Dataset Information

Efficacy and toxicity of reduced vs. standard dose pegylated asparaginase in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia.

ABSTRACT: Incorporation of asparaginase (ASNase) and pegylated asparaginase (PEG-ASP) into pediatric-inspired regimens for adults with acute lymphoblastic leukemia (ALL) has led to improved treatment outcomes albeit with increased toxicities. This study compared the efficacy and safety of the Children's Oncology Group standard PEG-ASP (SD) dosing (>1000, median 2500?IU/m2/dose) in adult Philadelphia chromosome-negative ALL patients receiving multiagent chemotherapy vs reduced dose PEG-ASP (RED) (?1000, median 500?IU/m2/dose) during induction. 51 patients were included, 26 in RED and 25 in SD (median age 49 vs 37?years, p?=?.027). Median day 7 ASNase activity level for RED was 0.16?IU/mL. All 11 patients who received PEG-ASP 1000?IU/m2 and 9/11 patients who received 500?IU/m2 achieved an ASNase level ?0.1?IU/mL. Patients receiving RED experienced fewer total grade 3/4 toxicities during induction compared to SD (p?=?.02) while still attaining therapeutic ASNase levels. RED permits safer ASNase use in adults with ALL and should be tested in a larger cohort prospectively.

SUBMITTER: Derman BA

PROVIDER: S-EPMC7028458 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Efficacy and toxicity of reduced vs. standard dose pegylated asparaginase in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia.

Derman Benjamin A BA Streck Mitchell M Wynne Joseph J Christ Trevor N TN Curran Emily E Stock Wendy W Knoebel Randall W RW

Leukemia & lymphoma 20191104 3

Incorporation of asparaginase (ASNase) and pegylated asparaginase (PEG-ASP) into pediatric-inspired regimens for adults with acute lymphoblastic leukemia (ALL) has led to improved treatment outcomes albeit with increased toxicities. This study compared the efficacy and safety of the Children's Oncology Group standard PEG-ASP (SD) dosing (>1000, median 2500 IU/m<sup>2</sup>/dose) in adult Philadelphia chromosome-negative ALL patients receiving multiagent chemotherapy vs reduced dose PEG-ASP (RED) ...[more]

PMID: 31680584

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Project description:IntroductionEfficacy of ponatinib-based treatment for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) has not been compared to imatinib-based treatments in head-to-head clinical trials. We evaluated its efficacy versus imatinib-based regimens using a matching adjusted indirect comparison.MethodsTwo ponatinib studies were used: the phase 2 MDACC study of ponatinib + hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in adult patients and the phase 2 GIMEMA LAL1811 study of ponatinib + steroids in patients > 60 years/unfit for intensive chemotherapy and stem cell transplant. Studies on imatinib as first-line treatment in adults with Ph + ALL were identified using a systematic literature search. Population adjustment was based on the prognostic factors and effect modifiers identified by clinical experts. Hazard ratios (HRs) were calculated for overall survival (OS) and odds ratios (ORs) for complete molecular response (CMR).ResultsThe systematic literature search identified two studies (GRAAPH-2005 and NCT00038610) reporting the efficacy of first-line imatinib + hyper-CVAD and one study reporting the efficacy of first-line imatinib monotherapy induction + imatinib-based consolidation (CSI57ADE10). Ponatinib + hyper-CVAD prolonged OS and gave a higher CMR rate than imatinib + hyper-CVAD. The adjusted HR [95% confidence interval (CI)] for OS was 0.35 (0.17-0.74) for MDACC vs. GRAAPH-2005 and 0.35 (0.18-0.70) for MDACC vs. NCT00038610; the adjusted OR (95% CI) for CMR was 12.11 (3.77-38.87) for MDACC vs. GRAAPH-2005 and 5.65 (2.02-15.76) for MDACC vs. NCT00038610. Ponatinib + steroids prolonged OS and gave a higher CMR rate than imatinib monotherapy induction + imatinib-containing consolidation. The adjusted HR (95% CI) for OS was 0.24 (0.09-0.64) and the adjusted OR (95% CI) for CMR was 6.20 (1.60-24.00) for GIMEMA LAL1811 vs. CSI57ADE10.ConclusionIn adults with newly diagnosed Ph + ALL, first-line treatment with ponatinib was associated with better outcomes than first-line treatment with imatinib.

Project description:BackgroundL-asparaginase (L-ASP) is a key component of acute lymphoblastic leukemia (ALL) treatment, but its use in clinical practice raises challenges to clinicians due to a relatively high incidence of drug-related adverse events, mainly in adult patients. In the past years the use of ASP in adult population has been mainly limited due to a poor knowledge of its safety profile and to an approximate management of ASP-related toxicity. Recently the development of pediatric-inspired treatment protocols for adult ALL has led to a wider use of ASP and since 2010 in Italy three national treatment protocols including Pegylated asparaginase (Peg-ASP) have been sequentially developed for adolescents, young adults and adults with Philadelphia-negative (Ph-) ALL.MethodsWith the aim to better understand the approach adopted in Italian centers for the management and prevention of Peg-ASP toxicity in adult ALL and to provide practical, consensus-based recommendations, a board of 6 Italian clinicians, with known expertise in adult ALL, designed 41 consensus statements on current challenges on the management of Peg-ASP associated toxicity. A group of 19 clinical experts in the field then rated these statements using the 5-point Likert-type scale (1 = strongly disagree; 5 = strongly agree).ResultsThe main Peg-ASP related issues identified by the board included: 1) clinician's attitudes; 2) toxicity profile; 3) hypersensitivity reactions; 4) hepatic toxicity; 5) hepatic and/or metabolic toxicity; 6) hemorrhagic/thrombotic toxicity; 7) pancreatitis; 8) metabolic toxicity management and prevention; 9) activity levels monitoring. Overall, participants agreed on most statements, except those addressing the potential contraindications to the treatment with Peg-ASP, such as patients with a diagnosis of chronic liver disease or the subsequent administrations of the drug in patients who had previously developed chemical pancreatitis or severe metabolic toxicity. Participants agreed that adult patients with ALL should receive Peg-Asp because this drug is essential to improve treatment results.ConclusionsThe panel agreed that a critical evaluation of specific risk factors for each patient is crucial in order to reduce the risk of adverse events and specific advices in the management of Peg-ASP toxicities are reported.

Dataset Information

Efficacy and toxicity of reduced vs. standard dose pegylated asparaginase in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia.

Publications

Efficacy and toxicity of reduced vs. standard dose pegylated asparaginase in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia.

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