TOLERANCE, COMPLIANCE AND EFFICACY OF L-ASPARAGINASE DURING INDUCTION PHASE IN ADULT PHILADELPHIA-NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA: EXPERIENCE OF THE GRAALL-2005.
(Abstract release date: 05/19/16)
EHA Library. Balsat M. 06/10/16; 133154; P166
Dr. Marie Balsat
Contributions
Contributions
Abstract
Abstract: P166
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
In adults aged 18-60 years, many acute lymphoblastic leukemia (ALL) protocols have now incorporated L-asparaginase (ASPA) as part of induction regimen. As in children, adult patients are thus often exposed to pancreatitis, thrombosis, liver injury and allergic reactions. Thus some investigators do not use ASPA at all, like in the Hyper-CVAD regimen. In the GRAALL network, most of the centers started to use ASPA during induction when the pediatric-inspired GRAALL protocol was introduced in 2003.
Aims
The aim of this study was to report the real-life experience of the use of ASPA in the GRAALL-2005 trial and to identify factors associated with 1) main ASPA-related Adverse Events (AEs) and 2) the frequency and the impact of suboptimal ASPA dose administration.
Methods
Between 2006 and 2014, 787 adult patients with newly diagnosed Ph1-negative ALL were included in the multicenter French-Belgian-Swiss GRAALL-2005 trial. After a 7-day steroid prophase, patients received a 5-drug sequential induction including prednisone (PDN), vincristine (VCR), daunorubicine (DNR), cyclophosphamide (CPM) and ASPA (6000 IU/sqm/day for 8 days). Patients with induction failure received a high-dose cytarabine-based salvage course. AEs were assessed according to WHO classification. Four patients were excluded due to the lack of data.
Results
The median age of this cohort of 783 patients (505 BCP- and 278 T-ALL) was 36.1 years (range: 18.1-60.0). Median body mass index (BMI) was 23.6 kg/sqm (range: 15.7-46.3). Initial median WBC was 11.8 G/L (range: 0.4-645) and 55 patients had CNS involvement (7.0%). A complete remission (CR) was achieved in 720/783 (92.0%). A resistance to first induction phase was observed in 36/738 (4.9%) patients evaluable for CR.A grade 3-4 liver toxicity was observed in 272 patients (34.6%), a grade 3-4 pancreatitis in 43 patients (5.5%), and a cerebral venous thrombosis (CVT) in 25 patients (3.3%). An older age was significantly associated with an increased incidence of liver toxicity but a lower incidence of CVT. Pancreatitis was not associated with age. A high BMI was associated with liver toxicity and pancreatitis. In multivariate analysis, age, BMI, CNS involvement, and BCP-phenotype were associated with liver toxicity; BMI and female gender were associated with pancreatitis.During induction phase, patients received 97.8% of ASPA scheduled dose, 99.0% if younger than 45 years old but only 84.8% if older (p<.0001). In comparison, no difference in the administration of myelosuppressive drugs (DNR, CPM) was observed. In multivariate analysis, patient-related variables associated with less than 90% of scheduled ASPA administration (41% of patients) were older age, high BMI, and high ECOG score. In this model, center enrollment volume but also inclusion time period were statistically associated with a higher rate of ASPA administration, suggesting a learning effect.Finally, covariates independently associated with induction failure were higher WBC (OR 1.04 [95%CI, 1.01-1.07]), slower bone marrow clearance at D8 (OR 0.07 [95%CI, 0.02-0.20]), lower ASPA injection number (OR 0.72 [95%CI, 0.60-0.85]), and lower VCR injection number (OR 0.69 [95%CI, 0.55-0.88]), excluding all other induction drug dose variation.
Conclusion
During ALL induction, most ASPA-related toxicities seen in adult patients are correlated to age and BMI. Experience in the management of ASPA administration may enhance protocol compliance and thus contribute to reduce induction failure risk.
Session topic: Acute lymphoblastic leukemia - Clinical 1
Keyword(s): ALL, L-asparaginase, Toxicity
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
In adults aged 18-60 years, many acute lymphoblastic leukemia (ALL) protocols have now incorporated L-asparaginase (ASPA) as part of induction regimen. As in children, adult patients are thus often exposed to pancreatitis, thrombosis, liver injury and allergic reactions. Thus some investigators do not use ASPA at all, like in the Hyper-CVAD regimen. In the GRAALL network, most of the centers started to use ASPA during induction when the pediatric-inspired GRAALL protocol was introduced in 2003.
Aims
The aim of this study was to report the real-life experience of the use of ASPA in the GRAALL-2005 trial and to identify factors associated with 1) main ASPA-related Adverse Events (AEs) and 2) the frequency and the impact of suboptimal ASPA dose administration.
Methods
Between 2006 and 2014, 787 adult patients with newly diagnosed Ph1-negative ALL were included in the multicenter French-Belgian-Swiss GRAALL-2005 trial. After a 7-day steroid prophase, patients received a 5-drug sequential induction including prednisone (PDN), vincristine (VCR), daunorubicine (DNR), cyclophosphamide (CPM) and ASPA (6000 IU/sqm/day for 8 days). Patients with induction failure received a high-dose cytarabine-based salvage course. AEs were assessed according to WHO classification. Four patients were excluded due to the lack of data.
Results
The median age of this cohort of 783 patients (505 BCP- and 278 T-ALL) was 36.1 years (range: 18.1-60.0). Median body mass index (BMI) was 23.6 kg/sqm (range: 15.7-46.3). Initial median WBC was 11.8 G/L (range: 0.4-645) and 55 patients had CNS involvement (7.0%). A complete remission (CR) was achieved in 720/783 (92.0%). A resistance to first induction phase was observed in 36/738 (4.9%) patients evaluable for CR.A grade 3-4 liver toxicity was observed in 272 patients (34.6%), a grade 3-4 pancreatitis in 43 patients (5.5%), and a cerebral venous thrombosis (CVT) in 25 patients (3.3%). An older age was significantly associated with an increased incidence of liver toxicity but a lower incidence of CVT. Pancreatitis was not associated with age. A high BMI was associated with liver toxicity and pancreatitis. In multivariate analysis, age, BMI, CNS involvement, and BCP-phenotype were associated with liver toxicity; BMI and female gender were associated with pancreatitis.During induction phase, patients received 97.8% of ASPA scheduled dose, 99.0% if younger than 45 years old but only 84.8% if older (p<.0001). In comparison, no difference in the administration of myelosuppressive drugs (DNR, CPM) was observed. In multivariate analysis, patient-related variables associated with less than 90% of scheduled ASPA administration (41% of patients) were older age, high BMI, and high ECOG score. In this model, center enrollment volume but also inclusion time period were statistically associated with a higher rate of ASPA administration, suggesting a learning effect.Finally, covariates independently associated with induction failure were higher WBC (OR 1.04 [95%CI, 1.01-1.07]), slower bone marrow clearance at D8 (OR 0.07 [95%CI, 0.02-0.20]), lower ASPA injection number (OR 0.72 [95%CI, 0.60-0.85]), and lower VCR injection number (OR 0.69 [95%CI, 0.55-0.88]), excluding all other induction drug dose variation.
Conclusion
During ALL induction, most ASPA-related toxicities seen in adult patients are correlated to age and BMI. Experience in the management of ASPA administration may enhance protocol compliance and thus contribute to reduce induction failure risk.
Session topic: Acute lymphoblastic leukemia - Clinical 1
Keyword(s): ALL, L-asparaginase, Toxicity
Abstract: P166
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
In adults aged 18-60 years, many acute lymphoblastic leukemia (ALL) protocols have now incorporated L-asparaginase (ASPA) as part of induction regimen. As in children, adult patients are thus often exposed to pancreatitis, thrombosis, liver injury and allergic reactions. Thus some investigators do not use ASPA at all, like in the Hyper-CVAD regimen. In the GRAALL network, most of the centers started to use ASPA during induction when the pediatric-inspired GRAALL protocol was introduced in 2003.
Aims
The aim of this study was to report the real-life experience of the use of ASPA in the GRAALL-2005 trial and to identify factors associated with 1) main ASPA-related Adverse Events (AEs) and 2) the frequency and the impact of suboptimal ASPA dose administration.
Methods
Between 2006 and 2014, 787 adult patients with newly diagnosed Ph1-negative ALL were included in the multicenter French-Belgian-Swiss GRAALL-2005 trial. After a 7-day steroid prophase, patients received a 5-drug sequential induction including prednisone (PDN), vincristine (VCR), daunorubicine (DNR), cyclophosphamide (CPM) and ASPA (6000 IU/sqm/day for 8 days). Patients with induction failure received a high-dose cytarabine-based salvage course. AEs were assessed according to WHO classification. Four patients were excluded due to the lack of data.
Results
The median age of this cohort of 783 patients (505 BCP- and 278 T-ALL) was 36.1 years (range: 18.1-60.0). Median body mass index (BMI) was 23.6 kg/sqm (range: 15.7-46.3). Initial median WBC was 11.8 G/L (range: 0.4-645) and 55 patients had CNS involvement (7.0%). A complete remission (CR) was achieved in 720/783 (92.0%). A resistance to first induction phase was observed in 36/738 (4.9%) patients evaluable for CR.A grade 3-4 liver toxicity was observed in 272 patients (34.6%), a grade 3-4 pancreatitis in 43 patients (5.5%), and a cerebral venous thrombosis (CVT) in 25 patients (3.3%). An older age was significantly associated with an increased incidence of liver toxicity but a lower incidence of CVT. Pancreatitis was not associated with age. A high BMI was associated with liver toxicity and pancreatitis. In multivariate analysis, age, BMI, CNS involvement, and BCP-phenotype were associated with liver toxicity; BMI and female gender were associated with pancreatitis.During induction phase, patients received 97.8% of ASPA scheduled dose, 99.0% if younger than 45 years old but only 84.8% if older (p<.0001). In comparison, no difference in the administration of myelosuppressive drugs (DNR, CPM) was observed. In multivariate analysis, patient-related variables associated with less than 90% of scheduled ASPA administration (41% of patients) were older age, high BMI, and high ECOG score. In this model, center enrollment volume but also inclusion time period were statistically associated with a higher rate of ASPA administration, suggesting a learning effect.Finally, covariates independently associated with induction failure were higher WBC (OR 1.04 [95%CI, 1.01-1.07]), slower bone marrow clearance at D8 (OR 0.07 [95%CI, 0.02-0.20]), lower ASPA injection number (OR 0.72 [95%CI, 0.60-0.85]), and lower VCR injection number (OR 0.69 [95%CI, 0.55-0.88]), excluding all other induction drug dose variation.
Conclusion
During ALL induction, most ASPA-related toxicities seen in adult patients are correlated to age and BMI. Experience in the management of ASPA administration may enhance protocol compliance and thus contribute to reduce induction failure risk.
Session topic: Acute lymphoblastic leukemia - Clinical 1
Keyword(s): ALL, L-asparaginase, Toxicity
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
In adults aged 18-60 years, many acute lymphoblastic leukemia (ALL) protocols have now incorporated L-asparaginase (ASPA) as part of induction regimen. As in children, adult patients are thus often exposed to pancreatitis, thrombosis, liver injury and allergic reactions. Thus some investigators do not use ASPA at all, like in the Hyper-CVAD regimen. In the GRAALL network, most of the centers started to use ASPA during induction when the pediatric-inspired GRAALL protocol was introduced in 2003.
Aims
The aim of this study was to report the real-life experience of the use of ASPA in the GRAALL-2005 trial and to identify factors associated with 1) main ASPA-related Adverse Events (AEs) and 2) the frequency and the impact of suboptimal ASPA dose administration.
Methods
Between 2006 and 2014, 787 adult patients with newly diagnosed Ph1-negative ALL were included in the multicenter French-Belgian-Swiss GRAALL-2005 trial. After a 7-day steroid prophase, patients received a 5-drug sequential induction including prednisone (PDN), vincristine (VCR), daunorubicine (DNR), cyclophosphamide (CPM) and ASPA (6000 IU/sqm/day for 8 days). Patients with induction failure received a high-dose cytarabine-based salvage course. AEs were assessed according to WHO classification. Four patients were excluded due to the lack of data.
Results
The median age of this cohort of 783 patients (505 BCP- and 278 T-ALL) was 36.1 years (range: 18.1-60.0). Median body mass index (BMI) was 23.6 kg/sqm (range: 15.7-46.3). Initial median WBC was 11.8 G/L (range: 0.4-645) and 55 patients had CNS involvement (7.0%). A complete remission (CR) was achieved in 720/783 (92.0%). A resistance to first induction phase was observed in 36/738 (4.9%) patients evaluable for CR.A grade 3-4 liver toxicity was observed in 272 patients (34.6%), a grade 3-4 pancreatitis in 43 patients (5.5%), and a cerebral venous thrombosis (CVT) in 25 patients (3.3%). An older age was significantly associated with an increased incidence of liver toxicity but a lower incidence of CVT. Pancreatitis was not associated with age. A high BMI was associated with liver toxicity and pancreatitis. In multivariate analysis, age, BMI, CNS involvement, and BCP-phenotype were associated with liver toxicity; BMI and female gender were associated with pancreatitis.During induction phase, patients received 97.8% of ASPA scheduled dose, 99.0% if younger than 45 years old but only 84.8% if older (p<.0001). In comparison, no difference in the administration of myelosuppressive drugs (DNR, CPM) was observed. In multivariate analysis, patient-related variables associated with less than 90% of scheduled ASPA administration (41% of patients) were older age, high BMI, and high ECOG score. In this model, center enrollment volume but also inclusion time period were statistically associated with a higher rate of ASPA administration, suggesting a learning effect.Finally, covariates independently associated with induction failure were higher WBC (OR 1.04 [95%CI, 1.01-1.07]), slower bone marrow clearance at D8 (OR 0.07 [95%CI, 0.02-0.20]), lower ASPA injection number (OR 0.72 [95%CI, 0.60-0.85]), and lower VCR injection number (OR 0.69 [95%CI, 0.55-0.88]), excluding all other induction drug dose variation.
Conclusion
During ALL induction, most ASPA-related toxicities seen in adult patients are correlated to age and BMI. Experience in the management of ASPA administration may enhance protocol compliance and thus contribute to reduce induction failure risk.
Session topic: Acute lymphoblastic leukemia - Clinical 1
Keyword(s): ALL, L-asparaginase, Toxicity
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