Fludarabine-based Conditioning for Severe Aplastic Anemia (BMT CTN 0301)

• Sponsor: Medical College of Wisconsin (Other)
• Overall Status: Completed
• CT.gov ID: NCT00326417
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Blood and Marrow Transplant Clinical Trials Network (Other), National Cancer Institute (NCI) (NIH), National Marrow Donor Program (Other)
• Enrollment: 97
• Locations: 22
• Arms: 4
• Duration (Months): 120
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of the current study is to continue to optimize conditioning regimens in high-risk patients with severe aplastic anemia transplanted with marrow from HLA-compatible unrelated donors. Specifically, the study will determine whether the addition of fludarabine to the conditioning regimen previously described by Deeg et al. will permit a reduction in the CY dose, to a point where sustained hematopoietic engraftment and survival are maintained (or improved), while the frequency of major regimen-related toxicity (RRT) and early deaths is reduced.

Condition or Disease	Intervention/Treatment	Phase
Anemia, Aplastic	Drug: Fludarabine; Drug: Cyclophosphamide 150mg; Drug: Cyclophosphamide 100mg; Drug: Cyclophosphamide 50mg	Phase 1/Phase 2

Detailed Description

BACKGROUND:

Aplastic anemia (AA) remains a life-threatening illness. Treatment options include supportive care (transfusions, growth factors, etc.), immunosuppression therapy and stem cell transplantation. Only the latter two have favorably impacted the natural history of the disease. The prognosis of AA patients, particularly severe aplastic anemia (SAA), as defined by Camitta et al., who fail to respond to immunosuppressive therapy (IS) or who relapse after an initial response to IS is poor. Although many of these patients can be supported in the short term with growth factors, transfusions and possibly rechallenged successfully with IS, the cumulative morbidity and mortality from infection, hemorrhage or transfusion-related complications is substantial.

While allogeneic bone marrow transplantation is potentially curative in AA, no more than 25% of patients have a human leukocyte antigen (HLA)-identical sibling donor. Cyclophosphamide (CY)-antithymocyte globulin (ATG) has been recommended as the preparative regimen of choice in sibling donor transplants. Results of bone marrow transplantation from alternative donors, such as matched unrelated donors and mismatched related donors in AA patients who have failed IS, have largely been unsatisfactory. The cyclophosphamide-ATG conditioning regimen has proved inadequate in ensuring engraftment in allogeneic transplants from matched, unrelated donors for AA. This was the major reason why total body radiation (TBI) has been added to the conditioning regimen.

Graft failure is a very serious and frequently life-threatening or fatal event following matched unrelated donor (MUD) allografts in aplastic anemia. It is an immunologically mediated event. Risk factors for graft failure include the use of HLA nonidentical or unrelated donors, a poor marrow nucleated cell dose as well as prolonged transfusional support prior to BMT (which increases the probability of patient sensitization to multiple antigens). While some patients may achieve autologous hematopoietic recovery, prolonged pancytopenia is common and infection-related morbidity and mortality are very substantial. Reconditioning for a second allograft from the same or a different donor is frequently not successful. While the addition of TBI and intensive pre-transplant conditioning has led to a sizable improvement in engraftment rates, this has come with a price, particularly in adult patients. Transplant-related toxicity has been a major and frequent problem. Radiation-induced pulmonary toxicity in particular has been common, usually in the form of diffuse alveolar damage or diffuse interstitial pneumonitis. In addition, Graft Versus Host Disease (GVHD)-related morbidity and mortality in these patients have also been substantial.

DESIGN NARRATIVE:

The study is a prospective Phase I/II dose optimization study. All patients are given a fixed dose of ATG (either thymoglobulin: 3 mg/kg IV daily x 3 or ATGAM 30 mg/kg IV daily x 3, on Days -4 to -2), Fludarabine (30 mg/m^2 IV daily x 4, on Days - 5 to -2), and TBI (200 cGy (centigray) from a linear accelerator at less than 20 cGy/min on Day -1). The starting CY dose will be 150 mg/kg (50 mg/kg intravenously daily, Days -4 to -2), and will be de-escalated depending on engraftment and toxicity. The Phase I portion of the trial (maximum of 24-27 patients) tests each of four dose levels of CY for adequate safety and graft retention. The Phase II portion of the trial refines the dose selection and allocates an additional 70 patients to the optimal dose, at which two-year post-transplant survival will be assessed. The combined enrollment in Phase I and II will total 94 patients.

The study is a prospective single-arm Phase I/II dose-selection and evaluation study. The study will seek the optimal dose level of CY based on assessments of graft failure, toxicity and early death during 100 days of follow-up post-transplant. A brief synopsis is given below.

Phase I - Test Each Dose for Adequate Safety and Graft Retention

1. Proceed from the highest dose (150 mg/kg CY) to the lowest dose (0 mg/kg CY), treating a minimum of six patients at each dose.

2. Evaluate the 100-Day outcomes for toxicity, death and graft failure on each patient enrolled at the current dose, or until stopping criteria are met.

3. If there are three or more graft failures at the current dose, the current dose and all lower doses are closed to further enrollment.

4. If there are five or more severe regimen-related toxicities and/or early deaths at the current dose, the current dose is closed to further enrollment, and the next lower dose is tested.

5. Dose de-escalation ceases once all four doses are tested or closed to further enrollment.

Phase II - Refine Dose Selection and Allocate Patients to the Optimal Dose

1. Treat each newly enrolled patient at the most desirable of the dose levels remaining open to enrollment. This can involve de-escalation, escalation, or no change in dose.

2. As each patient completes the observation period, evaluate the 100-Day outcomes for graft failure, toxicity and/or early death for this patient, or until stopping criteria are met.

3. If there are excess (according to the criteria in Table 5.8) graft failures, that patient's dose and all lower doses are closed to further enrollment.

4. If there are excess (according to the criteria in Table 5.8) toxicities and/or early deaths, that patient's dose is closed to further enrollment.

5. Re-evaluate the desirability of the current dose level based on the 100-Day outcomes for toxicity and/or early death and graft failure.

6. Repeat steps 1-5 until 54 patients are enrolled in Phase II, or all dose levels are closed to further enrollment.

Dosage Levels for CY:

3 Days (Day -4, -3, -2): Dose of 50 mg/kg/day; total dose of 150 mg/kg; dose level 3

2 Days (Day -3, -2): Dose of 50 mg/kg/day; total dose of 100 mg/kg; dose level 2

1 Day (Day -2): Dose of 50 mg/kg/day; total dose of 50 mg/kg; dose level 1

0 Days (None): No dose; no total dose; dose level 0

There may be wait periods between enrollment of successive patients and/or cohorts for endpoint assessment. Under these circumstances, the final decision about waiting versus treating the patient off study will be made at the local transplant center.

Study Design

• Study Type: Interventional
• Actual Enrollment: 97 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Fludarabine-based Conditioning for Allogeneic Marrow Transplantation From HLA-compatible Unrelated Donors in Severe Aplastic Anemia (BMT CTN #0301)
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cyclophosphamide 150mg Fludarabine plus 150 mg/kg Cyclophosphamide (total dose)	Drug: Fludarabine; Doses of 30 mg/m^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2); Other Names: Fludara ; Drug: Cyclophosphamide 150mg; A total dose of 150 mg/kg will be given as 50 mg/kg per day for 3 days (Days -4, -3, -2); Other Names: Cytoxan®
Experimental: Cyclophosphamide 100mg Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Drug: Fludarabine; Doses of 30 mg/m^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2); Other Names: Fludara ; Drug: Cyclophosphamide 100mg; A total dose of 100 mg/kg will be given as 50 mg/kg per day for 2 days (Days -3, -2); Other Names: Cytoxan®
Experimental: Cyclophosphamide 50mg Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)	Drug: Fludarabine; Doses of 30 mg/m^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2); Other Names: Fludara ; Drug: Cyclophosphamide 50mg; A total dose of 50 mg/kg will be given once at 50 mg/kg per day on Day -2; Other Names: Cytoxan®
Experimental: Fludarabine Fludarabine only (no Cyclophosphamide administered)	Drug: Fludarabine; Doses of 30 mg/m^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2); Other Names: Fludara

Outcome Measures

Primary Outcome Measures

1. Disease-free Survival (DFS) [Day 100]

   DFS includes graft failure, regimen-related toxicity (RRT), and early death. Graft Failure is defined by lack of neutrophil engraftment (ANC less than 0.5 x 10^9/L for 3 consecutive days on different days). Major RRT is defined as severity of grade 4 in any organ system or grade 3 for pulmonary, cardiac, renal, oral mucosal or hepatic. Early death is defined as death prior to Day 100 post-transplant.

Secondary Outcome Measures

1. Cumulative Incidence of Graft Failure [Day 365]

   Primary and secondary graft failure are included, secondary graft failure is defined by initial neutrophil engraftment followed by subsequent decline in the ANC to less than 0.5 x 10^9/L for three consecutive measurements on different days, unresponsive to growth factor.

2. Acute Graft vs Host Disease (GVHD) [Day 100]

   All GVHD grades 2-4 will be graded according to the BMT CTN Manual of Procedures (MOP)

3. Chronic GVHD [Day 365]

   Chronic GVHD is scored according to the BMT CTN MOP. The first day of chronic GVHD onset will be used to calculate cumulative incidence curves.

4. Overall Survival (OS) [Day 365]

   OS is defined as alive at 1 year, the event is death from any cause. Patients alive at the time of last observation, for statistical purposes, will have a survival time which is censored.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients up to 65 years of age at time of registration with a diagnosis of SAA; SAA is defined as follows:

1. Bone marrow cellularity less than 25% or marrow cellularity less than 50% but with less than 30% residual hematopoietic cells

2. Two out of three of the following (in peripheral blood): neutrophils less than 0.5 x 10^{9/L; platelets less than 20 x 10}9/L; reticulocytes less than 20 x 10^9/L

• Patient must have an available unrelated donor with a 7/8 or 8/8 match for HLA-A, B, C, and DRB1 antigen; typing is by DNA techniques: intermediate resolution for A, B, and C, and high resolution for DRB1; HLA-DQ typing is recommended but will not count in the match

• Patient and/or legal guardian able to provide signed informed consent

• Matched unrelated donor must consent to provide a marrow allograft

• Patients with adequate organ function as measured by:

1. Cardiac: left ventricular ejection fraction at rest must be greater than 40% or shortening fraction greater than 20%

2. Hepatic: serum bilirubin less than 2x upper limit of normal for age as per local laboratory) (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome), alanine transaminase (ALT) and aspartate transaminase (AST) less than 4x upper limit of normal for age (as per local laboratory)

3. Renal: serum creatinine less than 2x upper limit of normal for age (as per local laboratory)

4. Pulmonary: Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) (corrected for Hb) greater than 50% predicted; for patients in which pulse oxymetry is performed, O2 saturation greater than 92%

• Diagnosis of Fanconi anemia must be excluded in patients younger than 18 years of age by diepoxybutane testing on peripheral blood or comparable testing on marrow.

Exclusion Criteria:

• Clonal cytogenetic abnormalities associated with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) on marrow examination

• Diagnosis of other "congenital" aplastic anemias such as: Diamond-Blackfan; Shwachman-Diamond; congenital amegakaryocytosis

• Symptomatic or uncontrolled cardiac failure or coronary artery disease

• Karnofsky performance status less than 60% or Lansky less than 40% for patients younger than 16 years old

• Uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms)

• Seropositive for the human immunodeficiency virus (HIV)

• Pregnant (positive total HCG) or breastfeeding

• Presence of large accumulation of ascites or pleural effusions, which would be a contraindication to the administration of methotrexate for GVHD prophylaxis

• Known severe or life-threatening allergy or intolerance to ATG or cyclosporine/ tacrolimus

• Planned administration of alemtuzumab (Campath-1H) or other investigational agents as alternative agent for GVHD prophylaxis

• Concomitant enrollment in a Phase I study

• Positive patient anti-donor lymphocyte crossmatch in HLA-A or B mismatched transplants; the definition of match is in Section 2.2.1; the crossmatch would only apply to mismatches at HLA-A or B, not DRB1 or HLA-C

• Prior allogeneic marrow or stem cell transplantation

• Patients with prior malignancies except resected basal cell carcinoma or treated carcinoma in-situ; cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Medical Monitor or Protocol Chair; cancer treated with curative intent more than 5 years previously will be allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
2	City of Hope National Medical Center	Duarte	California	United States	91010
3	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
4	Mattel Children's Hospital at UCLA	Los Angeles	California	United States	90095
5	Stanford Hospital and Clinics	Stanford	California	United States	94305
6	H. Lee Moffitt Cancer Center	Tampa	Florida	United States	33624
7	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
8	BMT Program at Northside Hospital	Atlanta	Georgia	United States	30342
9	DFCI/Brigham & Women's Hospital	Boston	Massachusetts	United States	02114
10	University of Michigan	Ann Arbor	Michigan	United States	48109
11	University of Minnesota	Minneapolis	Minnesota	United States	55455
12	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
13	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
14	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
15	Duke University Medical Center	Durham	North Carolina	United States	27705
16	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
17	Oregon Health & Science University	Portland	Oregon	United States	97239-3098
18	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
19	University of Texas, MD Anderson CRC	Houston	Texas	United States	77030
20	Texas Transplant Institute	San Antonio	Texas	United States	78229
21	Virginia Commonwealth University, MCV Hospital	Richmond	Virginia	United States	23298
22	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Medical College of Wisconsin
• National Heart, Lung, and Blood Institute (NHLBI)
• Blood and Marrow Transplant Clinical Trials Network
• National Cancer Institute (NCI)
• National Marrow Donor Program

Investigators

• Study Director: Mary Horowitz, MD, Center for International Blood and Marrow Transplant Research

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Jun 6, 2013

More Information

Additional Information:

• Blood and Marrow Transplant Clinical Trials Network Website
• National Marrow Donor Program

Publications

• Pulsipher MA, Young NS, Tolar J, Risitano AM, Deeg HJ, Anderlini P, Calado R, Kojima S, Eapen M, Harris R, Scheinberg P, Savage S, Maciejewski JP, Tiu RV, DiFronzo N, Horowitz MM, Antin JH. Optimization of therapy for severe aplastic anemia based on clinical, biologic, and treatment response parameters: conclusions of an international working group on severe aplastic anemia convened by the Blood and Marrow Transplant Clinical Trials Network, March 2010. Biol Blood Marrow Transplant. 2011 Mar;17(3):291-9. doi: 10.1016/j.bbmt.2010.10.028. Epub 2010 Oct 27.

• Responsible Party: Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT00326417
• Other Study ID Numbers: BMTCTN0301; U01HL069294; 5U01HL069294-05; 5U24CA076518; NCT00335608; NCT00474747
• First Posted: May 16, 2006
• Last Update Posted: Oct 28, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Medical College of Wisconsin: Severe Aplastic Anemia
• Additional relevant MeSH terms: Anemia; Anemia, Aplastic; Cyclophosphamide; Fludarabine

Study Results

Participant Flow

Recruitment Details	Participants were enrolled from February 2006 to August 2007 for Phase I of the trial. Phase II opened in November 2007 and closed to accrual on December 2, 2013.

Arm/Group Title	Cyclophosphamide 150mg	Cyclophosphamide 100mg	Cyclophosphamide 50mg	Fludarabine
Arm/Group Description	Fludarabine plus 150 mg/kg Cyclophosphamide (total dose)	Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)	Fludarabine only (no Cyclophosphamide administered)
Period Title: Overall Study
STARTED	14	41	39	3
Phase I	6	6	6	3
Phase II	8	35	33	0
COMPLETED	0	41	38	0
NOT COMPLETED	14	0	1	3

Baseline Characteristics

Arm/Group Title	Cyclophosphamide 100mg	Cyclophosphamide 50mg	Total
Arm/Group Description	Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)	Total of all reporting groups
Overall Participants	41	38	79
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	17.6	24.5	20.6
Age, Customized (participants) [Number]
< 18	21 51.2%	11 28.9%	32 40.5%
18 - 40	14 34.1%	18 47.4%	32 40.5%
> 40	6 14.6%	9 23.7%	15 19%
Sex: Female, Male (Count of Participants)
Female	20 48.8%	19 50%	39 49.4%
Male	21 51.2%	19 50%	40 50.6%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	34 82.9%	30 78.9%	64 81%
Hispanic or Latino	6 14.6%	8 21.1%	14 17.7%
Unknown	1 2.4%	0 0%	1 1.3%
Recipient Cytomegalovirus Status (participants) [Number]
Positive	26 63.4%	17 44.7%	43 54.4%
Negative	15 36.6%	21 55.3%	36 45.6%
Karnofsky Score (participants) [Number]
100	18 43.9%	12 31.6%	30 38%
90	15 36.6%	17 44.7%	32 40.5%
80	3 7.3%	7 18.4%	10 12.7%
70	4 9.8%	2 5.3%	6 7.6%
60	1 2.4%	0 0%	1 1.3%
Immunosuppressive therapy prior to transplant (participants) [Number]
Yes	41 100%	35 92.1%	76 96.2%
No	0 0%	3 7.9%	3 3.8%
Donor-recipient HLA match (participants) [Number]
HLA-A, -B, -C,-DRB1 matched	27 65.9%	31 81.6%	58 73.4%
Single HLA-locus mismatch	14 34.1%	7 18.4%	21 26.6%
Type of anti-thymocyte globulin administered (participants) [Number]
Rabbit-derived	33 80.5%	29 76.3%	62 78.5%
Horse-derived	7 17.1%	9 23.7%	16 20.3%
None	1 2.4%	0 0%	1 1.3%

Outcome Measures

1. Primary Outcome

Title	Disease-free Survival (DFS)
Description	DFS includes graft failure, regimen-related toxicity (RRT), and early death. Graft Failure is defined by lack of neutrophil engraftment (ANC less than 0.5 x 10^9/L for 3 consecutive days on different days). Major RRT is defined as severity of grade 4 in any organ system or grade 3 for pulmonary, cardiac, renal, oral mucosal or hepatic. Early death is defined as death prior to Day 100 post-transplant.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cyclophosphamide 100mg	Cyclophosphamide 50mg
Arm/Group Description	Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)
Measure Participants	41	38
Graft Failure	6 14.6%	3 7.9%
Major RRT	9 22%	4 10.5%
Survival	39 95.1%	37 97.4%
Alive and engrafted	35 85.4%	35 92.1%

2. Secondary Outcome

Title	Cumulative Incidence of Graft Failure
Description	Primary and secondary graft failure are included, secondary graft failure is defined by initial neutrophil engraftment followed by subsequent decline in the ANC to less than 0.5 x 10^9/L for three consecutive measurements on different days, unresponsive to growth factor.
Time Frame	Day 365

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cyclophosphamide 100mg	Cyclophosphamide 50mg
Arm/Group Description	Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)
Measure Participants	41	38
Number [percentage of participants]	14.6 35.6%	11.7 30.8%

3. Secondary Outcome

Title	Acute Graft vs Host Disease (GVHD)
Description	All GVHD grades 2-4 will be graded according to the BMT CTN Manual of Procedures (MOP)
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cyclophosphamide 100mg	Cyclophosphamide 50mg
Arm/Group Description	Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)
Measure Participants	41	38
Number (95% Confidence Interval) [percentage of participants]	26.8 65.4%	23.7 62.4%

4. Secondary Outcome

Title	Chronic GVHD
Description	Chronic GVHD is scored according to the BMT CTN MOP. The first day of chronic GVHD onset will be used to calculate cumulative incidence curves.
Time Frame	Day 365

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cyclophosphamide 100mg	Cyclophosphamide 50mg
Arm/Group Description	Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)
Measure Participants	41	38
Number (95% Confidence Interval) [percentage of participants]	31.7 77.3%	22.5 59.2%

5. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as alive at 1 year, the event is death from any cause. Patients alive at the time of last observation, for statistical purposes, will have a survival time which is censored.
Time Frame	Day 365

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cyclophosphamide 100mg	Cyclophosphamide 50mg
Arm/Group Description	Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)	Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)
Measure Participants	41	38
Number (95% Confidence Interval) [percentage of participants]	80.5 196.3%	97.4 256.3%

Adverse Events

Time Frame	1 year post-transplant
Adverse Event Reporting Description	Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Arm/Group Title	Cyclophosphamide 150mg		Cyclophosphamide 100mg		Cyclophosphamide 50mg		Fludarabine
Arm/Group Description	Fludarabine plus 150 mg/kg Cyclophosphamide (total dose)		Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)		Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)		Fludarabine only (no Cyclophosphamide administered)
All Cause Mortality
	Cyclophosphamide 150mg		Cyclophosphamide 100mg		Cyclophosphamide 50mg		Fludarabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cyclophosphamide 150mg		Cyclophosphamide 100mg		Cyclophosphamide 50mg		Fludarabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/14 (57.1%)		4/41 (9.8%)		4/38 (10.5%)		1/3 (33.3%)
Eye disorders
Papilloedema	0/14 (0%)	0	0/41 (0%)	0	0/38 (0%)	0	1/3 (33.3%)	1
General disorders
Death	7/14 (50%)	7	2/41 (4.9%)	2	1/38 (2.6%)	1	0/3 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastasis	0/14 (0%)	0	1/41 (2.4%)	1	0/38 (0%)	0	0/3 (0%)	0
Nervous system disorders
Cerebral ischaemia	0/14 (0%)	0	1/41 (2.4%)	1	0/38 (0%)	0	0/3 (0%)	0
Somnolence	0/14 (0%)	0	0/41 (0%)	0	1/38 (2.6%)	1	0/3 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/14 (7.1%)	1	0/41 (0%)	0	0/38 (0%)	0	0/3 (0%)	0
Vascular disorders
Deep vein thrombosis	0/14 (0%)	0	0/41 (0%)	0	1/38 (2.6%)	1	0/3 (0%)	0
Peripheral arterial occlusive disease	0/14 (0%)	0	0/41 (0%)	0	1/38 (2.6%)	1	0/3 (0%)	0
Other (Not Including Serious) Adverse Events
	Cyclophosphamide 150mg		Cyclophosphamide 100mg		Cyclophosphamide 50mg		Fludarabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		1/41 (2.4%)		0/38 (0%)		0/3 (0%)
Cardiac disorders
Pericardial effusion	0/14 (0%)	0	1/41 (2.4%)	1	0/38 (0%)	0	0/3 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.