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Trial record 68 of 89 for:    "Acute Lymphoblastic Leukemia, Childhood" | "Antineoplastic Agents, Hormonal"

Treatment of Acute Lymphoblastic Leukemia in Children

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00400946
Recruitment Status : Active, not recruiting
First Posted : November 17, 2006
Results First Posted : June 14, 2017
Last Update Posted : August 21, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Lewis B. Silverman, M.D., Dana-Farber Cancer Institute

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Drug/Agent Toxicity by Tissue/Organ
Leukemia
Interventions Drug: asparaginase
Drug: cyclophosphamide
Drug: cytarabine
Drug: dexamethasone
Drug: dexrazoxane hydrochloride
Drug: doxorubicin hydrochloride
Drug: etoposide
Drug: leucovorin calcium
Drug: mercaptopurine
Drug: methotrexate
Drug: methylprednisolone
Drug: pegaspargase
Drug: prednisolone
Drug: therapeutic hydrocortisone
Drug: vincristine sulfate
Radiation: radiation therapy
Enrollment 800
Recruitment Details Patients enrolled from April 22, 2005 to Dec 13, 2011.
Pre-assignment Details  
Arm/Group Title Intramuscular Native E Coli L-asparaginase (IM-EC) Intravenous PEG-asparaginase (IV-PEG) IM-EC [Directly Assigned] Ineligible for Randomization Expansion Cohort
Hide Arm/Group Description 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. 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. 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. 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.
Period Title: Overall Study
Started 231 232 42 51 244
Evaluable for CNS Directed-Treatment [1] 231 232 42 21 227
Evaluable for Day 18 Marrow Morphology [2] 158 161 19 13 152
Evaluable for Day 32 MRD [3] 166 167 33 12 168
Eligible and Treated [4] 231 232 42 46 243
Completed 217 221 40 4 206
Not Completed 14 11 2 47 38
Reason Not Completed
Ineligible             0             0             0             5             1
Induction Failure             0             0             0             11             8
Induction Death             0             0             0             13             3
Lost to Follow-up             1             1             0             0             1
Remission Death             1             1             0             0             1
Relapse             9             2             1             1             5
Transplant in CR1             0             0             0             10             1
Withdrawal by Subject             2             5             1             5             8
Clinical             1             2             0             2             9
Other             0             0             0             0             1
[1]
Patients who achieved an induction complete remission with an evaluable sample at diagnosis.
[2]
Patients who achieved an induction complete remission with an optional evaluable sample at day 18.
[3]
B cell patients who achieved an induction complete remission with an evaluable sample at day 32.
[4]
Ineligible: Burkitt's leuk diag (n=2), pr therapy (n=1), hyperbilirubinemia (n=1), w/d consent (n=2)
Arm/Group Title Intramuscular Native E Coli L-asparaginase (IM-EC) Intravenous PEG-asparaginase (IV-PEG) IM-EC [Directly Assigned] Ineligible for Randomization Expansion Cohort Total
Hide Arm/Group Description 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. 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. 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 231 232 42 51 244 800
Hide Baseline Analysis Population Description
The analysis dataset is comprised of all enrolled patients.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 231 participants 232 participants 42 participants 51 participants 244 participants 800 participants
<=18 years
231
 100.0%
232
 100.0%
42
 100.0%
51
 100.0%
244
 100.0%
800
 100.0%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 231 participants 232 participants 42 participants 51 participants 244 participants 800 participants
Female
111
  48.1%
97
  41.8%
21
  50.0%
21
  41.2%
107
  43.9%
357
  44.6%
Male
120
  51.9%
135
  58.2%
21
  50.0%
30
  58.8%
137
  56.1%
443
  55.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 231 participants 232 participants 42 participants 51 participants 244 participants 800 participants
Hispanic or Latino
40
  17.3%
48
  20.7%
3
   7.1%
13
  25.5%
48
  19.7%
152
  19.0%
Not Hispanic or Latino
165
  71.4%
170
  73.3%
35
  83.3%
34
  66.7%
180
  73.8%
584
  73.0%
Unknown or Not Reported
26
  11.3%
14
   6.0%
4
   9.5%
4
   7.8%
16
   6.6%
64
   8.0%
Age Classification  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 231 participants 232 participants 42 participants 51 participants 244 participants 800 participants
< 10 years old
176
  76.2%
165
  71.1%
35
  83.3%
26
  51.0%
196
  80.3%
598
  74.8%
>/= 10 years old
55
  23.8%
67
  28.9%
7
  16.7%
25
  49.0%
48
  19.7%
202
  25.3%
1.Primary Outcome
Title Asparaginase-Related Toxicity Rate
Hide Description 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.
Time Frame 30-week post-induction asparaginase treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of all randomized patients.
Arm/Group Title Intramuscular Native E Coli L-asparaginase (IM-EC) Intravenous PEG-asparaginase (IV-PEG)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 231 232
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
26
(20 to 32)
28
(22 to 34)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Intramuscular Native E Coli L-asparaginase (IM-EC), Intravenous PEG-asparaginase (IV-PEG)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .60
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
2.Secondary Outcome
Title 5-Year Disease-Free Survival
Hide Description 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.
Time Frame Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of all randomized patients.
Arm/Group Title Intramuscular Native E Coli L-asparaginase (IM-EC) Intravenous PEG-asparaginase (IV-PEG)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 231 232
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
.89
(.85 to .93)
.90
(.86 to .94)
3.Secondary Outcome
Title Post-Induction Nadir Serum Asparaginase Activity Level
Hide Description Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods.
Time Frame Samples for nadir serum asparaginase activity analyses were obtained before doses administered at weeks 5, 11, 17, 23 and 29 of post-induction asparaginase treatment.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of all randomized patients who consented to research studies with an evaluable sample for analysis of serum asparaginase activity at the respective post-induction assessment timepoints.
Arm/Group Title Intramuscular Native E Coli L-asparaginase (IM-EC) Intravenous PEG-asparaginase (IV-PEG)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 231 232
Mean (Standard Deviation)
Unit of Measure: IU/mL
Week 5 NSAA Level Number Analyzed 76 participants 78 participants
0.129  (0.108) 0.726  (0.322)
Week 11 NSAA Level Number Analyzed 69 participants 76 participants
0.143  (0.131) 0.773  (0.231)
Week 17 NSAA Level Number Analyzed 85 participants 80 participants
0.159  (0.161) 0.787  (0.303)
Week 23 NSAA Level Number Analyzed 75 participants 66 participants
0.180  (0.261) 0.757  (0.255)
Week 29 NSAA Level Number Analyzed 53 participants 69 participants
0.123  (0.102) 0.806  (0.313)
4.Secondary Outcome
Title Post-Induction Therapeutic Nadir Serum Asparaginase Activity Rate
Hide Description 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.
Time Frame Samples for nadir serum asparaginase activity analyses were obtained before doses administered at weeks 5, 11, 17, 23 and 29 of post-induction asparaginase treatment.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of all randomized patients who consented to research studies with a one post-induction evaluable sample for analysis of serum asparaginase activity.
Arm/Group Title Intramuscular Native E Coli L-asparaginase (IM-EC) Intravenous PEG-asparaginase (IV-PEG)
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 170 168
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
71
(63 to 77)
99
(96 to 99)
5.Secondary Outcome
Title Induction Infection Toxicity Rate
Hide Description 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.
Time Frame Assessed daily during remission induction days 4-32.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of eligible and treated patients. This excludes the 6 enrolled but ineligible patients. Rates in this overall study cohort will be compared against historical controls (in particular patients treated with a more intensive induction regimen).
Arm/Group Title Overall
Hide Arm/Group Description:
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 Number of Participants Analyzed 794
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
26
(23 to 30)
6.Secondary Outcome
Title Induction Serum Asparaginase Activity Level
Hide Description Serum asparaginase activity (NSAA) levels were estimated based on established methods.
Time Frame Samples for serum asparaginase activity analyses were obtained days 4, 11, 18 and 25 post one-dose of IV-PEG on day 7 of the induction phase.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of all randomized patients who consented to research studies with an evaluable sample for analysis of serum asparaginase activity at the respective induction assessment timepoints.
Arm/Group Title Overall
Hide Arm/Group Description:
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 Number of Participants Analyzed 794
Median (Inter-Quartile Range)
Unit of Measure: IU/mL
Day 4 NSAA Level Number Analyzed 317 participants
.694
(.556 to .868)
Day 11 NSAA Level Number Analyzed 348 participants
.505
(.306 to .632)
Day 18 NSAA Level Number Analyzed 294 participants
.211
(.150 to .259)
Day 25 NSAA Level Number Analyzed 298 participants
.048
(.025 to .076)
7.Secondary Outcome
Title Induction Therapeutic Nadir Serum Asparaginase Activity Rate
Hide Description 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.
Time Frame Samples for serum asparaginase activity analyses were obtained days 4, 11, 18 and 25 post one-dose of IV-PEG on day 7 of the induction phase.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of all randomized patients who consented to research studies with an evaluable sample for analysis of serum asparaginase activity at the respective induction assessment timepoints.
Arm/Group Title Overall
Hide Arm/Group Description:
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 Number of Participants Analyzed 794
Measure Type: Number
Unit of Measure: percentage of participants
Day 4 NSAA Rate Number Analyzed 317 participants
97
Day 11 NSAA Rate Number Analyzed 348 participants
96
Day 18 NSAA Rate Number Analyzed 294 participants
87
Day 25 NSAA Rate Number Analyzed 298 participants
12
8.Secondary Outcome
Title 5-Year Disease-Free Survival by MRD Day 32 Status
Hide Description 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.
Time Frame Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of B cell ALL patients who achieved an induction complete remission with an evaluable sample at day 32 for analysis of MRD.
Arm/Group Title Low Day 32 MRD Level High Day 32 MRD Level
Hide Arm/Group Description:
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.
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
Overall Number of Participants Analyzed 50 496
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
.79
(.60 to .86)
.90
(.87 to .93)
9.Secondary Outcome
Title 5-Year Disease-Free Survival by Bone Marrow Day 18 Status
Hide Description 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.
Time Frame Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of patients who achieved an induction complete remission with an evaluable sample at day 18 (optional submission) for analysis of marrow morphology.
Arm/Group Title M1 Day 18 Bone Marrow Status M2/M3 Day 18 Bone Marrow Status Hypocellular Day 18 Bone Marrow Status
Hide Arm/Group Description:
M1 marrow morphology at day 18 was defined as <5% blasts.
M2 marrow morphology at day 18 was defined as 5-24% blasts. M3 marrow morphology at day 18 was defined as >25% blasts.
Hypocellular marrow morphology at day 18 was defined as empty blasts.
Overall Number of Participants Analyzed 284 26 193
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
.89
(.85 to .92)
.78
(.54 to .90)
.88
(.82 to .92)
10.Secondary Outcome
Title 5-year Disease-Free Survival by CNS Directed Treatment Group
Hide Description 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.
Time Frame Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of patients who achieved an induction complete remission with an evaluable sample at diagnosis for analysis of CNS-directed therapy .
Arm/Group Title CNS-1 CNS-2 CNS-3 Traumatic Tap With Blasts Traumatic Tap Without Blasts
Hide Arm/Group Description:
CNS-1: no blast cells in cytospin, regardless of cerebrospinal fluid (CSF) count
CNS-2: 5 or fewer WBC on CSF cell count, with blasts on cytospin
CNS-3: more than 5 WBC on CSF cell count, with blasts on cytospin
Traumatic Tap with Blasts: with blast cells and >100 RBCs on a wet prep
Traumatic Tap without Blasts: without blast cells and >100 RBCs on a wet prep
Overall Number of Participants Analyzed 579 114 9 32 19
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
.89
(.87 to .92)
.89
(.82 to .94)
1.00 [1] 
(NA to NA)
.84
(.67 to .93)
.87
(.58 to .97)
[1]
NA-not applicable since all patients were disease-free at 5 years.
Time Frame Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups.
Adverse Event Reporting Description Reporting included (trt-related, all grades [G] unless specified): asparaginase-related allergy, symptomatic pancreatitis (>G1), thrombotic or bleeding complications requiring intervention (>G1), infections (>G2), symptomatic osteonecrosis (>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
 
Arm/Group Title Intramuscular Native E Coli L-asparaginase (IM-EC) Intravenous PEG-asparaginase (IV-PEG) Overall
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Intramuscular Native E Coli L-asparaginase (IM-EC) Intravenous PEG-asparaginase (IV-PEG) Overall
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/231 (0.43%)   1/232 (0.43%)   2/794 (0.25%) 
Show Serious Adverse Events Hide Serious Adverse Events
Intramuscular Native E Coli L-asparaginase (IM-EC) Intravenous PEG-asparaginase (IV-PEG) Overall
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   132/231 (57.14%)   142/232 (61.21%)   574/794 (72.29%) 
Blood and lymphatic system disorders       
Hematologic-other  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Hemolysis  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Hemoglobin  1  4/231 (1.73%)  0/232 (0.00%)  12/794 (1.51%) 
Febrile neutropenia  1  6/231 (2.60%)  7/232 (3.02%)  18/794 (2.27%) 
Cardiac disorders       
Atrial flutter  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Cardiac-other  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Left ventricular systolic dysfunction  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Sinus tachycardia  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Ventricular tachycardia  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Gastrointestinal disorders       
Cecum/appendix- hemorrhage  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Enteritis  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Nausea  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Necrosis- pancreas  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Oral cavity- pain  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Perforation- stomach  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Ulcer- anus  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Ulcer- duodenum  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Ulcer- esophagus  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Ulcer- gastric  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Varices (esophageal)- hemorrhage  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Colitis  1  1/231 (0.43%)  0/232 (0.00%)  2/794 (0.25%) 
Duodenum- hemorrhage  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Esophagitis  1  1/231 (0.43%)  0/232 (0.00%)  2/794 (0.25%) 
Lower GI- hemorrhage NOS  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Oral gums- pain  1  1/231 (0.43%)  1/232 (0.43%)  2/794 (0.25%) 
Perforation- small bowel NOS  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Vomiting  1  1/231 (0.43%)  0/232 (0.00%)  2/794 (0.25%) 
Constipation  1  1/231 (0.43%)  0/232 (0.00%)  3/794 (0.38%) 
Diarrhea w/o prior colostomy  1  1/231 (0.43%)  0/232 (0.00%)  3/794 (0.38%) 
Upper GI- hemorrhage NOS  1  0/231 (0.00%)  0/232 (0.00%)  3/794 (0.38%) 
Abdomen- pain  1  0/231 (0.00%)  2/232 (0.86%)  4/794 (0.50%) 
Ileus  1  0/231 (0.00%)  0/232 (0.00%)  4/794 (0.50%) 
Muco/stomatitis (symptom) oral cavity  1  2/231 (0.87%)  2/232 (0.86%)  7/794 (0.88%) 
Typhlitis  1  0/231 (0.00%)  2/232 (0.86%)  16/794 (2.02%) 
Pancreatitis  1  3/231 (1.30%)  9/232 (3.88%)  26/794 (3.27%) 
Muco/stomatitis by exam- oral cavity  1  15/231 (6.49%)  21/232 (9.05%)  100/794 (12.59%) 
General disorders       
Death - multiorgan failure  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Death - sudden death  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Edema limb  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Pain NOS  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Fatigue  1  1/231 (0.43%)  1/232 (0.43%)  2/794 (0.25%) 
Fever w/o neutropenia  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Pain-other  1  1/231 (0.43%)  0/232 (0.00%)  2/794 (0.25%) 
Extremity-lower (gait/walking)  1  1/231 (0.43%)  1/232 (0.43%)  6/794 (0.76%) 
Hepatobiliary disorders       
Liver dysfunction/failure  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Immune system disorders       
Allergic reaction  1  6/231 (2.60%)  14/232 (6.03%)  33/794 (4.16%) 
Infections and infestations       
Infection Gr0-2 neut- bladder  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Infection Gr0-2 neut- bronchus  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection Gr0-2 neut- cervix  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Infection Gr0-2 neut- dental-tooth  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection Gr0-2 neut- middle ear  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Infection Gr0-2 neut- muscle  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Infection Gr0-2 neut- soft tissue  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Infection Gr0-2 neut- spleen  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- brain  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- brain + spinal  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- dental-tooth  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- eye NOS  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- lens  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- lip/perioral  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- liver  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- paranasal  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- pleura  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- sinus  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- spinal cord  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- spleen  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- trachea  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- vein  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ unk ANC abdomen NOS  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ unk ANC colon  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ unk ANC lymphatic  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ unk ANC meninges  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ unk ANC skin (cellulitis)  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ unk ANC ungual (nails)  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ unk ANC upper airway NOS  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ unk ANC urinary tract NOS  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection Gr0-2 neut- abdomen  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Infection Gr0-2 neut- catheter  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Infection Gr0-2 neut- eye NOS  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Infection Gr0-2 neut- liver  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Infection Gr0-2 neut- peritoneal  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Infection Gr0-2 neut- wound  1  2/231 (0.87%)  0/232 (0.00%)  2/794 (0.25%) 
Infection w/ gr3-4 neut- anal/perianal  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Infection w/ gr3-4 neut- kidney  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Infection w/ gr3-4 neut- meninges  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Infection w/ gr3-4 neut- middle ear  1  1/231 (0.43%)  0/232 (0.00%)  2/794 (0.25%) 
Infection w/ gr3-4 neut- peritoneal  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Infection w/ gr3-4 neut- urinary tract  1  1/231 (0.43%)  0/232 (0.00%)  2/794 (0.25%) 
Infection w/ unk ANC bladder  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Infection w/ unk ANC lung  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Infection w/ unk ANC wound  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Infection Gr0-2 neut- urinary tract  1  2/231 (0.87%)  0/232 (0.00%)  4/794 (0.50%) 
Infection w/ gr3-4 neut- catheter relate  1  0/231 (0.00%)  0/232 (0.00%)  4/794 (0.50%) 
Infection w/ gr3-4 neut- upper airway  1  2/231 (0.87%)  1/232 (0.43%)  4/794 (0.50%) 
Infection w/ gr3-4 neut- wound  1  0/231 (0.00%)  1/232 (0.43%)  4/794 (0.50%) 
Infection w/ gr3-4 neut- lung  1  0/231 (0.00%)  1/232 (0.43%)  7/794 (0.88%) 
Infection Gr0-2 neut- skin  1  3/231 (1.30%)  2/232 (0.86%)  8/794 (1.01%) 
Infection-other  1  1/231 (0.43%)  3/232 (1.29%)  9/794 (1.13%) 
Infection Gr0-2 neut- lung  1  5/231 (2.16%)  2/232 (0.86%)  10/794 (1.26%) 
Infection w/ gr3-4 neut- skin  1  6/231 (2.60%)  1/232 (0.43%)  12/794 (1.51%) 
Colitis- infectious (e.g. C.diff)  1  1/231 (0.43%)  2/232 (0.86%)  13/794 (1.64%) 
Opportunistic infection lymphopenia>=gr1  1  5/231 (2.16%)  6/232 (2.59%)  15/794 (1.89%) 
Infection Gr 0-2 neut- blood  1  33/231 (14.29%)  30/232 (12.93%)  103/794 (12.97%) 
Infection w/ gr 3-4 neut- blood  1  25/231 (10.82%)  29/232 (12.50%)  234/794 (29.47%) 
Injury, poisoning and procedural complications       
Intra-op injury Other (Specify)  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Intra-op injury Pleura  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Surgical hemorrhage  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Wound - non-infectious  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Fracture  1  5/231 (2.16%)  1/232 (0.43%)  11/794 (1.39%) 
Investigations       
ADH secretion abnormality (eg SIADH)  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Alkaline phosphatase  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Coagulation-other  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Creatinine  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
INR  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
PTT  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Hypercholesterolemia  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Fibrinogen  1  0/231 (0.00%)  0/232 (0.00%)  3/794 (0.38%) 
Leukocytes  1  0/231 (0.00%)  0/232 (0.00%)  3/794 (0.38%) 
Metabolic/Laboratory-other  1  0/231 (0.00%)  1/232 (0.43%)  4/794 (0.50%) 
Neutrophils  1  1/231 (0.43%)  2/232 (0.86%)  6/794 (0.76%) 
Platelets  1  1/231 (0.43%)  0/232 (0.00%)  6/794 (0.76%) 
GGT  1  1/231 (0.43%)  1/232 (0.43%)  7/794 (0.88%) 
Bilirubin  1  1/231 (0.43%)  4/232 (1.72%)  16/794 (2.02%) 
AST- SGOT  1  4/231 (1.73%)  8/232 (3.45%)  28/794 (3.53%) 
Amylase  1  5/231 (2.16%)  6/232 (2.59%)  37/794 (4.66%) 
ALT- SGPT  1  9/231 (3.90%)  10/232 (4.31%)  48/794 (6.05%) 
Lipase  1  12/231 (5.19%)  10/232 (4.31%)  49/794 (6.17%) 
Metabolism and nutrition disorders       
Hypoalbuminemia  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Iron overload  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Urinary electrolyte wasting  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Hyperkalemia  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Hyperuricemia  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Anorexia  1  2/231 (0.87%)  0/232 (0.00%)  4/794 (0.50%) 
Dehydration  1  1/231 (0.43%)  0/232 (0.00%)  4/794 (0.50%) 
Hypophosphatemia  1  1/231 (0.43%)  1/232 (0.43%)  4/794 (0.50%) 
Tumor lysis syndrome  1  0/231 (0.00%)  0/232 (0.00%)  4/794 (0.50%) 
Hypocalcemia  1  0/231 (0.00%)  0/232 (0.00%)  7/794 (0.88%) 
Hypoglycemia  1  4/231 (1.73%)  1/232 (0.43%)  7/794 (0.88%) 
Hyponatremia  1  1/231 (0.43%)  2/232 (0.86%)  11/794 (1.39%) 
Hypokalemia  1  8/231 (3.46%)  5/232 (2.16%)  22/794 (2.77%) 
Hyperglycemia  1  6/231 (2.60%)  1/232 (0.43%)  25/794 (3.15%) 
Hypertriglyceridemia  1  12/231 (5.19%)  20/232 (8.62%)  69/794 (8.69%) 
Musculoskeletal and connective tissue disorders       
Back- pain  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Joint- pain  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Muscular/skeletal hypoplasia  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Nonneuropathic lower extr muscle weak  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Osteoporosis  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Soft tissue necrosis- extremity lower  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Bone- pain  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Extremity-limb- pain  1  1/231 (0.43%)  1/232 (0.43%)  5/794 (0.63%) 
Osteonecrosis (avascular necrosis)  1  6/231 (2.60%)  6/232 (2.59%)  15/794 (1.89%) 
Nervous system disorders       
CNS cerebrovascular ischemia  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Head/headache  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Speech impairment  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Syncope  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Myelitis  1  0/231 (0.00%)  1/232 (0.43%)  3/794 (0.38%) 
Neurologic-other  1  1/231 (0.43%)  1/232 (0.43%)  3/794 (0.38%) 
Neuropathy-sensory  1  2/231 (0.87%)  0/232 (0.00%)  4/794 (0.50%) 
CNS- hemorrhage  1  2/231 (0.87%)  1/232 (0.43%)  6/794 (0.76%) 
Encephalopathy  1  2/231 (0.87%)  0/232 (0.00%)  6/794 (0.76%) 
Neuropathy-motor  1  2/231 (0.87%)  3/232 (1.29%)  14/794 (1.76%) 
Seizure  1  6/231 (2.60%)  6/232 (2.59%)  22/794 (2.77%) 
Psychiatric disorders       
Anxiety  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Insomnia  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Personality  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Agitation  1  0/231 (0.00%)  2/232 (0.86%)  2/794 (0.25%) 
Confusion  1  1/231 (0.43%)  0/232 (0.00%)  2/794 (0.25%) 
Depression  1  1/231 (0.43%)  1/232 (0.43%)  3/794 (0.38%) 
Psychosis  1  0/231 (0.00%)  1/232 (0.43%)  3/794 (0.38%) 
Renal and urinary disorders       
Kidney- pain  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Obstruction-ureteral  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Perforation- appendix  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Renal failure  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Reproductive system and breast disorders       
Pelvic- pain  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Respiratory, thoracic and mediastinal disorders       
Bronchopulmonary- hemorrhage  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Cough  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Lung- hemorrhage  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
(ARDS)  1  1/231 (0.43%)  0/232 (0.00%)  2/794 (0.25%) 
Dyspnea  1  1/231 (0.43%)  0/232 (0.00%)  2/794 (0.25%) 
Pleural effusion (non-malignant)  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Pulmonary/Upper Respiratory-other  1  0/231 (0.00%)  1/232 (0.43%)  3/794 (0.38%) 
Hypoxia  1  0/231 (0.00%)  0/232 (0.00%)  6/794 (0.76%) 
Pneumonitis/pulmonary infiltrates  1  3/231 (1.30%)  1/232 (0.43%)  9/794 (1.13%) 
Skin and subcutaneous tissue disorders       
Pruritus/itching  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Skin breakdown/decubitus ulcer  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Skin-other  1  1/231 (0.43%)  0/232 (0.00%)  3/794 (0.38%) 
Vascular disorders       
Acute vascular leak syndrome  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Chyle or lymph leakage  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Peripheral arterial ischemia  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Hypotension  1  2/231 (0.87%)  3/232 (1.29%)  10/794 (1.26%) 
Vascular access-Thrombosis/embolism  1  8/231 (3.46%)  2/232 (0.86%)  15/794 (1.89%) 
Hypertension  1  2/231 (0.87%)  3/232 (1.29%)  39/794 (4.91%) 
Thrombosis/thrombus/embolism  1  10/231 (4.33%)  12/232 (5.17%)  55/794 (6.93%) 
1
Term from vocabulary, CTCAE (3.0)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Intramuscular Native E Coli L-asparaginase (IM-EC) Intravenous PEG-asparaginase (IV-PEG) Overall
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   40/231 (17.32%)   38/232 (16.38%)   118/794 (14.86%) 
Blood and lymphatic system disorders       
Hemoglobin  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Febrile neutropenia  1  3/231 (1.30%)  2/232 (0.86%)  7/794 (0.88%) 
Cardiac disorders       
Sinus tachycardia  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Left ventricular systolic dysfunction  1  0/231 (0.00%)  0/232 (0.00%)  3/794 (0.38%) 
Ear and labyrinth disorders       
Otitis- middle ear (non-infectious)  1  0/231 (0.00%)  3/232 (1.29%)  3/794 (0.38%) 
Gastrointestinal disorders       
Enteritis  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Muco/stomatitis (symptom) anus  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Oral cavity- pain  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Perforation- stomach  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Diarrhea w/o prior colostomy  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Ulcer- anus  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Colitis  1  0/231 (0.00%)  1/232 (0.43%)  4/794 (0.50%) 
Constipation  1  0/231 (0.00%)  0/232 (0.00%)  4/794 (0.50%) 
Typhlitis  1  0/231 (0.00%)  0/232 (0.00%)  4/794 (0.50%) 
Muco/stomatitis (symptom) oral cavity  1  0/231 (0.00%)  1/232 (0.43%)  5/794 (0.63%) 
Muco/stomatitis by exam- oral cavity  1  7/231 (3.03%)  7/232 (3.02%)  31/794 (3.90%) 
Pancreatitis  1  15/231 (6.49%)  17/232 (7.33%)  61/794 (7.68%) 
General disorders       
Chest/thoracic pain NOS  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Extremity-lower (gait/walking)  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Fatigue  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Hypothermia  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Fever w/o neutropenia  1  1/231 (0.43%)  4/232 (1.72%)  5/794 (0.63%) 
Pain-other  1  1/231 (0.43%)  1/232 (0.43%)  5/794 (0.63%) 
Immune system disorders       
Allergy-other  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Allergic reaction  1  8/231 (3.46%)  13/232 (5.60%)  33/794 (4.16%) 
Infections and infestations       
Infection Gr0-2 neut- bladder  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Infection Gr0-2 neut- bronchus  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Infection Gr0-2 neut- external ear  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection Gr0-2 neut- eye NOS  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection Gr0-2 neut- kidney  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Infection Gr0-2 neut- lung  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Infection Gr0-2 neut- lymphatic  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Infection Gr0-2 neut- meninges  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- bronchus  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- catheter relate  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- eye NOS  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- larynx  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- middle ear  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- peritoneal  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- pharynx  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- urinary tract  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ gr3-4 neut- wound  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Infection w/ unk ANC catheter related  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ unk ANC skin (cellulitis)  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ unk ANC ungual (nails)  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ unk ANC upper airway NOS  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection w/ unk ANC wound  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Infection Gr0-2 neut- conjunctiva  1  1/231 (0.43%)  1/232 (0.43%)  2/794 (0.25%) 
Infection Gr0-2 neut- middle ear  1  1/231 (0.43%)  1/232 (0.43%)  2/794 (0.25%) 
Infection Gr0-2 neut- mucosa  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Infection Gr0-2 neut- ungual  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Infection Gr0-2 neut- upper airway  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Infection Gr0-2 neut- wound  1  1/231 (0.43%)  0/232 (0.00%)  2/794 (0.25%) 
Infection w/ unk ANC lung  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Infection w/ unk ANC urinary tract NOS  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Infection Gr0-2 neut- nose  1  2/231 (0.87%)  0/232 (0.00%)  3/794 (0.38%) 
Infection Gr0-2 neut- sinus  1  0/231 (0.00%)  1/232 (0.43%)  3/794 (0.38%) 
Infection Gr0-2 neut- skin  1  1/231 (0.43%)  1/232 (0.43%)  3/794 (0.38%) 
Infection Gr0-2 neut- urinary tract  1  0/231 (0.00%)  1/232 (0.43%)  3/794 (0.38%) 
Infection w/ gr 3-4 neut- blood  1  0/231 (0.00%)  1/232 (0.43%)  3/794 (0.38%) 
Infection Gr0-2 neut- oral cavity  1  0/231 (0.00%)  2/232 (0.86%)  4/794 (0.50%) 
Infection-other  1  2/231 (0.87%)  0/232 (0.00%)  4/794 (0.50%) 
Colitis- infectious (e.g. C.diff)  1  1/231 (0.43%)  1/232 (0.43%)  6/794 (0.76%) 
Opportunistic infection lymphopenia>=gr1  1  5/231 (2.16%)  1/232 (0.43%)  10/794 (1.26%) 
Infection Gr 0-2 neut- blood  1  12/231 (5.19%)  9/232 (3.88%)  32/794 (4.03%) 
Injury, poisoning and procedural complications       
Chemoradiation dermatitis  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Fracture  1  37/231 (16.02%)  38/232 (16.38%)  118/794 (14.86%) 
Investigations       
Creatinine  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Lipase  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Neutrophils  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Weight loss  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
ALT- SGPT  1  1/231 (0.43%)  0/232 (0.00%)  4/794 (0.50%) 
Amylase  1  1/231 (0.43%)  2/232 (0.86%)  4/794 (0.50%) 
AST- SGOT  1  2/231 (0.87%)  0/232 (0.00%)  6/794 (0.76%) 
Metabolism and nutrition disorders       
Dehydration  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Hypoglycemia  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Hyperglycemia  1  0/231 (0.00%)  0/232 (0.00%)  2/794 (0.25%) 
Hypertriglyceridemia  1  3/231 (1.30%)  7/232 (3.02%)  14/794 (1.76%) 
Musculoskeletal and connective tissue disorders       
Muscle- pain  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Musculoskeletal/soft tissue-other  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Nonneuropathic lower extr muscle weak  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Back- pain  1  0/231 (0.00%)  1/232 (0.43%)  2/794 (0.25%) 
Joint- pain  1  1/231 (0.43%)  0/232 (0.00%)  2/794 (0.25%) 
Bone- pain  1  1/231 (0.43%)  0/232 (0.00%)  3/794 (0.38%) 
Extremity-limb- pain  1  2/231 (0.87%)  1/232 (0.43%)  4/794 (0.50%) 
Osteonecrosis (avascular necrosis)  1  15/231 (6.49%)  15/232 (6.47%)  45/794 (5.67%) 
Nervous system disorders       
Neurologic-other  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Speech impairment  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Syncope  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
CNS- hemorrhage  1  4/231 (1.73%)  0/232 (0.00%)  4/794 (0.50%) 
Neuropathy-sensory  1  1/231 (0.43%)  0/232 (0.00%)  4/794 (0.50%) 
Neuropathy-motor  1  0/231 (0.00%)  0/232 (0.00%)  5/794 (0.63%) 
Seizure  1  5/231 (2.16%)  5/232 (2.16%)  17/794 (2.14%) 
Psychiatric disorders       
Agitation  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Psychosis  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Personality  1  1/231 (0.43%)  0/232 (0.00%)  2/794 (0.25%) 
Respiratory, thoracic and mediastinal disorders       
Atelectasis  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Cough  1  1/231 (0.43%)  0/232 (0.00%)  1/794 (0.13%) 
Hypoxia  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Pulmonary/Upper Respiratory-other  1  0/231 (0.00%)  1/232 (0.43%)  1/794 (0.13%) 
Pneumonitis/pulmonary infiltrates  1  0/231 (0.00%)  2/232 (0.86%)  2/794 (0.25%) 
Skin and subcutaneous tissue disorders       
Erythema multiforme  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Ulceration  1  0/231 (0.00%)  0/232 (0.00%)  1/794 (0.13%) 
Skin-other  1  2/231 (0.87%)  3/232 (1.29%)  5/794 (0.63%) 
Vascular disorders       
Hypotension  1  1/231 (0.43%)  1/232 (0.43%)  2/794 (0.25%) 
Vascular access-Thrombosis/embolism  1  1/231 (0.43%)  3/232 (1.29%)  6/794 (0.76%) 
Thrombosis/thrombus/embolism  1  9/231 (3.90%)  4/232 (1.72%)  22/794 (2.77%) 
Hypertension  1  8/231 (3.46%)  4/232 (1.72%)  58/794 (7.30%) 
1
Term from vocabulary, CTCAE (3.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Lewis B. Silverman, MD
Organization: Dana-Farber Cancer Institute
Phone: 617.632.6191
EMail: Lewis_Silverman@dfci.harvard.edu
Layout table for additonal information
Responsible Party: Lewis B. Silverman, M.D., Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT00400946     History of Changes
Obsolete Identifiers: NCT00165165
Other Study ID Numbers: 05-001 / CDR0000513019
P01CA068484 ( U.S. NIH Grant/Contract )
P30CA006516 ( U.S. NIH Grant/Contract )
DFCI-05001 ( Other Identifier: DFCI IRB Protocol Number )
First Submitted: November 16, 2006
First Posted: November 17, 2006
Results First Submitted: January 17, 2017
Results First Posted: June 14, 2017
Last Update Posted: August 21, 2018