Fludarabine and Busulfan Followed by Allogeneic Stem Cell Transplant in Treating Older Patients With Acute Myeloid Leukemia in First Complete Remission

• Sponsor: Alliance for Clinical Trials in Oncology (Other)
• Overall Status: Completed
• CT.gov ID: NCT00070135
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 121
• Locations: 21
• Arm: 1
• Actual Duration (Months): 149.5
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial studies how well fludarabine and busulfan followed by a donor (allogeneic) stem cell transplant work in treating older patients with acute myeloid leukemia that is in first complete remission. Giving low doses of chemotherapy, such as fludarabine and busulfan, before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stops the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving tacrolimus, methotrexate, and rabbit antithymocyte globulin before or after the transplant may stop this from happening.

Condition or Disease	Intervention/Treatment	Phase
Adult Acute Myeloid Leukemia in Remission; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome	Biological: filgrastim; Biological: Anti-Thymocyte Globulin; Drug: busulfan; Drug: fludarabine phosphate; Drug: methotrexate; Drug: tacrolimus; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine if allogeneic transplantation from a matched sibling or unrelated donor using a non-myeloablative preparative regimen results in a 2-year disease-free survival (DFS) that is better than historical results using standard chemotherapy.

SECONDARY OBJECTIVES:

1. Determine 2-year actuarial risks of transplant-related mortality, acute and chronic graft-versus-host (GVHD) disease and relapse among patients with acute myeloid leukemia (AML) in first complete remission (CR1) following a non-myeloablative preparative regimen.

2. To examine recovery of T and B cell number and function following non-myeloablative stem cell transplant.

3. To examine the time course of T, B and myeloid progenitor chimerism following this preparative regimen.

4. To characterize the pharmacokinetics of intravenous busulfan used in a non-myeloablative preparation regimen in AML patients age >= 60 years.

OUTLINE:

PREPARATIVE REGIMEN: Patients receive fludarabine intravenously (IV) over 30 minutes on days -7 to -3 and busulfan IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive tacrolimus orally (PO) or IV twice daily (BID) on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin IV over 4-6 hours on days -4 through -2.

ALLOGENEIC PERIPHERAL BLOOD STEM CELL TRASNPLANTATION (PBSC): Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim subcutaneously (SC) daily beginning on day 12 and continuing until blood counts recover.

Patients are followed monthly for 1 year, every 3 months for 1 year, and then every 6 months for 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 121 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study Of Allogeneic Transplant For Older Patients With AML In First Morphologic Complete Remission Using A Non-Myeloablative Preparative Regimen
• Actual Study Start Date: Jan 1, 2004
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Jun 15, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (fludarabine, busulfan, allogeneic PBSC) PREPARATIVE REGIMEN: Patients receive fludarabine IV over 30 minutes on days -7 to -3 and busulfan IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GVHD PROPHYLAXIS: Patients receive tacrolimus PO or IV BID on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin IV over 4-6 hours on days -4 through -2. ALLOGENEIC PBSC: Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim SC daily beginning on day 12 and continuing until blood counts recover.

Biological: filgrastim; Given SC; Biological: Anti-Thymocyte Globulin; Given IV; Drug: busulfan; Given IV; Drug: fludarabine phosphate; Given IV; Drug: methotrexate; Given IV; Drug: tacrolimus; Given PO or IV; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic PBSC transplantation; Other Names: HSC, HSCT

Outcome Measures

Primary Outcome Measures

1. 2 Year Disease Free Survival In Unrelated Donor Recipient Group [2 years]

   Percentage of participants who were alive and relapse free at 2 years for patients who were matched with an unrelated donor for transplant. The 2 year disease free survival, with 95% confidence interval, was estimated using the Kaplan Meier method. A relapse is defined as any of the following: Reappearance of leukemia blasts cells in peripheral blood >5% blasts in the marrow, not attributable to another cause (e.g., bone marrow regeneration) If there are no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow ≥ 1 week later with >5% blasts is necessary to meet the criteria for relapse The development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid

Secondary Outcome Measures

1. 2 Year DFS for All Patients [Up to 2 years]

   Percentage of participants who were alive and relapse free at 2 years for all patients. The 2 year disease free survival, with 95% confidence interval, was estimated using the Kaplan Meier method.

2. Non-relapse Mortality (NRM) [Up to 5 years]

   Percentage of patients who died due to causes other than relapse

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years to 74 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Eligibility Criteria:

• Patients with acute myeloid leukemia (AML) (excluding French-American-British [FAB] classification system M3) who have achieved a first morphologic complete remission and who meet the criteria below; patients with preceding myelodysplastic syndrome (MDS) or treatment-related AML are eligible; patients with prior central nervous system (CNS) involvement are eligible as long as disease is in remission at transplant; patients with acute leukemia following blast transformation of prior chronic myeloid leukemia (CML) or other myeloproliferative disease are excluded

• Complete remission (CR) will be defined according to the revised recommendations of the International Working Group (24) as all of the following:

• Normal bone marrow morphology with < 5% blasts

• Absolute neutrophil count (ANC) > 1,000/uL, referring to the count needed to confirm that the patient achieved a CR

• Platelet count > 100,000/uL

• No extramedullary leukemia

• No blasts in peripheral blood

• CR was achieved after one or two (but no more than two) cycles of induction chemotherapy with standard cytotoxic chemotherapy (e.g., cytarabine and an anthracycline) or after no more than four cycles of a hypomethylating agent containing regimen including either 5-azacytidine or decitabine

• Patients may have received as many as but no more than two cycles of consolidation therapy prior to transplant; any consolidation regimen that does not require transplant can be used; no more than 6 months can elapse from documentation of morphologic CR to transplant; the platelet count does not need to be > 100,000/uL after consolidation, as long as the bone marrow assessment prior to transplant does not show relapse

• Identification of hematopoietic cell donor

• = 4 weeks since prior chemotherapy, radiation therapy, and surgery

• Performance status 0-2

• Diffusion capacity of carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease

• Left ventricular ejection fraction (LVEF) by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) >= 30%

• No uncontrolled diabetes mellitus or active serious infection requiring antibiotics

• No known hypersensitivity to E. coli-derived products

• No human immunodeficiency virus (HIV) infection

• Calculated creatinine clearance >= 40 cc/min

• Bilirubin < 2 mg/dL

• If bilirubin is 2-3 mg/dL, but direct bilirubin is normal then patient will be considered eligible

• Aspartate aminotransferase (AST) < 3 x upper limit of normal

• DONOR: HLA-identical sibling (6/6); the donor must be determined to be an human leukocyte antigen (HLA)-identical sibling (6/6) by serologic typing for class (A, B) and low resolution molecular typing for class II (DRB1)

• DONOR: Matched unrelated donor (10/10); high resolution molecular typing at the following loci is required: HLA-A, -B, -C, -DRB1, and -DQB1

• DONOR: the donor must be healthy and must be an acceptable donor as per institutional standards for stem cell donation

• DONOR: the donor must have no significant cardiopulmonary, renal, endocrine, or hepatic disease

• DONOR: there is no donor age restriction if the donor is a matched sibling

• DONOR: syngeneic donors are not eligible

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
2	Tunnell Cancer Center at Beebe Medical Center	Lewes	Delaware	United States	19958
3	CCOP - Christiana Care Health Services	Newark	Delaware	United States	19713
4	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201
5	Union Hospital of Cecil County	Elkton	Maryland	United States	21921
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
7	Dana-Farber/Brigham and Women's Cancer Center	Boston	Massachusetts	United States	02115
8	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
9	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
10	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota	United States	55455
11	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
12	Cancer Institute of New Jersey at Cooper - Voorhees	Voorhees	New Jersey	United States	08043
13	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
14	Monter Cancer Center of the North Shore-LIJ Health System	Lake Success	New York	United States	11042
15	CCOP - North Shore University Hospital	Manhasset	New York	United States	11030
16	Don Monti Comprehensive Cancer Center at North Shore University Hospital	Manhasset	New York	United States	11030
17	Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
18	New York Weill Cornell Cancer Center at Cornell University	New York	New York	United States	10021
19	Mount Sinai Medical Center	New York	New York	United States	10029
20	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
21	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210-1240

Sponsors and Collaborators

• Alliance for Clinical Trials in Oncology
• National Cancer Institute (NCI)

Investigators

• Study Chair: Steven M. Devine, MD, Ohio State University Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alliance for Clinical Trials in Oncology
• ClinicalTrials.gov Identifier: NCT00070135
• Other Study ID Numbers: CALGB-100103; CDR0000330001; NCI-2009-00438; U10CA180821
• First Posted: Oct 7, 2003
• Last Update Posted: Jun 12, 2018
• Last Verified: May 1, 2018

• Keywords provided by Alliance for Clinical Trials in Oncology: adult acute myeloid leukemia in remission; secondary acute myeloid leukemia; adult acute monocytic leukemia (M5b); adult acute erythroid leukemia (M6); adult acute megakaryoblastic leukemia (M7); adult acute minimally differentiated myeloid leukemia (M0); adult acute myeloblastic leukemia with maturation (M2); adult acute myeloblastic leukemia without maturation (M1); adult acute myelomonocytic leukemia (M4); adult acute monoblastic leukemia (M5a); adult acute myeloid leukemia with t(8;21)(q22;q22); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with 11q23 (MLL) abnormalities
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Methotrexate; Fludarabine phosphate; Fludarabine; Busulfan; Tacrolimus; Antilymphocyte Serum

Study Results

Participant Flow

Recruitment Details	Between November 2004 and 2011, 121 participants were registered and received transplants at 21 centers.
Pre-assignment Detail	Seven (7) participants were excluded from the all analyses after they were deemed ineligible.

Arm/Group Title	Treatment (Fludarabine, Busulfan, Allogeneic PBSC)
Arm/Group Description	PREPARATIVE REGIMEN: Patients receive fludarabine 30 mg/m^2 IV over 30 minutes on days -7 to -3 and busulfan 0.8 mg/kg IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GVHD PROPHYLAXIS: Patients receive tacrolimus 0.03 mg/kg (suggested starting dose) PO BID on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate 5 mg/m^2 IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin 2.5 mg/kg IV over 4-6 hours on days -4 through -2. ALLOGENEIC PBSC: Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim 5 or 10 mcg/kg SC daily beginning on day 12 and continuing until blood counts recover.
Period Title: Overall Study
STARTED	114
COMPLETED	114
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Fludarabine, Busulfan, Allogeneic PBSC)
Arm/Group Description	PREPARATIVE REGIMEN: Patients receive fludarabine 30 mg/m^2 IV over 30 minutes on days -7 to -3 and busulfan 0.8 mg/kg IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GVHD PROPHYLAXIS: Patients receive tacrolimus 0.03 mg/kg (suggested starting dose) PO BID on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate 5 mg/m^2 IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin 2.5 mg/kg IV over 4-6 hours on days -4 through -2. ALLOGENEIC PBSC: Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim 5 or 10 mcg/kg SC daily beginning on day 12 and continuing until blood counts recover.
Overall Participants	114
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	43 37.7%
Male	71 62.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 2.6%
Not Hispanic or Latino	102 89.5%
Unknown or Not Reported	9 7.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 0.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 2.6%
White	105 92.1%
More than one race	1 0.9%
Unknown or Not Reported	4 3.5%
Region of Enrollment (participants) [Number]
United States	114 100%
Transplant Donor Type (participants) [Number]
Matched unrelated donor	59 51.8%
Matched related donor	55 48.2%

Outcome Measures

1. Primary Outcome

Title	2 Year Disease Free Survival In Unrelated Donor Recipient Group
Description	Percentage of participants who were alive and relapse free at 2 years for patients who were matched with an unrelated donor for transplant. The 2 year disease free survival, with 95% confidence interval, was estimated using the Kaplan Meier method. A relapse is defined as any of the following: Reappearance of leukemia blasts cells in peripheral blood >5% blasts in the marrow, not attributable to another cause (e.g., bone marrow regeneration) If there are no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow ≥ 1 week later with >5% blasts is necessary to meet the criteria for relapse The development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Participants who received a matched unrelated donor were included in this analysis.

Arm/Group Title	Treatment (Fludarabine, Busulfan, Allogeneic PBSC)
Arm/Group Description	PREPARATIVE REGIMEN: Patients receive fludarabine 30 mg/m^2 IV over 30 minutes on days -7 to -3 and busulfan 0.8 mg/kg IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GVHD PROPHYLAXIS: Patients receive tacrolimus 0.03 mg/kg (suggested starting dose) PO BID on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate 5 mg/m^2 IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin 2.5 mg/kg IV over 4-6 hours on days -4 through -2. ALLOGENEIC PBSC: Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim 5 or 10 mcg/kg SC daily beginning on day 12 and continuing until blood counts recover.
Measure Participants	59
Number (95% Confidence Interval) [percentage of participants]	40 35.1%

2. Secondary Outcome

Title	2 Year DFS for All Patients
Description	Percentage of participants who were alive and relapse free at 2 years for all patients. The 2 year disease free survival, with 95% confidence interval, was estimated using the Kaplan Meier method.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Fludarabine, Busulfan, Allogeneic PBSC)
Arm/Group Description	PREPARATIVE REGIMEN: Patients receive fludarabine 30 mg/m^2 IV over 30 minutes on days -7 to -3 and busulfan 0.8 mg/kg IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GVHD PROPHYLAXIS: Patients receive tacrolimus 0.03 mg/kg (suggested starting dose) PO BID on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate 5 mg/m^2 IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin 2.5 mg/kg IV over 4-6 hours on days -4 through -2. ALLOGENEIC PBSC: Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim 5 or 10 mcg/kg SC daily beginning on day 12 and continuing until blood counts recover.
Measure Participants	114
Number (95% Confidence Interval) [percentage of participants]	42 36.8%

3. Secondary Outcome

Title	Non-relapse Mortality (NRM)
Description	Percentage of patients who died due to causes other than relapse
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Fludarabine, Busulfan, Allogeneic PBSC)
Arm/Group Description	PREPARATIVE REGIMEN: Patients receive fludarabine 30 mg/m^2 IV over 30 minutes on days -7 to -3 and busulfan 0.8 mg/kg IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GVHD PROPHYLAXIS: Patients receive tacrolimus 0.03 mg/kg (suggested starting dose) PO BID on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate 5 mg/m^2 IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin 2.5 mg/kg IV over 4-6 hours on days -4 through -2. ALLOGENEIC PBSC: Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim 5 or 10 mcg/kg SC daily beginning on day 12 and continuing until blood counts recover.
Measure Participants	114
Number [percentage of patients]	16

Adverse Events

Arm/Group Title	Treatment (Fludarabine, Busulfan, Allogeneic PBSC)
Arm/Group Description	PREPARATIVE REGIMEN: Patients receive fludarabine 30 mg/m^2 IV over 30 minutes on days -7 to -3 and busulfan 0.8 mg/kg IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GVHD PROPHYLAXIS: Patients receive tacrolimus 0.03 mg/kg (suggested starting dose) PO BID on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate 5 mg/m^2 IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin 2.5 mg/kg IV over 4-6 hours on days -4 through -2. ALLOGENEIC PBSC: Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim 5 or 10 mcg/kg SC daily beginning on day 12 and continuing until blood counts recover
All Cause Mortality
	Treatment (Fludarabine, Busulfan, Allogeneic PBSC)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Fludarabine, Busulfan, Allogeneic PBSC)
	Affected / at Risk (%)	# Events
Total	38/114 (33.3%)
Blood and lymphatic system disorders
Blood disorder	1/114 (0.9%)	1
Febrile neutropenia	7/114 (6.1%)	8
Hemoglobin decreased	13/114 (11.4%)	24
Hemolysis	3/114 (2.6%)	5
Cardiac disorders
Atrial fibrillation	1/114 (0.9%)	1
Cardiac pain	1/114 (0.9%)	1
Cardiopulmonary arrest	1/114 (0.9%)	1
Left ventricular failure	2/114 (1.8%)	2
Myocardial ischemia	2/114 (1.8%)	2
Pericardial effusion	1/114 (0.9%)	1
Sinus tachycardia	2/114 (1.8%)	2
Ear and labyrinth disorders
Ear disorder	1/114 (0.9%)	1
Tinnitus	1/114 (0.9%)	1
Endocrine disorders
Adrenal insufficiency	1/114 (0.9%)	1
Hyperthyroidism	1/114 (0.9%)	1
Eye disorders
Dry eye syndrome	3/114 (2.6%)	4
Vision blurred	1/114 (0.9%)	1
Watering eyes	2/114 (1.8%)	3
Gastrointestinal disorders
Abdominal distension	1/114 (0.9%)	1
Abdominal pain	5/114 (4.4%)	5
Constipation	7/114 (6.1%)	7
Diarrhea	16/114 (14%)	25
Dry mouth	3/114 (2.6%)	5
Dyspepsia	3/114 (2.6%)	3
Dysphagia	2/114 (1.8%)	2
Ear, nose and throat examination abnormal	3/114 (2.6%)	4
Gastric hemorrhage	2/114 (1.8%)	2
Gastrointestinal disorder	1/114 (0.9%)	1
Lower gastrointestinal hemorrhage	1/114 (0.9%)	1
Mucositis oral	3/114 (2.6%)	5
Nausea	8/114 (7%)	15
Oral pain	1/114 (0.9%)	3
Tooth disorder	1/114 (0.9%)	1
Vomiting	3/114 (2.6%)	4
General disorders
Chest pain	1/114 (0.9%)	1
Chills	5/114 (4.4%)	5
Death NOS	1/114 (0.9%)	1
Disease progression	1/114 (0.9%)	1
Edema limbs	10/114 (8.8%)	12
Fatigue	15/114 (13.2%)	23
Fever	7/114 (6.1%)	7
General symptom	1/114 (0.9%)	1
Ill-defined disorder	1/114 (0.9%)	1
Localized edema	2/114 (1.8%)	2
Multi-organ failure	2/114 (1.8%)	2
Pain	2/114 (1.8%)	2
Immune system disorders
Hypersensitivity	2/114 (1.8%)	2
Infections and infestations
Bladder infection	3/114 (2.6%)	4
Bronchitis	1/114 (0.9%)	1
Catheter related infection	3/114 (2.6%)	3
Colitis, infectious (e.g., Clostridium difficile)	1/114 (0.9%)	1
Encephalitis infection	1/114 (0.9%)	1
Infection	2/114 (1.8%)	2
Infectious colitis	2/114 (1.8%)	2
Lip infection	1/114 (0.9%)	1
Opportunistic infection	1/114 (0.9%)	1
Paranasal sinus infection	1/114 (0.9%)	1
Phlebitis infective	1/114 (0.9%)	1
Pneumonia	2/114 (1.8%)	2
Sepsis	7/114 (6.1%)	9
Sinusitis	1/114 (0.9%)	1
Skin infection	1/114 (0.9%)	1
Soft tissue infection	1/114 (0.9%)	1
Upper respiratory infection	4/114 (3.5%)	6
Wound infection	1/114 (0.9%)	1
Injury, poisoning and procedural complications
Vascular access complication	1/114 (0.9%)	2
Investigations
Activated partial thromboplastin time prolonged	1/114 (0.9%)	1
Alanine aminotransferase increased	12/114 (10.5%)	12
Alkaline phosphatase increased	11/114 (9.6%)	17
Aspartate aminotransferase increased	10/114 (8.8%)	12
Blood bilirubin increased	7/114 (6.1%)	8
Creatinine increased	13/114 (11.4%)	16
INR increased	2/114 (1.8%)	3
Laboratory test abnormal	4/114 (3.5%)	8
Leukocyte count decreased	5/114 (4.4%)	8
Lymphocyte count decreased	6/114 (5.3%)	13
Neutrophil count decreased	21/114 (18.4%)	26
Platelet count decreased	28/114 (24.6%)	52
Serum cholesterol increased	1/114 (0.9%)	3
Weight gain	7/114 (6.1%)	13
Weight loss	7/114 (6.1%)	14
Metabolism and nutrition disorders
Acidosis	1/114 (0.9%)	1
Anorexia	8/114 (7%)	11
Blood glucose increased	15/114 (13.2%)	24
Blood uric acid increased	1/114 (0.9%)	1
Dehydration	2/114 (1.8%)	2
Iron overload	2/114 (1.8%)	3
Serum albumin decreased	9/114 (7.9%)	12
Serum calcium decreased	7/114 (6.1%)	12
Serum calcium increased	2/114 (1.8%)	3
Serum glucose decreased	1/114 (0.9%)	2
Serum magnesium decreased	14/114 (12.3%)	21
Serum magnesium increased	2/114 (1.8%)	3
Serum phosphate decreased	5/114 (4.4%)	6
Serum potassium decreased	9/114 (7.9%)	12
Serum potassium increased	6/114 (5.3%)	9
Serum sodium decreased	5/114 (4.4%)	8
Serum sodium increased	3/114 (2.6%)	4
Serum triglycerides increased	1/114 (0.9%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	5/114 (4.4%)	7
Back pain	7/114 (6.1%)	7
Bone pain	4/114 (3.5%)	4
Muscle weakness	4/114 (3.5%)	5
Muscle weakness left-sided	1/114 (0.9%)	1
Muscle weakness lower limb	5/114 (4.4%)	8
Muscle weakness right-sided	1/114 (0.9%)	1
Myalgia	1/114 (0.9%)	1
Neck pain	1/114 (0.9%)	1
Pain in extremity	4/114 (3.5%)	5
Scoliosis	1/114 (0.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplasia	1/114 (0.9%)	1
Nervous system disorders
Ataxia	1/114 (0.9%)	1
Depressed level of consciousness	3/114 (2.6%)	3
Dizziness	6/114 (5.3%)	7
Dysgeusia	1/114 (0.9%)	1
Facial nerve disorder	1/114 (0.9%)	1
Headache	6/114 (5.3%)	6
Intracranial hemorrhage	2/114 (1.8%)	2
Memory impairment	1/114 (0.9%)	1
Neuralgia	1/114 (0.9%)	1
Neurological disorder NOS	1/114 (0.9%)	1
Peripheral sensory neuropathy	1/114 (0.9%)	1
Speech disorder	1/114 (0.9%)	1
Syncope	1/114 (0.9%)	1
Tremor	2/114 (1.8%)	2
Psychiatric disorders
Agitation	4/114 (3.5%)	4
Anxiety	5/114 (4.4%)	5
Confusion	4/114 (3.5%)	4
Depression	6/114 (5.3%)	9
Insomnia	5/114 (4.4%)	5
Psychosis	1/114 (0.9%)	1
Renal and urinary disorders
Bladder pain	1/114 (0.9%)	1
Bladder spasm	1/114 (0.9%)	2
Cystitis	1/114 (0.9%)	1
Glomerular filtration rate decreased	1/114 (0.9%)	1
Kidney pain	1/114 (0.9%)	1
Renal failure	2/114 (1.8%)	2
Urethral pain	1/114 (0.9%)	1
Urinary frequency	3/114 (2.6%)	4
Urinary incontinence	2/114 (1.8%)	3
Urinary retention	3/114 (2.6%)	3
Reproductive system and breast disorders
Pelvic floor muscle weakness	1/114 (0.9%)	1
Scrotal pain	1/114 (0.9%)	1
Vaginal inflammation	1/114 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/114 (0.9%)	1
Allergic rhinitis	2/114 (1.8%)	2
Aspiration	1/114 (0.9%)	1
Cough	6/114 (5.3%)	9
Dyspnea	14/114 (12.3%)	17
Hypoxia	11/114 (9.6%)	12
Nasal congestion	2/114 (1.8%)	2
Pharyngolaryngeal pain	1/114 (0.9%)	1
Pleural effusion	1/114 (0.9%)	1
Pneumonitis	7/114 (6.1%)	9
Respiratory disorder	5/114 (4.4%)	5
Skin and subcutaneous tissue disorders
Alopecia	3/114 (2.6%)	8
Decubitus ulcer	1/114 (0.9%)	1
Dry skin	1/114 (0.9%)	2
Nail disorder	2/114 (1.8%)	2
Pain of skin	1/114 (0.9%)	1
Petechiae	1/114 (0.9%)	1
Pruritus	5/114 (4.4%)	6
Rash acneiform	1/114 (0.9%)	1
Rash desquamating	20/114 (17.5%)	31
Skin disorder	4/114 (3.5%)	8
Skin hyperpigmentation	1/114 (0.9%)	1
Vascular disorders
Hematoma	1/114 (0.9%)	1
Hemorrhage	1/114 (0.9%)	1
Hot flashes	1/114 (0.9%)	1
Hypertension	10/114 (8.8%)	13
Hypotension	11/114 (9.6%)	15
Thrombosis	2/114 (1.8%)	2
Other (Not Including Serious) Adverse Events
	Treatment (Fludarabine, Busulfan, Allogeneic PBSC)
	Affected / at Risk (%)	# Events
Total	109/114 (95.6%)
Blood and lymphatic system disorders
Blood disorder	1/114 (0.9%)	1
Febrile neutropenia	45/114 (39.5%)	49
Hemoglobin decreased	55/114 (48.2%)	141
Hemolysis	4/114 (3.5%)	6
Lymphatic disorder	1/114 (0.9%)	1
Cardiac disorders
Atrial fibrillation	1/114 (0.9%)	3
Cardiac disorder	2/114 (1.8%)	2
Conduction disorder	1/114 (0.9%)	1
Left ventricular dysfunction	3/114 (2.6%)	4
Left ventricular failure	5/114 (4.4%)	6
Myocardial ischemia	1/114 (0.9%)	1
Palpitations	1/114 (0.9%)	1
Sinus bradycardia	1/114 (0.9%)	1
Sinus tachycardia	4/114 (3.5%)	4
Ear and labyrinth disorders
Ear disorder	2/114 (1.8%)	5
Ear pain	1/114 (0.9%)	1
External ear pain	3/114 (2.6%)	4
Hearing impaired	3/114 (2.6%)	4
Tinnitus	1/114 (0.9%)	1
Endocrine disorders
Adrenal insufficiency	1/114 (0.9%)	1
Hypothyroidism	7/114 (6.1%)	11
Eye disorders
Cataract	5/114 (4.4%)	6
Conjunctivitis	1/114 (0.9%)	1
Diplopia	1/114 (0.9%)	1
Dry eye syndrome	15/114 (13.2%)	38
Extraocular muscle paresis	1/114 (0.9%)	1
Eye disorder	6/114 (5.3%)	6
Eye pain	2/114 (1.8%)	2
Optic nerve disorder	1/114 (0.9%)	1
Retinal detachment	1/114 (0.9%)	1
Vision blurred	4/114 (3.5%)	4
Vitreous hemorrhage	1/114 (0.9%)	1
Watering eyes	4/114 (3.5%)	4
Gastrointestinal disorders
Abdominal distension	1/114 (0.9%)	1
Abdominal pain	10/114 (8.8%)	14
Anal pain	2/114 (1.8%)	2
Colitis	2/114 (1.8%)	2
Constipation	26/114 (22.8%)	35
Diarrhea	52/114 (45.6%)	80
Dry mouth	18/114 (15.8%)	35
Dyspepsia	18/114 (15.8%)	29
Dysphagia	3/114 (2.6%)	3
Ear, nose and throat examination abnormal	16/114 (14%)	18
Enteritis	1/114 (0.9%)	1
Esophagitis	1/114 (0.9%)	1
Fecal incontinence	1/114 (0.9%)	1
Flatulence	1/114 (0.9%)	3
Gastric ulcer	1/114 (0.9%)	1
Gastritis	4/114 (3.5%)	5
Gastrointestinal disorder	4/114 (3.5%)	8
Hemorrhoidal hemorrhage	1/114 (0.9%)	1
Hemorrhoids	1/114 (0.9%)	1
Lip pain	1/114 (0.9%)	1
Lower gastrointestinal hemorrhage	2/114 (1.8%)	2
Mucositis oral	10/114 (8.8%)	10
Nausea	49/114 (43%)	76
Oesophagoscopy abnormal	1/114 (0.9%)	1
Oral hemorrhage	1/114 (0.9%)	1
Oral pain	1/114 (0.9%)	1
Rectal pain	2/114 (1.8%)	3
Typhlitis	1/114 (0.9%)	1
Vomiting	25/114 (21.9%)	30
General disorders
Chest pain	4/114 (3.5%)	4
Chills	20/114 (17.5%)	23
Edema limbs	23/114 (20.2%)	35
Fatigue	60/114 (52.6%)	128
Fever	27/114 (23.7%)	31
Gait abnormal	1/114 (0.9%)	1
General symptom	1/114 (0.9%)	1
Hypothermia	2/114 (1.8%)	2
Ill-defined disorder	1/114 (0.9%)	1
Injection site reaction	1/114 (0.9%)	1
Localized edema	2/114 (1.8%)	2
Pain	15/114 (13.2%)	18
Immune system disorders
Hypersensitivity	9/114 (7.9%)	9
Infections and infestations
Abdominal infection	1/114 (0.9%)	1
Bladder infection	2/114 (1.8%)	2
Bronchitis	4/114 (3.5%)	5
Catheter related infection	1/114 (0.9%)	2
Conjunctivitis infective	1/114 (0.9%)	1
Eye infection	1/114 (0.9%)	1
Gastric infection	1/114 (0.9%)	1
Gingival infection	3/114 (2.6%)	4
Ileal infection	1/114 (0.9%)	1
Infection	11/114 (9.6%)	13
Infectious colitis	1/114 (0.9%)	1
Infectious meningitis	1/114 (0.9%)	1
Lip infection	1/114 (0.9%)	1
Nail infection	1/114 (0.9%)	2
Opportunistic infection	2/114 (1.8%)	2
Pneumonia	7/114 (6.1%)	7
Scrotal infection	1/114 (0.9%)	1
Sepsis	11/114 (9.6%)	14
Sinusitis	5/114 (4.4%)	6
Skin infection	6/114 (5.3%)	7
Soft tissue infection	1/114 (0.9%)	1
Upper respiratory infection	9/114 (7.9%)	11
Urinary tract infection	6/114 (5.3%)	7
Vaginal infection	1/114 (0.9%)	1
Viral hepatitis	2/114 (1.8%)	2
Wound infection	1/114 (0.9%)	1
Injury, poisoning and procedural complications
Bruising	2/114 (1.8%)	2
Fracture	1/114 (0.9%)	1
Vascular access complication	2/114 (1.8%)	2
Venous injury - Extremity-lower	1/114 (0.9%)	1
Investigations
Activated partial thromboplastin time prolonged	7/114 (6.1%)	14
Alanine aminotransferase increased	41/114 (36%)	87
Alkaline phosphatase increased	34/114 (29.8%)	70
Amylase increased	1/114 (0.9%)	1
Aspartate aminotransferase increased	45/114 (39.5%)	106
Blood bilirubin increased	23/114 (20.2%)	34
CD4 lymphocytes decreased	1/114 (0.9%)	1
Creatinine increased	50/114 (43.9%)	116
Electrocardiogram QTc interval prolonged	1/114 (0.9%)	2
Gamma-glutamyltransferase increased	1/114 (0.9%)	1
INR increased	10/114 (8.8%)	13
Laboratory test abnormal	7/114 (6.1%)	12
Leukocyte count decreased	28/114 (24.6%)	54
Lymphocyte count decreased	26/114 (22.8%)	44
Neutrophil count decreased	95/114 (83.3%)	157
Platelet count decreased	97/114 (85.1%)	206
Serum cholesterol increased	10/114 (8.8%)	17
Weight gain	13/114 (11.4%)	17
Weight loss	12/114 (10.5%)	16
Metabolism and nutrition disorders
Anorexia	37/114 (32.5%)	53
Blood glucose increased	60/114 (52.6%)	133
Blood uric acid increased	2/114 (1.8%)	3
Dehydration	8/114 (7%)	8
Iron overload	2/114 (1.8%)	2
Obesity	1/114 (0.9%)	2
Serum albumin decreased	29/114 (25.4%)	52
Serum calcium decreased	26/114 (22.8%)	48
Serum calcium increased	6/114 (5.3%)	7
Serum glucose decreased	1/114 (0.9%)	1
Serum magnesium decreased	50/114 (43.9%)	87
Serum magnesium increased	3/114 (2.6%)	4
Serum phosphate decreased	13/114 (11.4%)	15
Serum potassium decreased	30/114 (26.3%)	42
Serum potassium increased	22/114 (19.3%)	32
Serum sodium decreased	40/114 (35.1%)	76
Serum sodium increased	6/114 (5.3%)	10
Serum triglycerides increased	10/114 (8.8%)	13
Musculoskeletal and connective tissue disorders
Abdominal soft tissue necrosis	1/114 (0.9%)	1
Arthralgia	19/114 (16.7%)	34
Back pain	20/114 (17.5%)	26
Bone pain	14/114 (12.3%)	14
Chest wall pain	3/114 (2.6%)	4
Fibrosis deep connective tissue	1/114 (0.9%)	1
Joint disorder	1/114 (0.9%)	2
Muscle weakness	13/114 (11.4%)	23
Muscle weakness lower limb	5/114 (4.4%)	6
Muscle weakness upper limb	1/114 (0.9%)	2
Musculoskeletal disorder	4/114 (3.5%)	5
Myalgia	6/114 (5.3%)	6
Neck pain	4/114 (3.5%)	9
Osteoporosis	1/114 (0.9%)	3
Pain in extremity	13/114 (11.4%)	24
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	2/114 (1.8%)	2
Nervous system disorders
Ataxia	1/114 (0.9%)	1
Dizziness	17/114 (14.9%)	22
Dysgeusia	9/114 (7.9%)	18
Extrapyramidal disorder	1/114 (0.9%)	1
Headache	28/114 (24.6%)	37
Intracranial hemorrhage	1/114 (0.9%)	1
Memory impairment	4/114 (3.5%)	6
Neuralgia	1/114 (0.9%)	1
Neurological disorder NOS	2/114 (1.8%)	2
Peripheral sensory neuropathy	8/114 (7%)	8
Seizure	2/114 (1.8%)	3
Sinus pain	1/114 (0.9%)	1
Syncope	4/114 (3.5%)	6
Tremor	10/114 (8.8%)	16
Psychiatric disorders
Agitation	2/114 (1.8%)	3
Anxiety	11/114 (9.6%)	14
Confusion	9/114 (7.9%)	15
Depression	12/114 (10.5%)	24
Insomnia	19/114 (16.7%)	30
Psychosis	1/114 (0.9%)	2
Renal and urinary disorders
Bladder pain	1/114 (0.9%)	1
Bladder spasm	2/114 (1.8%)	2
Hemorrhage urinary tract	3/114 (2.6%)	3
Proteinuria	1/114 (0.9%)	1
Renal failure	2/114 (1.8%)	2
Urethral stenosis	1/114 (0.9%)	1
Urinary frequency	10/114 (8.8%)	18
Urinary incontinence	3/114 (2.6%)	3
Urinary retention	1/114 (0.9%)	1
Urogenital disorder	3/114 (2.6%)	4
Reproductive system and breast disorders
Erectile dysfunction	2/114 (1.8%)	5
Irregular menstruation	3/114 (2.6%)	4
Perineal pain	1/114 (0.9%)	1
Scrotal pain	2/114 (1.8%)	2
Vaginal discharge	1/114 (0.9%)	1
Vaginal hemorrhage	1/114 (0.9%)	1
Vaginal pain	1/114 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/114 (0.9%)	1
Allergic rhinitis	8/114 (7%)	9
Apnea	1/114 (0.9%)	1
Cough	24/114 (21.1%)	38
Dyspnea	29/114 (25.4%)	52
Epistaxis	2/114 (1.8%)	2
Hiccups	2/114 (1.8%)	2
Hypoxia	13/114 (11.4%)	15
Laryngoscopy abnormal	1/114 (0.9%)	1
Nasal congestion	3/114 (2.6%)	4
Pharyngeal examination abnormal	1/114 (0.9%)	1
Pharyngeal hemorrhage	1/114 (0.9%)	1
Pharyngeal mucositis	2/114 (1.8%)	2
Pharyngolaryngeal pain	3/114 (2.6%)	4
Pleural effusion	1/114 (0.9%)	1
Pleuritic pain	2/114 (1.8%)	2
Pneumonitis	10/114 (8.8%)	11
Pneumothorax	1/114 (0.9%)	1
Respiratory disorder	4/114 (3.5%)	4
Voice alteration	1/114 (0.9%)	1
Skin and subcutaneous tissue disorders
Alopecia	14/114 (12.3%)	31
Decubitus ulcer	1/114 (0.9%)	1
Dry skin	15/114 (13.2%)	27
Hand-and-foot syndrome	2/114 (1.8%)	2
Nail disorder	3/114 (2.6%)	4
Petechiae	4/114 (3.5%)	4
Photosensitivity	1/114 (0.9%)	1
Pruritus	22/114 (19.3%)	36
Rash acneiform	2/114 (1.8%)	3
Rash desquamating	75/114 (65.8%)	151
Skin disorder	8/114 (7%)	11
Skin hyperpigmentation	3/114 (2.6%)	3
Skin hypopigmentation	1/114 (0.9%)	2
Skin ulceration	3/114 (2.6%)	4
Sweating	2/114 (1.8%)	3
Urticaria	1/114 (0.9%)	1
Vascular disorders
Hematoma	2/114 (1.8%)	3
Hemorrhage	2/114 (1.8%)	2
Hot flashes	1/114 (0.9%)	3
Hypertension	39/114 (34.2%)	68
Hypotension	26/114 (22.8%)	34
Thrombosis	4/114 (3.5%)	4
Vascular disorder	1/114 (0.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.