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Trial record 7 of 89 for:    "Acute Lymphoblastic Leukemia, Childhood" | "Antineoplastic Agents, Hormonal"

Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

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: NCT00103285
Recruitment Status : Completed
First Posted : February 8, 2005
Results First Posted : July 11, 2018
Last Update Posted : July 11, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions B-cell Childhood Acute Lymphoblastic Leukemia
Untreated Childhood Acute Lymphoblastic Leukemia
Interventions Drug: doxorubicin hydrochloride
Radiation: 3-dimensional conformal radiation therapy
Drug: cytarabine
Drug: dexamethasone
Drug: pegaspargase
Drug: methotrexate
Drug: leucovorin calcium
Drug: mercaptopurine
Drug: cyclophosphamide
Drug: thioguanine
Drug: vincristine sulfate
Enrollment 5377
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Group 0 Induction Therapy Group 1-SR-low ALL, Arm I-combination Chemotherapy Group 1-SR-low ALL, Arm II-combination Chemotherapy Group 2-SR-avg ALL, Arm I-combination Chemotherapy Group 2-SR-avg ALL, Arm II-combination Chemotherapy Group 2-SR-avg ALL, Arm III-combination Chemotherapy Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Group 3-SR-high ALL, Combination Chemotherapy
Hide Arm/Group Description

All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

vincristine sulfate: Given IV

Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive experimental consolidation therapy (vincristine sulfate, mercaptopurine, MTX, leucovorin calcium and pegaspargase), experimental interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine, MTX and pegaspargase), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine & vincristine sulfate, pegaspargase, methotrexate. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (2 courses - vincristine sulfate, methotrexate and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (2 courses - vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, methotrexate. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

3-dimensional conformal radiation therapy: Some patients undergo cranial radiotherapy

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine

Period Title: Induction
Started 5377 0 0 0 0 0 0 0
Completed 4028 0 0 0 0 0 0 0
Not Completed 1349 0 0 0 0 0 0 0
Reason Not Completed
Adverse Event             14             0             0             0             0             0             0             0
Death             24             0             0             0             0             0             0             0
Physician Decision             103             0             0             0             0             0             0             0
Withdrawal by Subject             1             0             0             0             0             0             0             0
Ineligible             43             0             0             0             0             0             0             0
Refusal             906             0             0             0             0             0             0             0
Other             258             0             0             0             0             0             0             0
Period Title: Response Assignment
Started 0 939 937 503 509 249 248 643
Completed 0 807 853 441 425 201 199 523
Not Completed 0 132 84 62 84 48 49 120
Reason Not Completed
Adverse Event             0             8             3             2             3             1             1             2
Death             0             5             2             2             3             1             0             8
Lost to Follow-up             0             9             5             5             1             2             2             5
Physician Decision             0             13             14             9             13             7             4             35
Protocol Violation             0             2             0             0             0             0             0             0
Withdrawal by Subject             0             4             1             1             2             2             0             2
Ineligible             0             8             6             2             0             3             1             5
Refusal             0             53             5             3             25             15             30             10
Other             0             30             48             38             37             17             11             53
Arm/Group Title Group 0 Induction Therapy
Hide Arm/Group Description

All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

vincristine sulfate: Given IV

Overall Number of Baseline Participants 5377
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5377 participants
<=18 years
5377
 100.0%
Between 18 and 65 years
0
   0.0%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 5377 participants
4.45  (2.10)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5377 participants
Female
2489
  46.3%
Male
2888
  53.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5377 participants
Hispanic or Latino
1097
  20.4%
Not Hispanic or Latino
4038
  75.1%
Unknown or Not Reported
242
   4.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5377 participants
American Indian or Alaska Native
36
   0.7%
Asian
253
   4.7%
Native Hawaiian or Other Pacific Islander
24
   0.4%
Black or African American
326
   6.1%
White
4046
  75.2%
More than one race
0
   0.0%
Unknown or Not Reported
692
  12.9%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 5377 participants
5377
1.Primary Outcome
Title Event-free Survival (EFS) for SR-Average ALL Patients
Hide Description EFS for SR-Average with standard and Intensified Consolidation. Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.
Time Frame 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
Only eligible patients are included in this population. Populations are based on enrollments for all four arms initially, and then only for Arms I and II (standard therapy) once Arms III and IV (intensified therapy) were closed to accrual.
Arm/Group Title Group 2-SR-avg ALL, Arm I-combination Chemotherapy Group 2-SR-avg ALL, Arm II-combination Chemotherapy Group 2-SR-avg ALL, Arm III-combination Chemotherapy Group 2-SR-avg ALL, Arm IV-combination Chemotherapy
Hide Arm/Group Description:

Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Overall Number of Participants Analyzed 500 509 245 246
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent probability
Standard and Intensified therapy Number Analyzed 244 participants 249 participants 245 participants 246 participants
83.82
(78.86 to 88.78)
88.89
(84.79 to 92.99)
88.34
(83.99 to 92.69)
90.51
(86.55 to 94.47)
Standard therapy Number Analyzed 500 participants 509 participants 0 participants 0 participants
87.41
(83.63 to 91.19)
88.29
(84.76 to 91.82)
2.Primary Outcome
Title Event-free Survival (EFS) for SR-Low Patients
Hide Description Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.
Time Frame 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
Only eligible patients are included in the analysis.
Arm/Group Title SR-low ALL, Arm I-combination Chemotherapy SR-low ALL, Arm II-combination Chemotherapy
Hide Arm/Group Description:

Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive experimental consolidation therapy (vincristine sulfate, mercaptopurine, MTX, leucovorin calcium and pegaspargase), experimental interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine, MTX and pegaspargase), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Overall Number of Participants Analyzed 928 929
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percent probability
95.22
(93.6 to 96.9)
93.96
(92.1 to 95.8)
3.Secondary Outcome
Title Health-related Quality of Life Relative to Physical, Social and Emotional Impairment
Hide Description To identify potentially modifiable factors associated with impaired health related quality of life (HRQOL) at different periods of therapy in the patients who are SR-average enrolled on the standard risk ALL study.Standardized scores will be computed for child function using the gender and age-adjusted scores available from normative data from a healthy population of about 10,000 children. The various domains of family functioning will be assessed using well-validated instruments and analyzed as a dichotomous variable (impaired vs. non-impaired family functioning). Multiple regression analysis will be used to test the effect of family functioning (adjusted for therapy given, age at diagnosis, gender, socioeconomic status and other factors) on child function.
Time Frame At 1, 6 and 12 months after diagnosis and, 3 months post-therapy
Hide Outcome Measure Data
Hide Analysis Population Description
This analysis is restricted to the 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites, who consented to and completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning).
Arm/Group Title Induction Therapy
Hide Arm/Group Description:
All patients for induction therapy.
Overall Number of Participants Analyzed 160
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
Physical Impairment 1 mth after diagnosis
76.39
(68.6 to 83.1)
Physical Impairment 6 mths after diagnosis
42.75
(34.2 to 51.7)
Physical Impairment 12 mths after diagnosis
29.41
(21.9 to 37.8)
Physical Impairment 3 mths post therapy
27.84
(19.2 to 37.9)
Social Impairment 1 mth after diagnosis
43.36
(35.1 to 51.9)
Social Impairment 6 mths after diagnosis
23.66
(16.7 to 31.9)
Social Impairment 12 mths after diagnosis
23.53
(16.7 to 31.6)
Social Impairment 3 mths post-therapy
25.77
(17.4 to 35.7)
Emotional Impairment 1 mth after diagnosis
38.89
(30.9 to 47.4)
Emotional Impairment 6 mths after diagnosis
17.56
(11.5 to 25.2)
Emotional Impairment 12 mths after diagnosis
13.97
(8.6 to 21.0)
Emotional Impairment 3 mths post-therapy
8.25
(3.6 to 15.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Induction Therapy
Comments Physical Functioning: Parents of 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning) and Family Assessment Device-General Functioning (FAD-GF) at 1, 6 and 12 months after diagnosis, and 3 months post-therapy.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 5.17
Confidence Interval (2-Sided) 95%
1.61 to 16.63
Estimation Comments Odds Ratios in this Statistical Analysis corresponds to all four time points.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Induction Therapy
Comments Social Functioning: Parents of 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning) and Family Assessment Device-General Functioning (FAD-GF) at 1, 6 and 12 months after diagnosis, and 3 months post-therapy.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.99
Confidence Interval (2-Sided) 95%
1.21 to 3.27
Estimation Comments Odds Ratios in this Statistical Analysis corresponds to all four time points
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Induction Therapy
Comments Parents of 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning) and Family Assessment Device-General Functioning (FAD-GF) at 1, 6 and 12 months after diagnosis, and 3 months post-therapy.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.85
Confidence Interval (2-Sided) 95%
1.03 to 3.34
Estimation Comments Odds Ratios in this Statistical Analysis corresponds to all four time points
4.Secondary Outcome
Title Event-Free Survival Probability According to MRD Status End Induction (Day 29)
Hide Description Event-Free survival by Day 29 MRD status (negative vs positive), Event Free Probability (time from study entry to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.
Time Frame MRD at Day 29 of therapy
Hide Outcome Measure Data
Hide Analysis Population Description
4981 eligible evaluable patients enrolled on AALL0331 had MRD data at Day 29
Arm/Group Title Induction Therapy, MRD Negative Induction Therapy, MRD Positive
Hide Arm/Group Description:

All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

vincristine sulfate: Given IV

All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

vincristine sulfate: Given IV

Overall Number of Participants Analyzed 4614 367
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percent Probability
91.39
(90.41 to 92.37)
79.86
(75.04 to 84.68)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Induction Therapy, MRD Negative, Induction Therapy, MRD Positive
Comments 4981 eligible evaluable patients enrolled on AALL0331 had MRD evaluation at Day 29 of induction. MRD status defined as negative (<0.1%) or positive (>=0.1%). MRD status ( positive vs. negative) was correlated with EFS using Cox regression analysis.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 2.542
Confidence Interval (2-Sided) 95%
1.974 to 3.273
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Overall Survival Probability (OS) According to Induction Day 29 MRD Status
Hide Description Overall survival by Day 29 MRD status (negative vs positive), Overall survival defined as time from study entry to death or date of last contact for patients who are alive.
Time Frame Overall Survival Probability of 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
4981 eligible evaluable patients enrolled on AALL0331 had MRD data at Day 29.
Arm/Group Title Induction Therapy, MRD Negative Induction Therapy, MRD Positive
Hide Arm/Group Description:

All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

vincristine sulfate: Given IV

All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

vincristine sulfate: Given IV

Overall Number of Participants Analyzed 4614 367
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent probability
97.07
(96.5 to 97.68)
90.47
(86.92 to 94.02)
6.Secondary Outcome
Title Early Marrow Status (EMS) by MRD Status End Induction (Day 29)
Hide Description Early Marrow Status defined as M1 versus M2/M3 marrow is correlated with MRD (Positive vs. Negative)
Time Frame Early Marrow Status at Day 15, MRD Status at Day 29 of therapy.
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who had MRD day 29 data but their Bone Marrow (BM) days 8/15 data were missing are excluded. This analysis was done with patients who had both MRD and BM data. There were 5 patients excluded in both MRD Negative and MRD Positive groups due to missing days 8/15 BM.
Arm/Group Title All Patients for Induction, MRD Negative All Patients for Induction, MRD Positive
Hide Arm/Group Description:

All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

vincristine sulfate: Given IV

All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

vincristine sulfate: Given IV

Overall Number of Participants Analyzed 4609 362
Measure Type: Count of Participants
Unit of Measure: Participants
4378
  95.0%
258
  71.3%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection All Patients for Induction, MRD Negative, All Patients for Induction, MRD Positive
Comments MRD status ( positive vs. negative) was correlated with Early Marrow Status (M1 vs M2/M3) using Chi Square test.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.131
Confidence Interval (2-Sided) 95%
0.101 to 0.17
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Optimal Time Point for Advance Health Related Quality of Life Intervention
Hide Description Percentage of patients with elevated Anxiety.
Time Frame At 1 month after diagnosis and 3 months post-therapy.
Hide Outcome Measure Data
Hide Analysis Population Description
Parents of 159 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the BASC-2 Anxiety Scale at 1 month after diagnosis, and 3 months post-therapy. Of these, 159 patients had data at 1 month after diagnosis and 96 patients had data at 3 months post therapy.
Arm/Group Title Induction Therapy
Hide Arm/Group Description:

All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

vincristine sulfate: Given IV

Overall Number of Participants Analyzed 159
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
At 1 month after diagnosis Number Analyzed 159 participants
25.2
(18.5 to 31.9)
At 3 months post-therapy Number Analyzed 96 participants
24.0
(16.0 to 32.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Induction Therapy
Comments Parents of 159 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the BASC-2 Anxiety Scale at 1 month after diagnosis, and 3 months post-therapy. Of these 159 had data at 1 month after diagnosis and 96 at 3 months post therapy.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.1
Confidence Interval (2-Sided) 95%
1.31 to 12.73
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Event-free Survival (EFS) for SR-High Patients.
Hide Description Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.
Time Frame 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
CCR: Complete Continuous Remission, where time to event is defined as the time from start of consolidation therapy to first event or date of last follow up for those who did not experience an event. All patients enrolled on the SR-High were used in this analysis regardless of completion of therapy.
Arm/Group Title Group 3-SR-high ALL, Combination Chemotherapy
Hide Arm/Group Description:

Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, methotrexate. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (2 courses - vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium, and augmented DI therapy (2 courses - vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine,MTX. Patients with DS receive (dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

3-dimensional conformal radiation therapy: Some patients undergo cranial radiotherapy

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

Overall Number of Participants Analyzed 636
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent probability
85.58
(85.55 to 85.61)
9.Secondary Outcome
Title Event-Free Survival (EFS) for Low MRD (Negative) Subjects by Genetic Subset (TEL/Trisomy Positive vs Negative)
Hide Description Event-free probability where EFS is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.
Time Frame 6 years
Hide Outcome Measure Data
Hide Analysis Population Description
Patients on the two arms being compared got similar therapy. All patients included in this analysis are MRD negative. SR-Average patients who were CNS2 at diagnosis were excluded in order to have comparable patient cohorts. SR-Low patients are TEL/Trisomy positive while SR-Average patients are TEL/Trisomy negative.
Arm/Group Title Group 1-SR-low ALL, Arm I-combination Chemotherapy Group 2-SR-avg ALL, Arm I-combination Chemotherapy
Hide Arm/Group Description:

Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Overall Number of Participants Analyzed 926 422
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percent probability
95.22
(93.58 to 96.86)
88.52
(84.56 to 92.48)
Time Frame [Not Specified]
Adverse Event Reporting Description Only eligible patients are included in the toxicity analysis.
 
Arm/Group Title Group 0 Induction Therapy Group 1-SR-low ALL, Arm I-combination Chemotherapy Group 1-SR-low ALL, Arm II-combination Chemotherapy Group 2-SR-avg ALL, Arm I-combination Chemotherapy Group 2-SR-avg ALL, Arm II-combination Chemotherapy Group 2-SR-avg ALL, Arm III-combination Chemotherapy Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Group 3-SR-high ALL, Combination Chemotherapy
Hide Arm/Group Description

All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) < 0.1% OR MRD >= 0.1% and < 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD >= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study.

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

vincristine sulfate: Given IV

Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive experimental consolidation therapy (vincristine sulfate, mercaptopurine, MTX, leucovorin calcium and pegaspargase), experimental interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine, MTX and pegaspargase), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine: Given PO

cyclophosphamide: Given IV

thioguanine: Given PO

vincristine sulfate: Given IV

Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine & vincristine sulfate, pegaspargase, methotrexate. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (2 courses - vincristine sulfate, methotrexate and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (2 courses - vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, methotrexate. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years.

doxorubicin hydrochloride: Given IV or IT

3-dimensional conformal radiation therapy: Some patients undergo cranial radiotherapy

cytarabine: Given IV or SC

dexamethasone: Given IV or PO

pegaspargase: Given IM

methotrexate: Given IM or IT

leucovorin calcium: Given PO

mercaptopurine

All-Cause Mortality
Group 0 Induction Therapy Group 1-SR-low ALL, Arm I-combination Chemotherapy Group 1-SR-low ALL, Arm II-combination Chemotherapy Group 2-SR-avg ALL, Arm I-combination Chemotherapy Group 2-SR-avg ALL, Arm II-combination Chemotherapy Group 2-SR-avg ALL, Arm III-combination Chemotherapy Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Group 3-SR-high ALL, Combination Chemotherapy
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Group 0 Induction Therapy Group 1-SR-low ALL, Arm I-combination Chemotherapy Group 1-SR-low ALL, Arm II-combination Chemotherapy Group 2-SR-avg ALL, Arm I-combination Chemotherapy Group 2-SR-avg ALL, Arm II-combination Chemotherapy Group 2-SR-avg ALL, Arm III-combination Chemotherapy Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Group 3-SR-high ALL, Combination Chemotherapy
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   29/1306 (2.22%)      14/931 (1.50%)      7/931 (0.75%)      4/501 (0.80%)      3/509 (0.59%)      0/246 (0.00%)      1/247 (0.40%)      12/638 (1.88%)    
Blood and lymphatic system disorders                 
Anemia  1/1306 (0.08%)  1 2/931 (0.21%)  2 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Disseminated intravascular coagulation  3/1306 (0.23%)  3 2/931 (0.21%)  2 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Febrile neutropenia  0/1306 (0.00%)  0 2/931 (0.21%)  2 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Hemolysis  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Cardiac disorders                 
Cardiac arrest  2/1306 (0.15%)  2 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Myocardial infarction  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Gastrointestinal disorders                 
Abdominal pain  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Ascites  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Cecal hemorrhage  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Colitis  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Colonic perforation  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Diarrhea  1/1306 (0.08%)  1 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Esophageal perforation  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Esophagitis  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Gastrointestinal disorders - Other, specify  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Mucositis oral  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Oral hemorrhage  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Pancreatitis  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Rectal hemorrhage  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Rectal necrosis  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Rectal pain  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Small intestinal perforation  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Typhlitis  2/1306 (0.15%)  2 2/931 (0.21%)  2 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
General disorders                 
Death NOS  4/1306 (0.31%)  4 0/931 (0.00%)  0 0/931 (0.00%)  0 2/501 (0.40%)  2 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Edema trunk  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
General disorders and administration site conditions - Other, specify  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Multi-organ failure  0/1306 (0.00%)  0 2/931 (0.21%)  2 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Sudden death NOS  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Hepatobiliary disorders                 
Cholecystitis  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Hepatic failure  1/1306 (0.08%)  1 1/931 (0.11%)  1 1/931 (0.11%)  1 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Hepatobiliary disorders - Other, specify  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Portal hypertension  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Immune system disorders                 
Anaphylaxis  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 1/247 (0.40%)  1 2/638 (0.31%)  2
Infections and infestations                 
Appendicitis  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Appendicitis perforated  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Encephalitis infection  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Encephalomyelitis infection  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Enterocolitis infectious  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Infections and infestations - Other, specify  6/1306 (0.46%)  6 4/931 (0.43%)  4 0/931 (0.00%)  0 1/501 (0.20%)  1 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 7/638 (1.10%)  7
Lung infection  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Pleural infection  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Sepsis  1/1306 (0.08%)  1 0/931 (0.00%)  0 1/931 (0.11%)  1 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Injury, poisoning and procedural complications                 
Vascular access complication  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Investigations                 
Activated partial thromboplastin time prolonged  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Alanine aminotransferase increased  0/1306 (0.00%)  0 2/931 (0.21%)  2 1/931 (0.11%)  1 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Alkaline phosphatase increased  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Aspartate aminotransferase increased  0/1306 (0.00%)  0 3/931 (0.32%)  3 1/931 (0.11%)  1 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Blood bilirubin increased  0/1306 (0.00%)  0 3/931 (0.32%)  3 1/931 (0.11%)  1 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
CPK increased  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Fibrinogen decreased  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Investigations - Other, specify  1/1306 (0.08%)  1 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Lipase increased  0/1306 (0.00%)  0 0/931 (0.00%)  0 2/931 (0.21%)  2 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Neutrophil count decreased  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Platelet count decreased  1/1306 (0.08%)  1 2/931 (0.21%)  2 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Serum amylase increased  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
White blood cell decreased  1/1306 (0.08%)  1 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Metabolism and nutrition disorders                 
Acidosis  1/1306 (0.08%)  2 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Dehydration  1/1306 (0.08%)  1 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Hyperglycemia  1/1306 (0.08%)  1 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Hypoalbuminemia  1/1306 (0.08%)  1 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Hypocalcemia  1/1306 (0.08%)  1 1/931 (0.11%)  1 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Hypoglycemia  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Hypokalemia  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Hyponatremia  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Nervous system disorders                 
Depressed level of consciousness  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Encephalopathy  3/1306 (0.23%)  3 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Intracranial hemorrhage  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Nervous system disorders - Other, specify  1/1306 (0.08%)  1 0/931 (0.00%)  0 1/931 (0.11%)  1 1/501 (0.20%)  1 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Peripheral motor neuropathy  2/1306 (0.15%)  2 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Seizure  3/1306 (0.23%)  3 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Psychiatric disorders                 
Confusion  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Renal and urinary disorders                 
Acute kidney injury  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Bladder perforation  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                 
Adult respiratory distress syndrome  3/1306 (0.23%)  3 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 2/638 (0.31%)  2
Apnea  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Bronchopulmonary hemorrhage  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Dyspnea  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Hypoxia  3/1306 (0.23%)  3 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Pleural effusion  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Respiratory failure  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Vascular disorders                 
Hypotension  4/1306 (0.31%)  4 1/931 (0.11%)  1 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Thromboembolic event  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
1
Term from vocabulary, CTCv4
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Group 0 Induction Therapy Group 1-SR-low ALL, Arm I-combination Chemotherapy Group 1-SR-low ALL, Arm II-combination Chemotherapy Group 2-SR-avg ALL, Arm I-combination Chemotherapy Group 2-SR-avg ALL, Arm II-combination Chemotherapy Group 2-SR-avg ALL, Arm III-combination Chemotherapy Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Group 3-SR-high ALL, Combination Chemotherapy
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   790/1306 (60.49%)      901/931 (96.78%)      909/931 (97.64%)      487/501 (97.21%)      500/509 (98.23%)      237/246 (96.34%)      234/247 (94.74%)      629/638 (98.59%)    
Blood and lymphatic system disorders                 
Anemia  86/1306 (6.58%)  88 258/931 (27.71%)  438 232/931 (24.92%)  356 119/501 (23.75%)  183 127/509 (24.95%)  213 55/246 (22.36%)  113 90/247 (36.44%)  150 213/638 (33.39%)  466
Blood and lymphatic system disorders - Other, specify  2/1306 (0.15%)  2 8/931 (0.86%)  16 6/931 (0.64%)  8 1/501 (0.20%)  1 4/509 (0.79%)  5 2/246 (0.81%)  2 1/247 (0.40%)  1 9/638 (1.41%)  9
Bone marrow hypocellular  0/1306 (0.00%)  0 2/931 (0.21%)  2 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 1/246 (0.41%)  2 0/247 (0.00%)  0 0/638 (0.00%)  0
Disseminated intravascular coagulation  2/1306 (0.15%)  2 6/931 (0.64%)  7 2/931 (0.21%)  2 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 2/638 (0.31%)  2
Febrile neutropenia  130/1306 (9.95%)  131 531/931 (57.04%)  1045 555/931 (59.61%)  1045 272/501 (54.29%)  513 330/509 (64.83%)  733 144/246 (58.54%)  259 150/247 (60.73%)  316 475/638 (74.45%)  1260
Hemolysis  2/1306 (0.15%)  2 6/931 (0.64%)  6 3/931 (0.32%)  3 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Hemolytic uremic syndrome  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Leukocytosis  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Spleen disorder  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Cardiac disorders                 
Cardiac arrest  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Cardiac disorders - Other, specify  3/1306 (0.23%)  3 1/931 (0.11%)  1 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 1/246 (0.41%)  1 0/247 (0.00%)  0 2/638 (0.31%)  2
Conduction disorder  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Left ventricular systolic dysfunction  1/1306 (0.08%)  1 0/931 (0.00%)  0 2/931 (0.21%)  3 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 4/638 (0.63%)  4
Mobitz (type) II atrioventricular block  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 1/246 (0.41%)  1 0/247 (0.00%)  0 0/638 (0.00%)  0
Myocarditis  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Pericardial effusion  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  2
Sinus bradycardia  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Sinus tachycardia  1/1306 (0.08%)  1 4/931 (0.43%)  4 1/931 (0.11%)  1 1/501 (0.20%)  1 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 2/638 (0.31%)  3
Supraventricular tachycardia  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Ventricular arrhythmia  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Ventricular tachycardia  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 1/501 (0.20%)  1 0/509 (0.00%)  0 1/246 (0.41%)  1 0/247 (0.00%)  0 0/638 (0.00%)  0
Wolff-Parkinson-White syndrome  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Ear and labyrinth disorders                 
Ear and labyrinth disorders - Other, specify  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 2/638 (0.31%)  3
Ear pain  0/1306 (0.00%)  0 2/931 (0.21%)  4 1/931 (0.11%)  1 1/501 (0.20%)  1 2/509 (0.39%)  2 1/246 (0.41%)  1 0/247 (0.00%)  0 1/638 (0.16%)  1
External ear inflammation  1/1306 (0.08%)  1 0/931 (0.00%)  0 1/931 (0.11%)  1 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
External ear pain  0/1306 (0.00%)  0 1/931 (0.11%)  1 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Hearing impaired  0/1306 (0.00%)  0 1/931 (0.11%)  1 2/931 (0.21%)  2 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Middle ear inflammation  2/1306 (0.15%)  2 8/931 (0.86%)  8 6/931 (0.64%)  7 4/501 (0.80%)  4 2/509 (0.39%)  2 3/246 (1.22%)  8 5/247 (2.02%)  5 7/638 (1.10%)  14
Endocrine disorders                 
Adrenal insufficiency  0/1306 (0.00%)  0 2/931 (0.21%)  2 1/931 (0.11%)  1 3/501 (0.60%)  4 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Endocrine disorders - Other, specify  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Eye disorders                 
Blurred vision  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 1/247 (0.40%)  1 0/638 (0.00%)  0
Extraocular muscle paresis  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 2/501 (0.40%)  2 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Eye disorders - Other, specify  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 1/501 (0.20%)  1 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Eye pain  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Glaucoma  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Keratitis  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 1/246 (0.41%)  1 0/247 (0.00%)  0 0/638 (0.00%)  0
Optic nerve disorder  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 1/247 (0.40%)  1 0/638 (0.00%)  0
Photophobia  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 1/247 (0.40%)  1 0/638 (0.00%)  0
Retinal detachment  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Retinopathy  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Vitreous hemorrhage  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Gastrointestinal disorders                 
Abdominal distension  7/1306 (0.54%)  7 10/931 (1.07%)  10 5/931 (0.54%)  5 2/501 (0.40%)  2 0/509 (0.00%)  0 1/246 (0.41%)  1 1/247 (0.40%)  1 5/638 (0.78%)  5
Abdominal pain  24/1306 (1.84%)  24 32/931 (3.44%)  38 27/931 (2.90%)  32 27/501 (5.39%)  32 24/509 (4.72%)  29 7/246 (2.85%)  10 15/247 (6.07%)  19 36/638 (5.64%)  42
Anal mucositis  1/1306 (0.08%)  1 2/931 (0.21%)  2 1/931 (0.11%)  1 2/501 (0.40%)  2 0/509 (0.00%)  0 1/246 (0.41%)  1 0/247 (0.00%)  0 4/638 (0.63%)  4
Anal necrosis  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Anal pain  2/1306 (0.15%)  2 2/931 (0.21%)  2 0/931 (0.00%)  0 1/501 (0.20%)  1 1/509 (0.20%)  1 0/246 (0.00%)  0 1/247 (0.40%)  1 2/638 (0.31%)  2
Ascites  2/1306 (0.15%)  2 6/931 (0.64%)  6 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 4/638 (0.63%)  4
Cecal hemorrhage  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 1/247 (0.40%)  1 0/638 (0.00%)  0
Colitis  5/1306 (0.38%)  6 7/931 (0.75%)  7 5/931 (0.54%)  5 0/501 (0.00%)  0 7/509 (1.38%)  7 1/246 (0.41%)  1 0/247 (0.00%)  0 10/638 (1.57%)  12
Colonic fistula  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Colonic hemorrhage  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Colonic obstruction  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Colonic perforation  1/1306 (0.08%)  1 2/931 (0.21%)  2 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Colonic ulcer  0/1306 (0.00%)  0 2/931 (0.21%)  2 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Constipation  12/1306 (0.92%)  12 15/931 (1.61%)  17 12/931 (1.29%)  12 8/501 (1.60%)  10 10/509 (1.96%)  11 2/246 (0.81%)  2 5/247 (2.02%)  5 14/638 (2.19%)  15
Dental caries  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Diarrhea  24/1306 (1.84%)  24 82/931 (8.81%)  91 63/931 (6.77%)  67 47/501 (9.38%)  56 44/509 (8.64%)  49 17/246 (6.91%)  20 26/247 (10.53%)  28 68/638 (10.66%)  88
Duodenal hemorrhage  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Duodenal perforation  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Duodenal ulcer  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Dyspepsia  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Dysphagia  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 2/501 (0.40%)  2 2/509 (0.39%)  2 0/246 (0.00%)  0 4/247 (1.62%)  4 2/638 (0.31%)  2
Enterocolitis  0/1306 (0.00%)  0 4/931 (0.43%)  4 1/931 (0.11%)  1 0/501 (0.00%)  0 2/509 (0.39%)  2 2/246 (0.81%)  2 1/247 (0.40%)  1 2/638 (0.31%)  2
Esophageal obstruction  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Esophageal pain  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 1/247 (0.40%)  1 0/638 (0.00%)  0
Esophageal stenosis  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Esophageal ulcer  1/1306 (0.08%)  1 2/931 (0.21%)  2 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Esophagitis  0/1306 (0.00%)  0 6/931 (0.64%)  6 4/931 (0.43%)  4 2/501 (0.40%)  2 1/509 (0.20%)  1 0/246 (0.00%)  0 4/247 (1.62%)  4 2/638 (0.31%)  2
Gastric fistula  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Gastric perforation  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Gastritis  0/1306 (0.00%)  0 7/931 (0.75%)  7 4/931 (0.43%)  4 1/501 (0.20%)  1 5/509 (0.98%)  5 2/246 (0.81%)  2 1/247 (0.40%)  1 9/638 (1.41%)  10
Gastrointestinal disorders - Other, specify  3/1306 (0.23%)  3 3/931 (0.32%)  3 4/931 (0.43%)  4 0/501 (0.00%)  0 5/509 (0.98%)  5 2/246 (0.81%)  2 3/247 (1.21%)  3 5/638 (0.78%)  6
Gastrointestinal fistula  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Gastrointestinal pain  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 2/501 (0.40%)  2 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Gingival pain  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 1/247 (0.40%)  1 0/638 (0.00%)  0
Ileal hemorrhage  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Ileal perforation  3/1306 (0.23%)  3 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Ileal ulcer  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Ileus  10/1306 (0.77%)  10 8/931 (0.86%)  9 5/931 (0.54%)  5 3/501 (0.60%)  3 7/509 (1.38%)  7 2/246 (0.81%)  2 3/247 (1.21%)  3 4/638 (0.63%)  4
Intra-abdominal hemorrhage  1/1306 (0.08%)  1 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Lip pain  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Lower gastrointestinal hemorrhage  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Malabsorption  0/1306 (0.00%)  0 2/931 (0.21%)  2 1/931 (0.11%)  1 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Mucositis oral  9/1306 (0.69%)  9 62/931 (6.66%)  64 53/931 (5.69%)  61 36/501 (7.19%)  42 41/509 (8.06%)  52 19/246 (7.72%)  28 23/247 (9.31%)  28 81/638 (12.70%)  93
Nausea  6/1306 (0.46%)  6 14/931 (1.50%)  14 9/931 (0.97%)  10 14/501 (2.79%)  16 11/509 (2.16%)  12 2/246 (0.81%)  2 4/247 (1.62%)  4 21/638 (3.29%)  25
Oral hemorrhage  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 1/247 (0.40%)  1 1/638 (0.16%)  1
Oral pain  3/1306 (0.23%)  3 11/931 (1.18%)  13 5/931 (0.54%)  5 14/501 (2.79%)  17 10/509 (1.96%)  12 3/246 (1.22%)  3 5/247 (2.02%)  5 18/638 (2.82%)  18
Pancreatic hemorrhage  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Pancreatic necrosis  0/1306 (0.00%)  0 2/931 (0.21%)  2 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Pancreatitis  18/1306 (1.38%)  19 6/931 (0.64%)  7 2/931 (0.21%)  3 5/501 (1.00%)  6 9/509 (1.77%)  12 3/246 (1.22%)  3 5/247 (2.02%)  7 20/638 (3.13%)  28
Proctitis  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  2 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Rectal fistula  0/1306 (0.00%)  0 2/931 (0.21%)  2 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Rectal hemorrhage  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Rectal mucositis  0/1306 (0.00%)  0 3/931 (0.32%)  3 1/931 (0.11%)  1 2/501 (0.40%)  2 0/509 (0.00%)  0 1/246 (0.41%)  1 1/247 (0.40%)  1 2/638 (0.31%)  2
Rectal pain  1/1306 (0.08%)  1 4/931 (0.43%)  4 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 1/247 (0.40%)  1 3/638 (0.47%)  3
Small intestinal mucositis  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Small intestinal obstruction  1/1306 (0.08%)  1 2/931 (0.21%)  2 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Small intestinal perforation  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Stomach pain  3/1306 (0.23%)  3 4/931 (0.43%)  4 0/931 (0.00%)  0 1/501 (0.20%)  1 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 4/638 (0.63%)  4
Toothache  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Typhlitis  6/1306 (0.46%)  6 9/931 (0.97%)  9 6/931 (0.64%)  6 1/501 (0.20%)  1 8/509 (1.57%)  8 3/246 (1.22%)  3 3/247 (1.21%)  3 11/638 (1.72%)  13
Upper gastrointestinal hemorrhage  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 1/246 (0.41%)  1 0/247 (0.00%)  0 2/638 (0.31%)  2
Vomiting  11/1306 (0.84%)  11 48/931 (5.16%)  53 37/931 (3.97%)  42 36/501 (7.19%)  47 33/509 (6.48%)  40 19/246 (7.72%)  24 18/247 (7.29%)  19 52/638 (8.15%)  65
General disorders                 
Chills  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 1/247 (0.40%)  1 0/638 (0.00%)  0
Edema face  1/1306 (0.08%)  1 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Edema limbs  0/1306 (0.00%)  0 2/931 (0.21%)  3 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Edema trunk  3/1306 (0.23%)  3 1/931 (0.11%)  1 1/931 (0.11%)  1 3/501 (0.60%)  3 0/509 (0.00%)  0 0/246 (0.00%)  0 1/247 (0.40%)  1 3/638 (0.47%)  3
Facial pain  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 1/501 (0.20%)  1 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 2/638 (0.31%)  2
Fatigue  4/1306 (0.31%)  4 16/931 (1.72%)  16 2/931 (0.21%)  2 8/501 (1.60%)  11 8/509 (1.57%)  9 3/246 (1.22%)  3 2/247 (0.81%)  2 11/638 (1.72%)  11
Fever  6/1306 (0.46%)  6 84/931 (9.02%)  104 108/931 (11.60%)  128 49/501 (9.78%)  58 53/509 (10.41%)  66 36/246 (14.63%)  45 20/247 (8.10%)  23 71/638 (11.13%)  84
Flu like symptoms  1/1306 (0.08%)  1 2/931 (0.21%)  2 4/931 (0.43%)  4 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 1/247 (0.40%)  1 0/638 (0.00%)  0
Gait disturbance  2/1306 (0.15%)  2 6/931 (0.64%)  6 2/931 (0.21%)  2 3/501 (0.60%)  4 1/509 (0.20%)  1 1/246 (0.41%)  1 0/247 (0.00%)  0 3/638 (0.47%)  3
General disorders and administration site conditions - Other, specify  1/1306 (0.08%)  1 5/931 (0.54%)  6 9/931 (0.97%)  13 4/501 (0.80%)  4 2/509 (0.39%)  2 0/246 (0.00%)  0 3/247 (1.21%)  3 7/638 (1.10%)  7
Hypothermia  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Injection site reaction  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Irritability  2/1306 (0.15%)  3 6/931 (0.64%)  9 4/931 (0.43%)  6 3/501 (0.60%)  3 1/509 (0.20%)  1 1/246 (0.41%)  2 1/247 (0.40%)  1 5/638 (0.78%)  5
Localized edema  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Multi-organ failure  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Non-cardiac chest pain  1/1306 (0.08%)  1 2/931 (0.21%)  2 0/931 (0.00%)  0 1/501 (0.20%)  1 1/509 (0.20%)  1 0/246 (0.00%)  0 1/247 (0.40%)  1 2/638 (0.31%)  2
Pain  9/1306 (0.69%)  9 14/931 (1.50%)  14 14/931 (1.50%)  14 2/501 (0.40%)  2 7/509 (1.38%)  8 8/246 (3.25%)  9 2/247 (0.81%)  2 19/638 (2.98%)  26
Hepatobiliary disorders                 
Cholecystitis  0/1306 (0.00%)  0 1/931 (0.11%)  1 2/931 (0.21%)  2 1/501 (0.20%)  1 0/509 (0.00%)  0 0/246 (0.00%)  0 2/247 (0.81%)  2 0/638 (0.00%)  0
Gallbladder obstruction  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 2/247 (0.81%)  2 1/638 (0.16%)  1
Gallbladder pain  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Hepatic failure  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 3/501 (0.60%)  3 1/509 (0.20%)  2 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Hepatic necrosis  1/1306 (0.08%)  1 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 0/638 (0.00%)  0
Hepatic pain  0/1306 (0.00%)  0 1/931 (0.11%)  1 0/931 (0.00%)  0 0/501 (0.00%)  0 0/509 (0.00%)  0 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Hepatobiliary disorders - Other, specify  1/1306 (0.08%)  1 9/931 (0.97%)  10 4/931 (0.43%)  5 2/501 (0.40%)  3 1/509 (0.20%)  1 0/246 (0.00%)  0 0/247 (0.00%)  0 4/638 (0.63%)  4
Portal hypertension  0/1306 (0.00%)  0 10/931 (1.07%)  10 1/931 (0.11%)  1 0/501 (0.00%)  0 1/509 (0.20%)  1 0/246 (0.00%)  0 1/247 (0.40%)  1 8/638 (1.25%)  8
Immune system disorders                 
Allergic reaction  0/1306 (0.00%)  0 0/931 (0.00%)  0 0/931 (0.00%)  0 0/501 (0.00%)  0 2/509 (0.39%)  2 0/246 (0.00%)  0 0/247 (0.00%)  0 1/638 (0.16%)  1
Anaphylaxis  4/1306 (0.31%)  4 76/931 (8.16%)  83 9/931 (0.97%)  9 5/501 (1.00%)  5 62/509 (12.18%)  66 31/246 (12.60%)  32 32/247 (12.96%)  35 92/638 (14.42%)  102
Autoimmune disorder  0/1306 (0.00%)  0 0/931 (0.00%)  0 1/931 (0.11%)  1 0/501 (0.00%)  0 0/509 (0.00%)  0 1/246 (0.41%)  1 0/247 (0.00%)  0 1/638 (0.16%)  2
Immune system disorders - Other, specify  1/1306 (0.08%)  1 1/931 (0.11%)  1 2/931 (0.21%)  2 1/501 (0.20%)  1 3/509 (0.59%)  5 2/246 (0.81%)  2 2/247 (0.81%)  4 5/638 (0.78%)  5
Infections and infestations