Nutritional morbidities are a persistent problem facing pediatric patients during and after treatment and age-gender groups that are at risk for nutritional conditions have not been clearly identified. Therapy is a contributing factor; however, the role of dietary intake remains largely unknown. Prior to conduct of interventional trials, an understanding of the effects of treatment on fluctuations in dietary intake is necessary. Methods: We enrolled 794 children with ALL in a prospective clinical trial. Dietary intake was collected with a food frequency questionnaire at diagnosis and throughout the course of treatment for pediatric ALL. Reported values were compared to the Dietary Recommended Intake (DRI), and normative values (NHANES). Hierarchical linear models and multilevel mixed-effects ordered logistic regression models were used to evaluate longitudinal changes in dietary intake; independent samples t-test with Bonferroni correction was performed to compare to NHANES. Results: Of the evaluable participants at each timepoint, dietary intake was obtained on 81% (n ¼ 640), 74% (n ¼ 580) and 74% (n ¼ 558) at diagnosis, end of induction phase of treatment, and continuation, respectively. Despite exposure to corticosteroids, caloric intake decreased over therapy for most agegender groups. Predictive models of excess intake found reduced odds of over-consuming calories (OR 0.738, P < 0.05); however, increased odds of over-consuming fat (OR 6.971, P < 0.001). When compared to NHANES, we consistently found that 1/3 of children were consuming calories in excess of normative
Pediatric Blood & Cancer, 2022
Background/objectivesAlthough thromboembolism (TE) is a serious complication in patients with acu... more Background/objectivesAlthough thromboembolism (TE) is a serious complication in patients with acute lymphoblastic leukemia (ALL), thromboprophylaxis is not commonly used due to the inherent bleeding risk in this population. Identifying prothrombotic risk factors will help target thromboprophylaxis to those at highest thrombotic risk. We aimed to define predictors and the impact of TE on ALL outcome in children (1‐18 years) treated on the Dana‐Farber Cancer Institute ALL 05‐001 trial.MethodsClinical and laboratory data including TE events were prospectively collected. PCR‐based allelic discrimination assay identified single‐nucleotide polymorphisms (SNP) for prothrombin G20210A (rs1799963) and Factor V G1691A (rs6025). Univariate and multivariable competing risk regression models evaluated the effect of diagnostic clinical (age, sex, body mass index, ALL‐immunophenotype, risk group) and laboratory variables (presenting leukocyte count, blood group, SNPs) on the cumulative incidence o...
Pharmacogenomics, 2019
Aim: To evaluate top-ranking genes identified through genome-wide association studies for an asso... more Aim: To evaluate top-ranking genes identified through genome-wide association studies for an association with corticosteroid-related osteonecrosis in children with acute lymphoblastic leukemia (ALL) who received Dana–Farber Cancer Institute treatment protocols. Patients & methods: Lead SNPs from these studies, as well as other variants in the same genes, pooled from whole exome sequencing data, were analyzed for an association with osteonecrosis in childhood ALL patients from Quebec cohort. Top-ranking variants were verified in the replication patient group. Results: The analyses of variants in the ACP1-SH3YL1 locus derived from whole exome sequencing data showed an association of several correlated SNPs (rs11553746, rs2290911, rs7595075, rs2306060 and rs79716074). The rs79716074 defines *B haplotype of the APC1 gene, which is well known for its functional role. Conclusion: This study confirms implication of the ACP1 gene in the treatment-related osteonecrosis in childhood ALL and i...
Pediatric Blood & Cancer, 2019
BackgroundL‐asparaginase is a cornerstone treatment for children with acute lymphoblastic leukemi... more BackgroundL‐asparaginase is a cornerstone treatment for children with acute lymphoblastic leukemia (ALL). However, immune reaction to the drug may increase the clearance or impair the function of L‐asparaginase and reduces its therapeutic efficacy. The objective of this study was to identify potential plasma proteins that could be used as proxies for L‐asparaginase activity.MethodsFibrinogen, von Willebrand factor antigen (VWF:Ag), total protein, and albumin levels as well as antithrombin (AT) and L‐asparaginase activities were measured in 97 children with ALL treated for prolonged period of time with L‐asparaginase. Binary logistic regression and a receiver operating characteristic (ROC) curve analysis were performed to evaluate the predictive value of plasma proteins for L‐asparaginase activity.ResultsMedian E. coli L‐asparaginase activity was 220 IU/L (range, 0–1308) throughout the treatment period. L‐asparaginase activity was below 100 IU/L in 23% of measured samples. L‐asparagi...
Drug Metabolism and Pharmacokinetics, 2019
The Pharmacogenomics Journal, 2017
Nous avons investigué la relation entre les polymorphismes de nucléotides simples (SNPs) chez tro... more Nous avons investigué la relation entre les polymorphismes de nucléotides simples (SNPs) chez trois gènes/loci candidats : DARC, CXCL2 et le loci ORMDL3-GSDMA-CSF3 situés sur le chromosome 17q21 et les complications neutropéniques et infectieuses qui en résultent durant la chimiothérapie chez les patients atteints de la leucémie lymphoblastique aigue. Ces loci codent pour certaines composantes du système immunitaire altérant la concentration de chémokines et leur distribution (DARC), stimulant le relâchement et la migration des neutophiles de la moelle épinière (CXCL2) et régulant la prolifération et la survie des granulocytes (G-CSF). Il est possible que des polymorphismes dans ces loci lorsqu'associés à de la chimiothérapie puissent mettre des individus suceptibles à un risque plus élevé de complication reliées à la chimiothérapie. Une sélection des marqueurs SNPs dans ces gènes ont été génotypés chez des enfants traités au CHU Ste-Justine pour une ALL entre 1989 et 2005. Après correction pour tests multiples, un polymorphisme DARC rs3027012 situé dans le 5'UTR a été associé à un compte phagocytaire peu élevé (APC<500 et <1000 cellules/µL, p=0.001 and p=0.0005, respectivement) ainsi qu'une hospitalisation due à une neutropénie (p=0.007) ou due à une infection et/ou neutropénie (p=0.007). Un effet protecteur a été identifié pour la mutation non sense Gly42Asp variant rs12075 (p=0.006). Des polymorphismes sur le chromosome 17q2 étaient associés à une hospitalisation due à une infection (rs3859192, p= 0.004) et à une neutropénie (rs17609240, p=0.006) L'infection était aussi modulée par CXCL2 (rs16850408, p=0.008) Cette étude identifie pour la première fois que les loci modulant le décompte des leucocytes et des neutrophiles pourraient jouer un rôle dans de déclenchement de complications dues à la chimiothérapie et pourraient ainsi servir de marqueurs pour un ajustement et un suivi du traitement.
Journal of Clinical Oncology, 1990
Polymorphic B-cell lymphoma seen in four patients with congenital immunodeficiencies and in two p... more Polymorphic B-cell lymphoma seen in four patients with congenital immunodeficiencies and in two patients with leukemia receiving chemotherapy was associated with the Epstein-Barr virus (EBV). The tumors had characteristic histologic features: they were polymorphic consisting of a mixture of lymphoblasts and differentiated cells including plasma cells, and areas of hemorrhagic necrosis were prominent. The tumors were either polyclonal, monoclonal, or multiclonal. Patients with congenital immunodeficiencies who developed these tumors died despite radiotherapy, corticosteroids plus acyclovir, or a combination of intravenous (IV) immunoglobulins and alpha 2 interferon. Patients with leukemia recovered when immunosuppressive drugs were discontinued and leukemia has not recurred over a period of 2 and 4 years, respectively, in the two patients.
Cancer Research, 2017
Childhood cancer is a group of heterogeneous complex diseases. Although 80% of these children are... more Childhood cancer is a group of heterogeneous complex diseases. Although 80% of these children are cured with conventional therapies, it remains the first cause of death among children in Western countries. A significant number of refractory/relapse patients will eventually succumb to their disease and the lack of therapeutic advances for these patients is even more worrisome. Indeed, no significant progress has been noted over the last decade for these patients, urging the need for new and more effective therapeutic approaches. Precision medicine and more effective personalized targeted therapies (PTT) are a major breakthrough leading to increased cure rates and decreased treatment-related morbidity and mortality for the patients with refractory or relapsed tumors. To address this challenge, the TRICEPS study was initiated on April 2014 at the Sainte-Justine UHC (Montreal, Canada) with an overreaching goal to explore the feasibility of performing genomic-driven targeted therapy in p...
Cancer Research, 2016
In Canada, about 1500 pediatric cancers are diagnosed each year. Despite improvements in risk-str... more In Canada, about 1500 pediatric cancers are diagnosed each year. Despite improvements in risk-stratified treatments, around 20% of childhood cancer patients do not respond to current therapies and ultimately succumb to their disease, urging the need for new and more effective therapeutic approaches. Personalized targeted therapy (PTT) based on next generation sequencing (NGS) may be a key component to increase cure rates and decrease treatment-related morbidity and mortality. To assess the feasibility of performing PTT clinical trials in the context of childhood cancers, a pilot study is currently underway at the Sainte-Justine UHC, Montreal, where 30 relapsed or refractory cancer patients (aged 0-21 years) are being recruited over a 2 year period and offered in-depth genomic and transcriptomic investigation to identify patient-specific alterations. This pilot study will allow us to determine the number of children with cancer who are suitable candidates for targeted therapy, to det...
Quality of Life Research, 1998
This study examined the reliability and validity of the Health Utilities Index (HUI) Mark 2 syste... more This study examined the reliability and validity of the Health Utilities Index (HUI) Mark 2 system, a healthrelated quality of life (QoL) instrument, in children with cancer. The sample consisted of 61 mothers of paediatric oncology patients, aged 4.1-17.3 years, who were either on treatment (n = 20) or off treatment (n = 41). The test-retest reliability was very good for the HUI Mark 2 system global score and all of its dimensions except pain. The HUI Mark 2 dimensions of emotion, pain and self-care as well as its overall score showed moderate convergent validity with other measures. In addition, the HUI Mark 2 system demonstrated good discriminant validity. However, the content validity of the HUI Mark 2 system when considered as a multiattribute descriptive health profile is questionable because it fails to assess domains such as neuropsychological and psychosocial functioning. Overall, the results indicate that the HUI Mark 2 system is reliable and valid as a measure of health-related QoL for paediatric oncology patients.
Medical and Pediatric Oncology, 2001
Background. Neuroblastoma has several characteristics that suggest that preclinical diagnosis mig... more Background. Neuroblastoma has several characteristics that suggest that preclinical diagnosis might improve outcome. Therefore, the Quebec Neuroblastoma Screening Project was undertaken from 1989 to 1994 to examine infants at 3 weeks and 6 months by measuring urinary catecholamine metabolites. Procedure. Over the 5-yr period, 45 tumors were detected by screening, 20 were identified clinically prior to the third week, and 64 were identified clinically at a later time. We analyzed available tumors for Shimada histopathology, tumor ploidy, MYCN copy number and serum ferritin. Results. Of the tumors detected by screening, only 2 of 45 tested had unfavorable histology, 2 of 45 had diploid or tetraploid DNA content, 0 of 43 had MYCN amplification, and 4 of 44 had elevated serum ferritin. All of these patients are alive and well. The 20 patients detected prior to the 3-week screen had similar biological characteristics. In contrast, of the patients detected clinically after 3 weeks of age, 19 of 51 testedhad unfavorable histology, 25 of 66 had diploid or tetraploid tumors, 12 of 56 had MYCN amplification, and 14 of 54 had elevated ferritin. Conclusions. The difference between the screened and clinically detected cases was highly significant for each biological variable. Preliminary data on other biological variables, such as neurotrophin expression and allelic loss on 1p in these patients are consistent with the above findings. These data suggest that mass screening for neuroblastoma at or before 6 months of age detects almost exclusively tumors that have favorable biological characteristics, many of which might have regressed spontaneously. Thus, continued mass screening for neuroblastoma at 6 months is unlikely to accomplish its intended goal, and should probably be discontinued. Med. Pediatr. Oncol. 36:157-159 2001.
Journal of Pediatric Hematology/Oncology, 1991
Journal of Pediatric Hematology/Oncology, 1999
Journal of Immunotherapy, 1995
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Papers by Jean-Marie Leclerc