Asparaginase May Affect Mercaptopurine Tolerability in the Context of Multi-Agent Therapy for Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 179-179
Author(s):  
Chengcheng Liu ◽  
Deqing Pei ◽  
Cheng Cheng ◽  
Jun J Yang ◽  
Kristine R Crews ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Linear Regression ◽  
Maintenance Therapy ◽  
Linear Regression Model ◽  
Lymphoblastic Leukemia ◽  
Dose Intensity ◽  
Low Risk ◽  
Remission Induction ◽  
P Values

Abstract Background: Mercaptopurine (MP) and asparaginase (ASP) are critical components in the treatment of acute lymphoblastic leukemia (ALL). Dose-limiting toxicities of the two drugs are common, resulting in therapy interruption, which has been associated with inferior treatment outcome in some studies. However, the interaction between these drugs has not been clearly identified. Merryman et al (Pediatr Blood Cancer 2012) reported that in DFCI ALL 05-01, patients had lower blood counts and more dosage reductions of MP during consolidation therapy (with concomitant ASP treatment) than during continuation therapy (identical treatment without concomitant ASP). Among groups of homogeneously treated patients with ALL, variability in ASP exposure due to inactivating antibodies can affect ASP pharmacodynamics: we have reported that ASP antibodies were associated with lower plasma ASP activity and higher dexamethasone (DEX) clearance, leading to a lower risk of osteonecrosis and a higher risk of CNS relapse (Liu, Leukemia 2012; Kawedia, Blood 2012). Here we studied the possible effect of ASP antibodies on MP tolerability in St. Jude Children's Research Hospital Total XV, a clinical trial featured intensive ASP treatment. Methods: A total of 390 children with ALL treated on St. Jude Total XV protocol were evaluable. TPMT genotype was used to guide starting doses of MP. During maintenance treatment, planned MP doses were higher on the low-risk arm (LR; n = 202) than on the standard/high-risk arm (SHR; n = 188). MP dose intensity was estimated as (prescribed dose)/(protocol dose) for weeks 1-146 (boys) or 1-120 (girls) for patients on the LR and SHR arms of maintenance therapy. Native E.coli-ASP (Elspar) was administered intramuscularly at 10000 U/m2 thrice weekly for 6 or 9 doses during remission induction. During maintenance therapy, patients on the LR arm received ASP only during reinductions I (weeks 7-9) and II (weeks 17-19), whereas those on the SHR arm received 19 weekly doses at 25000 U/m2 during weeks 1-19. Patients were tested for serum anti-Elspar antibodies at days 5, 19, 34 of remission induction, day 1 of reinduction I and day 1 of reinduction II, and were grouped based on whether they were ever positive for antibodies at any time during therapy or not. The area under the antibody concentration-time curve (AUC) for the entire period up to week 19 was also estimated in 360 patients. Result: Overall MP dose intensity was higher in those with vs without ASP antibodies in patients on the LR (median 83 vs 75%, P = 0.003) and SHR arms (median 86 vs 76%, P = 3.3 × 10-5; Figure 1A), and MP dose intensity was correlated with ASP antibody AUC in patients on both treatment arms (LR, P = 7.7 × 10-3 and SHR, P = 2.4 × 10-4; Figure 1B). In a multivariate model including age, sex, risk arm, ancestry, TPMT status, NUDT15 genotype and ASP antibody status, TPMT genotype was the strongest determinant of MP dose intensity (-17% in heterozygotes, P = 1.9 × 10-8), followed by ASP antibody positivity (+8.9% dose intensity in those with antibodies, P = 5.8 × 10-6). The model also confirmed previously identified associations of higher MP dose intensity with higher African ancestry (Bhatia et al. Blood 2014) (P = 1.8 × 10-4) and lower Asian ancestry (P = 0.05) (Yang et al. J Clin Oncol 2015). Conclusion: Interindividual differences in ASP systemic exposure, as reflected by ASP antibodies, had a strong impact on MP tolerance, especially in patients on the SHR arm who received intensive ASP therapy. We have previously shown that patients who are positive for ASP antibodies not only have lower exposure to ASP but also to dexamethasone (Kawedia, Blood 2012; Liu, Leukemia 2012). These data further emphasize the capacity for variation in ASP exposure to impact yet another critical component of ALL therapy. Figure 1 Asparaginase antibodies associated with higher mercaptopurine tolerance in patients on the low-risk (n = 202) and standard/high-risk (n = 188) arms. P values were estimated using the (A) Mann-Whitney U test and (B) linear regression model. DI, dose intensity; MP, mercaptopurine; ASP, asparaginase; NEG, anti-asparaginase antibody negative; POS, anti-asparaginase antibody positive. Figure 1. Asparaginase antibodies associated with higher mercaptopurine tolerance in patients on the low-risk (n = 202) and standard/high-risk (n = 188) arms. / P values were estimated using the (A) Mann-Whitney U test and (B) linear regression model. DI, dose intensity; MP, mercaptopurine; ASP, asparaginase; NEG, anti-asparaginase antibody negative; POS, anti-asparaginase antibody positive. Disclosures Evans: Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Relling:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

scholarly journals Response Adapted Therapy in ETV6/RUNX1-Positive Childhood Acute Lymphoblastic Leukemia Treated per Modified St Jude Total XV Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Mayada Abu Shanap ◽  
Iyad Sultan ◽  
Amal Abu-Ghosh ◽  
Hasan Hashem ◽  
Abdelghani Tbakhi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Induction Therapy ◽  
Leukocyte Count ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Low Risk ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Standard Risk

Introduction: ETV6-RUNX1 is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL), occurring in approximately 25% of cases with a precursor-B phenotype. The presence of ETV6-RUNX1 has been associated with a relatively low rate of relapse in multiple studies. Relapses tend to occur late and have a better salvage rate than other ALL subtypes. Moreover, conflicting data in literature regarding the prognostic significance of ETV6-RUNX1 after accounting for age, initial count and treatment intensity. We sought to study the clinical features, therapy response in newly diagnosed ETV6-RUNX1-positive treated at King Hussein Cancer Center. Methods: Patients were treated per modified St Jude Total (XV) study, risk stratification was further refined by including minimal residual disease (MRD)measurements on day 15 and day 46 of remission induction therapy. Patients with the ETV6- RUNX1 fusion or hyperdiploidy without CNS or testicular disease and a satisfactory early MRD decline (<1% on day 15 and <0.01% on day 46) were classified as being low-risk for relapse and were treated on lower -risk arm regardless of age and leukocyte count. Results: Seventy patients (n=70) with ETV6-RUNX1-positive treated at our institution between May 2006 to October 2017. The median age at diagnosis, 5.8 years (range, 1.5-10.8). ETV6-RUNX1 was associated with favorable age between 1- and 6-years in 55 patients (79%), male gender in 41 patients (59%), initial leukocyte count <10 in 39 patients (56%), CNS status 1 in 100% of patients. The majority, n= 58 (83%) of patients had NCI standard risk (SR) and n=12 (17%) had NCI high risk (HR). Sixty-six patients (94%) had MRD <1% at day 15 and all patients achieved remission with MRD<0.01% at day 46 of remission induction. All patients were treated as LR ALL per modified St Jude total XV protocol. At median follow up of (36 months; range, 26 to 154), in the subgroups of ETV6-RUNX1-positive patients classified as NCI standard risk (SR)and NCI high risk (HR) the 5-year EFS estimates were 94.1% ± 3.2 and 82%±1(P=.13), 5-year OS estimates were 100% and 92% ± 8 (p=0.31) respectively. Conclusion: MRD treatment schema in ETV6/RUNX1 -positive patients have excellent outcomes if they achieved favorable response at day 15 and end of remission induction regardless of the age and Initial leukocyte count. Treatment reduction is feasible and declared safe for children with NCI-HR who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD post remission induction therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Precision medicine in acute lymphoblastic leukemia

2020 ◽  
Vol 14 (6) ◽  
pp. 689-700 ◽  
Author(s):  
Ching-Hon Pui
Keyword(s):  
Targeted Therapy ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Cellular Therapy ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Dose Intensity ◽  
Remission Induction ◽  
T Cell Therapy

AbstractThe cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional chemotherapy has been pushed to its limit. Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno-and cellular-therapy approaches together with precise risk stratification. Children with ETV6-RUNX1 or hyperdiploid > 50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment. Patients with Philadelphia chromosome (Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib. BH3 profiling and other preclinical methods have identified several high-risk subtypes, such as hypodiplod, early T-cell precursor, immature T-cell, KMT2A-rearranged, Ph-positive and TCF-HLF-positive ALL, that may respond to BCL-2 inhibitor venetoclax. There are other fusions or mutations that may serve as putative targets, but effective targeted therapy has yet to be established. For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions, current approaches that offer hope include blinatumomab, inotuzumab and CAR-T cell therapy for B-ALL, and daratumumab and nelarabine for T-ALL. With the expanding therapeutic armamentarium, we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.

Asparaginase May Influence Dexamethasone Pharmacokinetics in Acute Lymphoblastic Leukemia

2008 ◽  
Vol 26 (12) ◽  
pp. 1932-1939 ◽  
Author(s):  
Lei Yang ◽  
John C. Panetta ◽  
Xiangjun Cai ◽  
Wenjian Yang ◽  
Deqing Pei ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Serum Albumin ◽  
Lymphoblastic Leukemia ◽  
Low Risk ◽  
Posteriori Probability ◽  
Albumin Concentration ◽  
Serum Albumin Concentration ◽  
Apparent Clearance ◽  
Risk Treatment

Purpose Dexamethasone is used widely in oncology, but pharmacokinetic studies are lacking. We evaluated dexamethasone pharmacokinetics in children with acute lymphoblastic leukemia. Patients and Methods We assessed 214 children with acute lymphoblastic leukemia who received 418 courses of oral dexamethasone (8 mg/m2/d) on days 1 and 8 of reinduction. Extensive asparaginase use preceded reinduction in the 101 children in the standard/high-risk treatment arm but not in the 113 children in the low-risk treatment arm. A one-compartment model with first-order absorption and disposition was fit to dexamethasone plasma concentrations by using maximum a posteriori probability estimation; we evaluated covariates by using linear mixed models. Results Interpatient and intrapatient variabilities in apparent clearance were substantial; they were 46% and 53%, respectively. Variability was explained by the serum albumin concentration (P < .0001), concomitant use of fentanyl (P = .008) and ketoconazole (P = .03), and age (P = .006). Apparent clearance was higher in the low-risk arm (P < .001) and was related to a greater serum albumin concentration (P < .001) and to a lower exposure to asparaginase than in the standard/high-risk arm. Hypoalbuminemia, a biomarker of asparaginase activity, was associated with a lower dexamethasone apparent clearance (P = .04) in patients in the standard/high-risk arm that was more pronounced in those not allergic to asparaginase. Ethnicity or gender did not explain apparent clearance variability. Conclusion Dexamethasone pharmacokinetics are highly variable and are related to the concurrent use of particular drugs, age, and treatment intensity. Patients allergic to asparaginase may be doubly disadvantaged: they not only suffer from diminished exposure to asparaginase but also, by maintaining high clearance of dexamethasone, may experience fewer antileukemic effects of dexamethasone.

scholarly journals Oncogenetic Risk Classification Based on NOTCH1/FBXW7/RAS/PTEN Mutation Profiles Improves Outcome Prediction in Pediatric T-Cell Acute Lymphoblastic Leukemia, Treated According the Fralle 2000 T Guidelines

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1083-1083 ◽  
Author(s):  
Arnaud Petit ◽  
Amélie Trinquand ◽  
Sylvie Chevret ◽  
Paola Fabiola Ballerini ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Low Risk ◽  
Study Cohort ◽  
Risk Patients ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Wbc Count ◽  
Risk Of Relapse

Abstract Background: Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is crucial to drive treatment decisions. Since patients with induction failure or relapse are often refractory to further treatment, identifying high risk patients up-front will allow improved treatment. While minimal residual disease (MRD) is the strongest prognosis risk factor used after complete remission (CR), NOTCH1/FBXW7 (N/F) and RAS/PTEN (R/P) mutation profiles at diagnosis have recently been identified to predict outcome in adult T-ALL. Objective: to test whether an oncogenetic classifier using N/F and R/P mutations could improve the detection of children with T-ALL at risk of relapse. Methods: 405 patients with T-ALL aged from 1 to 14 years were treated according to FRALLE T guidelines (FRALLE Study group) between 2000 and 2010. Among them, 220 patients, for whom biological material at diagnosis was available, were tested retrospectively for N/F and R/P mutations. These study cohort patients were representative of overall FRALLE 2000 T-ALLs. CR was achieved in 213 patients. MRD (IgH-TCR markers) tested at CR (day 35) was available for 191 patients. MRD was <10-4 for 114 patients (60%) and ≥10-4 for 77 patients. Patients with N/F mutation and R/P germline (GL) were defined as oncogenetic low risk (LoR), while N/F GL and R/P GL or mutation and N/F mutation and R/P mutation were defined as high risk (HiR). Results: 111 patients were classified as LoR and 109 as HiR. Five-year-CIR and DFS were respectively 35.5% (95% CI, 26.7-44.3) and 59% (95%CI, 50.2-69.6) for HiR versus 13% (95% CI, 6.8-19.2) and 86.8% (80.5-93.5) for the LoR group (Figures A and B). HiR patients were significantly associated with MRD ≥ 10-4 (p=0.0004) and higher risk of relapse (p=0.00002). Among patients with MRD ≥ 10-4, HiR feature worsened the risk of relapse: 5-year-CIR and DFS were respectively 42.8% (95% CI, 28.9-56.7) and 71.1% (95%CI, 56.0-90.2) in HiR versus 28.9% (95% CI, 11.7-46.1) and 50.9% (95%CI, 38.4-67.6) in the LoR group. Among patients with MRD <10-4, 5-year-CIR and DFS were respectively 28.9 % (95% CI, 15.0-42.8) and 71.0% (95%CI, 58.4-86.3) in HiR group versus 4.4% (95% CI, 0-9.2) and 95.5% (95%CI, 90.7-1.00) in LoR group (Figures C and D). As such, the classifier allowed identification of 63% of very low risk patients amongst the MRD<10-4 population. Prognostic values of new oncogenetic risk factors were then analyzed with conventional factors. By univariate analysis, factors identified to predict relapse were male gender (p=0.036), WBC count ≥ 200 G/L (p=0.023), chemoresistance at day 21 (p=0.007), MRD ≥10-4 (p=0.0006) and oncogenetic HiR (p<0.0001). A multivariable cox model including these variables selected the classifier together with WBC count, day 21 chemo-sensitivity and MRD. Based on a stepwise selection procedure, the three most discriminating variables were classifier, WBC count and MRD. The cause specific Hazard Ratio (HR) was 3.22 (95% CI, 1.64-6.28) for oncogenetic HiR versus LoR (p=0.0006), 2.30 (95% CI, 1.26-4.20) for MRD≥10-4 versus MRD<10-4(p=0.0070) and 1.85 (95% CI, 1.01-3.37) for WBC≥200G/L versus <200 G/L (p=0.0456). Based on these three parameters, 8 subsets of patients were defined according to the estimated 5-year CIR. The 58 patients (30%) associating WBC count < 200G/L, classifier LoR and MRD<10-4 were at very low risk of relapse, with a 5-y-CIR of 1.7%. Patients harboring at least one of: WBC count ≥200G/L, classifier HiR or MRD>10-4, demonstrated an increasing CIR, up to 45.8% if all three were associated. Conclusion: in childhood T-ALL, oncogenetic classification using N/F and R/P mutation profiles is an independent predictor of relapse. When combined with MRD and WBC count ≥200 G/L, it significantly improved relapse prediction, particularly amongst the 60% of T-ALLs with MRD <10-4 at day 35. Appropriate integrating these 3 factors, will help optimize treatment. Figure Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Body Mass Index Is Not Associated with Early Treatment Response or Clinical Outcome in Children with Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1299-1299
Author(s):  
Hesham Eissa ◽  
Yinmei Zhou ◽  
John C Panetta ◽  
Emily Browne ◽  
Sima Jeha ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Treatment Response ◽  
Body Mass ◽  
Early Treatment ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Cell Phenotype ◽  
Early Treatment Response

Abstract Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with survival rates exceeding 90% in recent trials. Obesity is increasingly prevalent in the general population, and studies in children with ALL have correlated obesity with higher risk of persistent minimal residual disease (MRD) at the end of induction as well as worse outcome. We, therefore, determined whether obesity affected treatment response in children with ALL who were enrolled in a recent trial including MRD-guided therapy. Methods: Patients enrolled in the Total XV study at St. Jude Children's Research Hospital from 2000 to 2007 were included in the analysis. The protocol used MRD levels prospectively for risk assignment together with age, white blood cell counts, and cytogenetic profiles. Drug dosages were based on actual (rather than ideal) body surface area. Body mass index (BMI) was calculated by using height and weight for patients older than 2 years at diagnosis. Four BMI categories (underweight, normal, overweight, and obese) based on Center for Disease Control and Prevention guidelines were used. The association between BMI categories at diagnosis and MRD, cumulative incidences of refractory/relapsed disease (CIR), and event-free survival (EFS) were evaluated. The changes in BMI percentile from diagnosis to the end of induction were also calculated. Results: Among 409 patients enrolled, 26 who were younger than 2 years with no available BMI and 9 with Down syndrome were excluded. Of the 374 evaluable patients, 26 (7.0%) were underweight; 245 (65.5%) had normal BMI; 45 (12.0%) were overweight; and 58 (15.5%) were obese. Older age at diagnosis (P = 0.008) and being on the standard/high-risk treatment arm (P = 0.040) were associated with higher BMI categories. Among the 4 BMI categories, there was no significant difference in the proportion of patients with MRD ≥1% on day 19 of remission-induction therapy (P = 0.437) or MRD ≥0.01% at the end of induction (P = 0.182). There were also no differences in CIR (P = 0.259) or EFS (P = 0.158) among the 4 categories. EFS was significantly worse in male patients (P = 0.027) and in those with T-cell phenotype (P = 0.006), standard/high risk (P < 0.001), MRD ≥1% on day 19 (P < 0.001), or MRD ≥0.01% at the end of induction (P < 0.001). We reanalyzed the data by using 2 BMI categories (non-obese and obese). No significant differences were observed in the proportions of patients with MRD ≥1% on day 19 (P = 0.766) or MRD ≥0.01% at the end of induction (P = 0.177), and there was no difference in CIR between the 2 categories (P = 0.395). Although not statistically significant, EFS was marginally worse in obese patients (P=0.053). EFS among 4 or 2 BMI categories was evaluated by using a multiple Cox regression model including treatment arm, sex, race, and BMI categories as variables. No differences were observed for analysis by 4 (P = 0.368) or 2 (P = 0.151) BMI categories. In these analyses, only treatment arm (standard/high risk) remained a significant predictor (all P < 0.001). BMI percentile change from diagnosis to the end of induction also lacked significant association with MRD, CIR, and EFS. Conclusion: In contrast to published reports, body mass index had no effect on early treatment response as measured by MRD, incidence of relapse, or EFS in children with ALL enrolled in the Total XV study. These results indicate that obesity should not be considered an adverse prognostic factor in children with ALL in the context of contemporary treatment programs. Figure 1. Association of BMI with MRD, CIR, and EFS Figure 1. Association of BMI with MRD, CIR, and EFS Disclosures Evans: Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

Validation of a Predictive Model for Indentifying An Increased Risk for Thromboembolism in Children with Acute Lymphoblastic Leukemia: Results of a Multicenter Cohort Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 524-524
Author(s):  
Silke Flege ◽  
Lesley Mitchell ◽  
Gili Kenet ◽  
Christine Heller ◽  
Michael Fruhwald ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Predictive Model ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Low Risk ◽  
Carrier Status ◽  
Central Venous ◽  
Increased Risk ◽  
Genetic Abnormalities

Abstract Children with acute lymphoblastic leukemia (ALL) are at increased risk for venous thromboembolism (VTE), however, not all children experience a VTE. Developing a predictive model for determining children at increased risk would be beneficial in targeting interventional studies to only high risk groups. A recent meta-analysis of studies in VTE in children with ALL identified four potential risk factors: treatment with Escherichia coli asparaginase (CASP), concomitant use of steroids, presence of central venous lines and thrombophilic genetic abnormalities. As VTE in childhood ALL is well recognized as serious clinical problem and due to the lack of studies on prevention, the standard of practice varies and some centres use enoxaparin prophylaxis for these children. However, the risks and benefits of the intervention are unknown. The aim of the study was to develop a simple model for predicting ALL-chemotherapy-associated VTE using baseline clinical and laboratory variables, and to evaluate, on an explorative basis, the increasing off-label use of enoxaparin for VTE prophylaxis in ALL children. For development of the risk model the predictive variables were scored as follows: treatment with CASP (5000–10000/m2) in combination with prednisone or dexamethasone, presence of central venous lines, thrombophilic genetic abnormalities, e.g. positive family history for VTE or identification of a single thrombophilic trait (1 point each), or carrier status of combined thrombophilic traits (2 points). A definition of VTE risk by score was low (1–2) and high (□ 3). The risk score was than prospectively validated in an independent cohort of 136 newly recruited patients enrolled into the German database. Seven patients were excluded (lost to follow-up n=2; death n=2, secondary malignancy, VTE before ALL-onset, infant &lt; 12 months of age: each n=1). The cumulative VTE rates at 3.5 months in the validation cohorts were 3.6% (95% CI 1%–9%) in the low-risk group (4 of 112), and 47% (95%CI 23%–72%) in the high-risk category (8 of 17). In multivariate analysis [Cox regression] the high risk group was significantly associated with VTE when compared to the low risk group even after adjusting for age at ALL-onset, duration of CASP administration, steroid administered (prednisone/dexamethasone), and presence or absence of enoxaparin prophylaxis [hazard/95%CI: 4.16/1.13–15.34]. The negative predictive value for VTE was 96.3% [95%CI: 92.9–99.8]. Early enoxaparin prophylaxis reduced the absolute VTE-risk about 60% [95%CI: 23–96]. Therefore, the model can identify ALL-children with an increased risk for symptomatic VTE.

scholarly journals Comparative Value of the Assessment of Minimal Residual Disease in Peripheral Blood at Days 8 and 15 By Flow Cytometry in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5270-5270
Author(s):  
Marie Loosveld ◽  
Vanessa Nivaggioni ◽  
Isabelle Arnoux ◽  
Denis Bernot ◽  
Chantal Fossat ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Low Risk ◽  
The Impact ◽  
Minimal Residual

Abstract Introduction Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood, but treatments' progress now allowsto obtain prolonged remission or curein over 90% of the patients. Consequently, therapeutic de-escalation is now an objective for future treatment protocols, providing that biomarkers allow to reliablyidentifygood responders. Among such indicators, low levels of Minimal Residual Disease (MRD) obtained early after induction chemotherapy stand out as good candidates. The latter can be investigated usingmultiparameterflow cytometry (MFC) or real-time polymerase chain reaction (RT-PCR) for immunoglobulins or T-cell receptors (IG TCR) rearrangements. In this study we report the impact on survival of two early points of peripheral blood (PB) MRD assessment by MFC at days 8 and 15 on a cohort of 125 children with B-ALL enrolled in the French FRALLE trial and compared to molecular MRD in the bone marrow (BM) at day 35. Patients and methods. The study enrolled 67 boys and 58 girls and the duration of the study allowed for a median follow up of 52,1months. Median age at diagnosis was 57 months old (range 18 to 196), 101 children were between 1 to 10 years old and 24 were older than 10. Complete blood counts (CBC) at diagnosis showed a median of 6.7x109/L leucocytes (range 0.47 - 151x109/L) and 33% blasts (range 0 to 97%). One hundred and eight children had less than 50x109/L leucocytes while 17 had higher counts. EGIL classification at diagnosis allowed to classify patients as three B-I, 94 B-II, 27 B-III and 1 B-IV. Cytogenetic analyses were performed for 118 patients who were partitioned as follows: low risk n=47, intermediate risk n=55 and high risk n=16 (Harrisson CJ et al., BJH, 2010). Eighty-three patients were in the low risk group and 42 in the high-risk group as described by the FRALLE protocol. Seven patients of the 64 tested had an IKZF1 deletion. During the duration of the study, 20 patients relapsed and 8 died. Corticosensitivitywas defined by less than 1x109/L PB blasts on day 8 andchemosensitivity by less than 5% BM blasts on day 21 on BM smears. PB MRD was assessed in MFC with a single five or ten colors tube adapted to each patient's leukemia associatedimmunophenotypeon a backbone of CD45, CD19, CD10 and CD38. Statistical analyzes examined factors impacting disease-free survival (DFS) using Log rank test and Kaplan-Meier using theMedcalc® software (Ostend, Belgium). P values <0.05 were considered significant. Results None of diagnosis features had any significant impact on DFS: age (p=0,95), risk group (p=0,17), EGIL classification (p=0,55), cytogenetics (p= 0,87), leucocyte count (p=0,36) nor IKZF1 deletion (p=0,2). Of the 125 patients, 9 were corticoresistant, 79 corticosensitive and 37 not evaluable because of less than 1x109/L leucocyte at diagnosis.Corticosensitivity had no impact on DFS (p=0,11). Conversely,chemosensitivity had a significant positive impact on DFS (p= 0,009). Day 8 PB MRD did not oultlineany significantly different DFS, whether considering detectable vs undetectable MRD (p=0.65) or MRD levels (logwisefrom >10-1 to <10-4, p=0,22). Conversely, PB MFC at day 15 appeared highly discriminant. Considering notdetectablevs detectable MRD, 4 years DFS was 91,6+3% vs. 67,6+9% p=0,0013 (Figure 1). Further refining the thresholds of MRD logwisedid not modify the significance (p=0.004; Figure 2). Indeed, DFS at 48 months was 61+15 % (n=16) for MRD >10-3, 74+11% ( n=18) for MRD <10-3->10-4 and 92+3% ( n=91) for MRD<10-4. Comparison of PB MFC MRD on day 15 with day 35 BM molecular MRD showed concordance in 72% of the cases (83 negative/negative and 7 positive/positive, 48 months DFS 94.6+2.7% and 38+20% respectively). Eight patients were negative in PB but positive in BM (DFS 62.5+17%).Twenty seven where positive in PB but negative in BM (DFS 83.5+7.6%).These differences were statistically highly significant (p <0.0001). Conclusion This study demonstrates that even in the good prognosis context of childhood ALL, early MRD retains a highly significant prognostic value. It is of importance that this result was obtained not only on day 35 BM but interestingly, even earlier on day 15 PB. This less invasive procedure can easily be applied, especially for children. It should allow to detectgood responders, with MFC MRD levels below 10-4 for whom a de-escalation of chemotherapy could be considered. Conversely, the detection of blasts by MFC in day 15 PB is worrisome. Disclosures No relevant conflicts of interest to declare.

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

2000 ◽  
Vol 18 (7) ◽  
pp. 1517-1524 ◽  
Author(s):  
G. Michel ◽  
J. Landman-Parker ◽  
M.F. Auclerc ◽  
C. Mathey ◽  
T. Leblanc ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Dose Intensity ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Chemotherapy Dose ◽  
Stimulating Factor ◽  
Very High ◽  
Chemotherapy Dose Intensity

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 × 109/L and platelet count was > 100 × 109/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.

Minimal Residual Disease–Guided Treatment Deintensification for Children With Acute Lymphoblastic Leukemia: Results From the Malaysia-Singapore Acute Lymphoblastic Leukemia 2003 Study

2012 ◽  
Vol 30 (19) ◽  
pp. 2384-2392 ◽  
Author(s):  
Allen Eng Juh Yeoh ◽  
Hany Ariffin ◽  
Elaine Li Leng Chai ◽  
Cecilia Sze Nga Kwok ◽  
Yiong Huak Chan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Intermediate Risk ◽  
Risk Patients ◽  
Standard Risk ◽  
Minimal Residual

Purpose To improve treatment outcome for childhood acute lymphoblastic leukemia (ALL), we designed the Malaysia-Singapore ALL 2003 study with treatment stratification based on presenting clinical and genetic features and minimal residual disease (MRD) levels measured by polymerase chain reaction targeting a single antigen-receptor gene rearrangement. Patients and Methods Five hundred fifty-six patients received risk-adapted therapy with a modified Berlin-Frankfurt-Münster–ALL treatment. High-risk ALL was defined by MRD ≥ 1 × 10−3 at week 12 and/or poor prednisolone response, BCR-ABL1, MLL gene rearrangements, hypodiploid less than 45 chromosomes, or induction failure; standard-risk ALL was defined by MRD ≤ 1 × 10−4 at weeks 5 and 12 and no extramedullary involvement or high-risk features. Intermediate-risk ALL included all remaining patients. Results Patients who lacked high-risk presenting features (85.7%) received remission induction therapy with dexamethasone, vincristine, and asparaginase, without anthracyclines. Six-year event-free survival (EFS) was 80.6% ± 3.5%; overall survival was 88.4% ± 3.1%. Standard-risk patients (n = 172; 31%) received significantly deintensified subsequent therapy without compromising EFS (93.2% ± 4.1%). High-risk patients (n = 101; 18%) had the worst EFS (51.8% ± 10%); EFS was 83.6% ± 4.9% in intermediate-risk patients (n = 283; 51%). Conclusion Our results demonstrate significant progress over previous trials in the region. Three-drug remission-induction therapy combined with MRD-based risk stratification to identify poor responders is an effective strategy for childhood ALL.

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