Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.

Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.

Intramuscular Native E Coli L-asparaginase (IM-EC)

Intravenous PEG-asparaginase (IV-PEG)

Ph+ ALL patients did not participate in asparaginase randomization but were directly assigned to receive intramuscular E coli L-asparaginase during post-induction therapy. Patients who were eligible but declined randomization were also directly assigned to receive intramuscular E coli L-asparaginase.

IM-EC [Directly Assigned]

All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who did not achieve complete remission and were not assigned a final risk group by the end of the induction phase of treatment were not eligible for randomization. Patients who developed severe pancreatitis (defined as symptoms persisting for >72 h) during induction were not eligible for randomization and received no further doses of asparaginase. Patients who had hypersensitivity to intravenous PEG-asparaginase during induction were also ineligible for randomization, but received twice-weekly IM-EC (25 000 IU/m2) during the post-induction treatment phases.

Ineligible for Randomization

Patients were enrolled in an expansion cohort to determine the prognostic significance of response to remission induction chemotherapy as measured by morphologic and minimal residual disease (MRD), and to further evaluate the efficacy of patients by final risk classification.

Expansion Cohort

Total

Sex: Female, Male

Ethnicity (NIH/OMB)

Age Classification

Asparaginase-related toxicity rate is defined as the percentage of patients who experience allergy (all grades), symptomatic pancreatitis (grade 2 or worse), thrombotic or bleeding complications requiring intervention (grade 2 or worse) with treatment attribution of possibly, probably or definite based on CTCAEv3.

Asparaginase-Related Toxicity Rate

Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.

5-Year Disease-Free Survival

Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods.

Post-Induction Nadir Serum Asparaginase Activity Level

Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods. Post-Induction therapeutic NSAA rate is defined as the percentage of patients achieving a NSAA level above 0.1 IU/mL ever during post-induction therapy.

Post-Induction Therapeutic Nadir Serum Asparaginase Activity Rate

Infection toxicity rate is defined as the percentage of patients who experience bacterial or fungal infection of grade 3 or higher with treatment attribution of possibly, probably or definite based on CTCAEv3 during remission induction phase of combination chemotherapy.

Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization wherein patients received either E. coli L-asparaginase or peg-asparaginase. Standard risk and high-risk patients began post-induction randomized asparaginase therapy at the start of the CNS phase, whereas very high-risk patients began asparaginase therapy on day 8 of consolidation phase IC. Patients who did not achieve complete remission by the end of the induction phase were not eligible for randomization, were removed from protocol treatment, and received alternative therapy according to the discretion of their treating physician. Further details are provided in the study description section.

Overall

Induction Infection Toxicity Rate

Serum asparaginase activity (NSAA) levels were estimated based on established methods.

Induction Serum Asparaginase Activity Level

Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods. Induction therapeutic NSAA rate is defined as the percentage of patients achieving a NSAA level above 0.1 IU/mL at a given timepoint.

Induction Therapeutic Nadir Serum Asparaginase Activity Rate

Low end-induction (day 32) minimal residual disease (MRD) evaluated was defined as <0.001. This MRD classification was one component of determining final risk classification. Peripheral blood samples were collected for evaluation of MRD using PCR methods.

Low Day 32 MRD Level

High end-induction (day 32) minimal residual disease (MRD) evaluated was defined as >/=0.001. This MRD classification was one component of determining final risk classification. Peripheral blood samples were collected for evaluation of MRD using PCR methods

High Day 32 MRD Level

5-Year Disease-Free Survival by MRD Day 32 Status

M1 marrow morphology at day 18 was defined as <5% blasts.

M1 Day 18 Bone Marrow Status

M2 marrow morphology at day 18 was defined as 5-24% blasts. M3 marrow morphology at day 18 was defined as >25% blasts.

M2/M3 Day 18 Bone Marrow Status

Hypocellular marrow morphology at day 18 was defined as empty blasts.

Hypocellular Day 18 Bone Marrow Status

5-Year Disease-Free Survival by Bone Marrow Day 18 Status

CNS-1: no blast cells in cytospin, regardless of cerebrospinal fluid (CSF) count

CNS-1

CNS-2: 5 or fewer WBC on CSF cell count, with blasts on cytospin

CNS-2

CNS-3: more than 5 WBC on CSF cell count, with blasts on cytospin

CNS-3

Traumatic Tap with Blasts: with blast cells and >100 RBCs on a wet prep

Traumatic Tap With Blasts

Traumatic Tap without Blasts: without blast cells and >100 RBCs on a wet prep

pancreatitis/tyrosine

Treatment of Acute Lymphoblastic Leukemia in Children

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