Trial Outcomes & Findings for Treatment of Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplasia (NCT NCT00136084)

Last Updated: 2012-12-05

Results Overview

Detection of Minimal Residual Disease following one course of chemotherapy where positive MRD was defined as one or more leukemic cell per 1000 mononuclear bone-marrow cells (\>=0.1%).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

238 participants

Primary outcome timeframe

Day 22 MRD measurement

Results posted on

2012-12-05

Participant Flow

238 patients were recruited between October, 2002 and June, 2008.

238 patients were enrolled on the study. This report is based on results for 223 patients. 15 patients were excluded for the following reasons: 7 were switched to lymphoid-directed therapy shortly after enrollment, 6 were determined to be ineligible shortly after enrollment (wrong diagnosis), and 2 were not randomized.

Participant milestones

Participant milestones
Measure	Arm 1: (HDAC) High-dose Cytarabine (HDAC)	Arm 2:(LDAC) Low-dose Cytarabine (LDAC)
Overall Study STARTED	109	114
Overall Study COMPLETED	61	72
Overall Study NOT COMPLETED	48	42

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm 1: (HDAC) High-dose Cytarabine (HDAC)	Arm 2:(LDAC) Low-dose Cytarabine (LDAC)
Overall Study Death	12	5
Overall Study Unacceptable toxicity	8	11
Overall Study Relapse	20	23
Overall Study Lost to Follow-up	2	0
Overall Study No Response	1	2
Overall Study Withdrawal by Subject	5	1

Baseline Characteristics

Treatment of Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplasia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm 1: (HDAC) n=109 Participants High-dose Cytarabine (HDAC)	Arm 2:(LDAC) n=114 Participants Low-dose Cytarabine (LDAC)	Total n=223 Participants Total of all reporting groups
Age Continuous	8.57 years STANDARD_DEVIATION 6.08 • n=5 Participants	8.48 years STANDARD_DEVIATION 6.32 • n=7 Participants	8.49 years STANDARD_DEVIATION 6.19 • n=5 Participants
Sex: Female, Male Female	50 Participants n=5 Participants	48 Participants n=7 Participants	98 Participants n=5 Participants
Sex: Female, Male Male	59 Participants n=5 Participants	66 Participants n=7 Participants	125 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 22 MRD measurement

Population: Of the 223 randomized patients, 205 patients were included in the day 22 MRD analysis. 18 patients were not included in the day 22 MRD analysis. 5 patients had inadequate sample for MRD, 11 patients had no suitable phenotype to determine MRD, 1 patient was not done on MRD, and 1 patient was lost for follow-up.

Detection of Minimal Residual Disease following one course of chemotherapy where positive MRD was defined as one or more leukemic cell per 1000 mononuclear bone-marrow cells (\>=0.1%).

Outcome measures

Outcome measures
Measure	Arm 1: (HDAC) n=99 Participants High-dose Cytarabine (HDAC)	Arm 2:(LDAC) n=106 Participants Low-dose Cytarabine (LDAC)
Minimal Residual Disease (MRD). MRD Positive	31 participants	43 participants
Minimal Residual Disease (MRD). MRD Negative	68 participants	63 participants

SECONDARY outcome

Timeframe: Consolidation I

Population: Sixteen patients received GO treatment during consolidation I. One patient with negative MRD received GO treatment, which was not consistent with the protocol definition. 15 patients were analyzed. Out of the 15 patients, 7 patients were treated on HDAC arm and 8 patients were treated on LDAC arm.

To estimate the proportion of minimal residual disease (MRD)+ patients who become MRD- after one course of gemtuzumab ozogamicin (GO)

Outcome measures

Outcome measures
Measure	Arm 1: (HDAC) n=15 Participants High-dose Cytarabine (HDAC)	Arm 2:(LDAC) Low-dose Cytarabine (LDAC)
Proportion of Minimal Residual Disease (MRD)+ Patients Who Become MRD- After One Course of Gemtuzumab Ozogamicin (GO) Negative	11 Participants	—
Proportion of Minimal Residual Disease (MRD)+ Patients Who Become MRD- After One Course of Gemtuzumab Ozogamicin (GO) Positive	4 Participants	—

SECONDARY outcome

Timeframe: Induction II

Population: Out of the 30 patients received ADE + GO treatment, one patient had inevaluable MRD prior to and after the treatment. 29 patients were analyzed. Out of the 29 patients, 10 patients were treated on HDAC arm and 19 patients were treated on LDAC arm.

To estimate proportion of patients with MRD reduction after one course of Induction II (cytarabine + daunomycin + etoposide (ADE) + GO), who had no response to first course of induction therapy.

Outcome measures

Outcome measures
Measure	Arm 1: (HDAC) n=29 Participants High-dose Cytarabine (HDAC)	Arm 2:(LDAC) Low-dose Cytarabine (LDAC)
Proportion of MRD Reduction After One Course of Cytarabine + Daunomycin + Etoposide (ADE) + GO Decrease	27 Participants	—
Proportion of MRD Reduction After One Course of Cytarabine + Daunomycin + Etoposide (ADE) + GO Increase or no change	2 Participants	—

SECONDARY outcome

Timeframe: Induction II

Population: 30 patients received ADE + GO during induction II and were analyzed. Out of the 30 patients, 11 patients were treated on HDAC arm, and 19 patients were treated on LDAC arm.

To estimate proportion of patients experiencing CTC Grade 3 or 4 toxicity during Induction II (Cytarabine + Daunomycin + Etoposide (ADE) + GO), who had no response to first course of induction therapy

Outcome measures

Outcome measures
Measure	Arm 1: (HDAC) n=30 Participants High-dose Cytarabine (HDAC)	Arm 2:(LDAC) Low-dose Cytarabine (LDAC)
Proportion of Patients Experienced Toxicity of Cytarabine + Daunomycin + Etoposide (ADE) + GO. Experienced Grade 3 or 4 toxicities	27 Participants	—
Proportion of Patients Experienced Toxicity of Cytarabine + Daunomycin + Etoposide (ADE) + GO. Did not experience Grade 3 or 4 toxicities	3 Participants	—

SECONDARY outcome

Timeframe: Five Year

Population: 238 patients were enrolled on the study. Out of 238, 6 were determined to be ineligible and 2 were not randomized. Of the 230 patients, 14 bi-phenotypic leukemia patients were excluded. 216 AML patients were included to estimate EFS.

Overall event-free survival (EFS) was defined as the time from study enrollment to induction failure, relapse, secondary malignancy, death, or study withdrawal for any reason, with event-free patients censored on the date of the last follow-up

Outcome measures

Outcome measures
Measure	Arm 1: (HDAC) n=216 Participants High-dose Cytarabine (HDAC)	Arm 2:(LDAC) Low-dose Cytarabine (LDAC)
To Estimate the Overall Event-free Survival (EFS) of AML Patients Who Undergo Risk-adapted and Genotype-directed Therapy	62.4 Percentage of Participants	—

SECONDARY outcome

Timeframe: Measurements were assessed in Induction I chemotherapy

Population: Of 232 eligible patients, 49 had DNA synthesis rate performed prior to araC treatment. Of the 49 patients, 23 had no 24-hr samples and 3 did not have enough cells in 24-hr samples. 21 patients with both pre and post araC samples were included in the DNA inhibition study. Of the 21 patients, 9 were treated on HDAC and 12 were treated on LDAC.

Inhibition of DNA synthesis is defined as the percentage of DNA synthesis rate at 24-hour post-araC treatment over DNA synthesis rate pre-araC treatment.

Outcome measures

Outcome measures
Measure	Arm 1: (HDAC) n=9 Participants High-dose Cytarabine (HDAC)	Arm 2:(LDAC) n=12 Participants Low-dose Cytarabine (LDAC)
To Assess Whether Inhibition of DNA Synthesis is Greater After High-dose Ara-C (HDAC) Than After Low-dose Ara-C (LDAC) Therapy	60.6 Percent Inhibition of DNA Synthesis Standard Error 16.0	72.8 Percent Inhibition of DNA Synthesis Standard Error 15.6

SECONDARY outcome

Timeframe: Measurements were assessed in Induction I chemotherapy

Clinical response is defined as MRD (minimal residual disease) measured by flow cytometry at day 22. The MRD at day 22 is classified as positive (with MRD) or negative (no detectable MRD). The relation between inhibition of DNA synthesis and MRD was performed by logistic regression. In the model, logit of probability of MRD positive was regressed on inhibition of DNA synthesis.

Outcome measures

Outcome measures
Measure	Arm 1: (HDAC) n=17 Participants High-dose Cytarabine (HDAC)	Arm 2:(LDAC) Low-dose Cytarabine (LDAC)
Relationship of Inhibition of DNA Synthesis and Clinical Response	66.7 Percent inhibition of DNA Synthesis Standard Error 12.6	—

Adverse Events

Arm 1: (HDAC)

Serious events: 23 serious events

Other events: 107 other events

Deaths: 0 deaths

Arm 2:(LDAC)

Serious events: 19 serious events

Other events: 112 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Jeffrey Rubnitz, M.D

St. Jude Children's Research Hospital

Phone: 1-866-278-5833

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Arm 1: (HDAC) n=109 participants at risk High-dose Cytarabine (HDAC)	Arm 2:(LDAC) n=114 participants at risk Low-dose Cytarabine (LDAC)
Metabolism and nutrition disorders Acidosis (metabolic or respiratory)	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Cardiac disorders Acute vascular leak syndrome	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Respiratory, thoracic and mediastinal disorders Adult respiratory distress syndrome (ARDS)	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Anorexia	4.6% 5/109 • Number of events 8 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	2.6% 3/114 • Number of events 3 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Nervous system disorders Arachnoiditis/meningismus/radiculitis	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Nervous system disorders CNS cerebrovascular ischemia	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Nervous system disorders CNS hemorrhage/bleeding	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	1.8% 2/114 • Number of events 4 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Cardiac disorders Cardiac left ventricular function	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Cardiac disorders Cardiovascular/Arrhythmia-Other	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Nervous system disorders Confusion	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Blood and lymphatic system disorders DIC (disseminated intravascular coagulation	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Nervous system disorders Depressed level of consciousness	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Diarrhea patients without colostomy	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	1.8% 2/114 • Number of events 2 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Respiratory, thoracic and mediastinal disorders Dyspnea (shortness of breath)	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Infections and infestations Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infe	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	3.5% 4/114 • Number of events 7 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Infections and infestations Fever (in the absence of neutropenia, where neutropenia is defined as AGC<1.0 x 10e9/L)	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Gastritis	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Nervous system disorders Hallucinations	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Blood and lymphatic system disorders Hemorrhage-Other	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Blood and lymphatic system disorders Hemorrhage/bleeding associated with surgery	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Blood and lymphatic system disorders Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Hyperglycemia	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Hyperkalemia	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Hypernatremia	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Cardiac disorders Hypertension	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Hypocalcemia	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Hypokalemia	5.5% 6/109 • Number of events 8 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	3.5% 4/114 • Number of events 4 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Cardiac disorders Hypotension	1.8% 2/109 • Number of events 2 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Infections and infestations Infection (documented clinically or microbiologically) with grade 3 or 4 neutropenia (ANC <1.0 x 10e	11.9% 13/109 • Number of events 19 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	8.8% 10/114 • Number of events 15 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Infections and infestations Infection with unknown ANC	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 3 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Infections and infestations Infection without neutropenia	0.92% 1/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Infections and infestations Infection/Febrile Neutropenia-Other	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 3 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Lipase	1.8% 2/109 • Number of events 2 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Hepatobiliary disorders Liver dysfunction/failure (clinical)	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Pancreatitis	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Cardiac disorders Peripheral arterial ischemia	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Respiratory, thoracic and mediastinal disorders Pneumonitis/pulmonary infiltrates	2.8% 3/109 • Number of events 4 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Respiratory, thoracic and mediastinal disorders Pulmonary-Other	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	2.6% 3/114 • Number of events 3 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Renal and urinary disorders Renal failure	2.8% 3/109 • Number of events 3 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Hepatobiliary disorders SGOT (AST) (serum glutamic oxaloacetic transaminase)	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Hepatobiliary disorders SGPT (ALT) (serum glutamic pyruvic transaminase)	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Nervous system disorders Seizure(s)	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Cardiac disorders Sinus tachycardia	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	1.8% 2/114 • Number of events 2 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Cardiac disorders Thrombosis/embolism	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Typhlitis (inflammation of cecum)	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	1.8% 2/114 • Number of events 2 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Vascular disorders Veno-Occlusive Dease (VOD)	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Vomiting	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	1.8% 2/114 • Number of events 2 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Skin and subcutaneous tissue disorders Wound-infectious	0.92% 1/109 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.88% 1/114 • Number of events 1 • Adverse events have been collected from study inception (October, 2002) through February, 2009.

Measure	Arm 1: (HDAC) n=109 participants at risk High-dose Cytarabine (HDAC)	Arm 2:(LDAC) n=114 participants at risk Low-dose Cytarabine (LDAC)
General disorders Abdominal pain or cramping	10.1% 11/109 • Number of events 12 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Acidosis (metabolic or respiratory)	5.5% 6/109 • Number of events 8 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Immune system disorders Allergic reaction/hypersensitivity (including drug fever)	15.6% 17/109 • Number of events 19 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	14.0% 16/114 • Number of events 19 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Anorexia	21.1% 23/109 • Number of events 28 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	14.0% 16/114 • Number of events 26 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Hepatobiliary disorders Bilirubin	6.4% 7/109 • Number of events 8 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Colitis	5.5% 6/109 • Number of events 7 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Eye disorders Conjunctivitis	6.4% 7/109 • Number of events 7 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Blood and lymphatic system disorders DIC (disseminated intravascular coagulation)	5.5% 6/109 • Number of events 6 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Dehydration	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	5.3% 6/114 • Number of events 6 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Diarrhea patients without colostomy	19.3% 21/109 • Number of events 26 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	17.5% 20/114 • Number of events 27 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Blood and lymphatic system disorders Epistaxis	6.4% 7/109 • Number of events 9 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	7.9% 9/114 • Number of events 14 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Infections and infestations Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infe	63.3% 69/109 • Number of events 138 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	80.7% 92/114 • Number of events 181 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Infections and infestations Fever (in the absence of neutropenia, where neutropenia is defined as AGC<1.0 x 10e9/L)	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	7.0% 8/114 • Number of events 9 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Hepatobiliary disorders GGT (Gamma-Glutamyl transpeptidase)	12.8% 14/109 • Number of events 21 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	7.0% 8/114 • Number of events 9 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Gastrointestinal-Other	7.3% 8/109 • Number of events 8 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
General disorders Headache	5.5% 6/109 • Number of events 7 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	7.9% 9/114 • Number of events 11 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Blood and lymphatic system disorders Hemorrhage-Other	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	10.5% 12/114 • Number of events 14 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Blood and lymphatic system disorders Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	5.3% 6/114 • Number of events 6 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Hyperglycemia	13.8% 15/109 • Number of events 21 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	8.8% 10/114 • Number of events 13 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Hyperkalemia	6.4% 7/109 • Number of events 8 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	5.3% 6/114 • Number of events 14 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Cardiac disorders Hypertension	7.3% 8/109 • Number of events 9 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	6.1% 7/114 • Number of events 9 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Hypocalcemia	11.0% 12/109 • Number of events 13 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	10.5% 12/114 • Number of events 17 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Hypokalemia	33.9% 37/109 • Number of events 79 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	33.3% 38/114 • Number of events 84 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Hypomagnesmia	7.3% 8/109 • Number of events 9 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	6.1% 7/114 • Number of events 11 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Hyponatremia	5.5% 6/109 • Number of events 8 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	7.9% 9/114 • Number of events 11 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Hypophosphatemia	11.0% 12/109 • Number of events 14 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	10.5% 12/114 • Number of events 14 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Cardiac disorders Hypotension	10.1% 11/109 • Number of events 14 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	17.5% 20/114 • Number of events 21 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Respiratory, thoracic and mediastinal disorders Hypoxia	17.4% 19/109 • Number of events 20 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	14.9% 17/114 • Number of events 19 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Infections and infestations Infection (documented clinically or microbiologically) with grade 3 or 4 neutropenia (ANC <1.0 x 10e	76.1% 83/109 • Number of events 193 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	71.9% 82/114 • Number of events 178 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Infections and infestations Infection without neutropenia	9.2% 10/109 • Number of events 10 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	11.4% 13/114 • Number of events 15 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Metabolism and nutrition disorders Lipase	5.5% 6/109 • Number of events 7 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Nausea	5.5% 6/109 • Number of events 6 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	7.0% 8/114 • Number of events 11 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
General disorders Pain-Other	5.5% 6/109 • Number of events 6 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Respiratory, thoracic and mediastinal disorders Pleural effusion (non-malignant)	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	6.1% 7/114 • Number of events 7 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Respiratory, thoracic and mediastinal disorders Pneumonitis/pulmonary infiltrates	9.2% 10/109 • Number of events 12 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Skin and subcutaneous tissue disorders Rash/desquamation	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	7.0% 8/114 • Number of events 9 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Hepatobiliary disorders SGOT (AST) (serum glutamic oxaloacetic transaminase)	9.2% 10/109 • Number of events 10 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	0.00% 0/114 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Hepatobiliary disorders SGPT (ALT) (serum glutamic pyruvic transaminase)	16.5% 18/109 • Number of events 21 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	7.0% 8/114 • Number of events 9 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Stomatitis/pharyngitis (oral/pharyngeal mucositis)	13.8% 15/109 • Number of events 18 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	16.7% 19/114 • Number of events 22 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Typhlitis (inflammation of cecum)	7.3% 8/109 • Number of events 10 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	14.0% 16/114 • Number of events 17 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Gastrointestinal disorders Vomiting	12.8% 14/109 • Number of events 15 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	13.2% 15/114 • Number of events 20 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Skin and subcutaneous tissue disorders Wound-infectious	0.00% 0/109 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	9.6% 11/114 • Number of events 12 • Adverse events have been collected from study inception (October, 2002) through February, 2009.
Skin and subcutaneous tissue disorders Wound-non-infectious	8.3% 9/109 • Number of events 10 • Adverse events have been collected from study inception (October, 2002) through February, 2009.	5.3% 6/114 • Number of events 6 • Adverse events have been collected from study inception (October, 2002) through February, 2009.