Donor Stem Cell Transplant in Treating Patients With High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

• Sponsor: Alliance for Clinical Trials in Oncology (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01027000
• Collaborator: National Cancer Institute (NCI) (NIH), Genentech, Inc. (Industry), Biologics, Inc. (Industry)
• Enrollment: 68
• Locations: 25
• Arm: 1
• Patients Per Site: 2.7

Study Details

Study Description

Brief Summary

RATIONALE: Giving low doses of chemotherapy before a donor stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. Also, monoclonal antibodies, such as rituximab, can find cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus, sirolimus, and methotrexate after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well donor stem cell transplant works in treating patients with high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Lymphoma	Biological: rituximab; Drug: busulfan; Drug: cyclophosphamide; Drug: fludarabine phosphate; Drug: methotrexate; Drug: sirolimus; Drug: tacrolimus; Procedure: allogeneic stem cell transplant	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To determine if this treatment can improve 2-year current progression-free survival (PFS) in the early disease cohort compared to historical controls. Specifically, we plan to study whether we can achieve 2-year PFS ≥ 70% and to exclude 2 year PFS ≤ 50%

Secondary

• To determine whether in the advanced disease cohort we can achieve 2-year current PFS ≥ 50% and to exclude 2-year PFS ≤ 30%

• To assess objective response rate.

• To assess the incidence of grade 2-4 and 3-4 acute graft-vs-host disease (GVHD).

• To assess the incidence of extensive chronic GVHD.

• To assess the incidence of treatment-related mortality at 100 days and 1 year

• To assess overall survival

• To assess donor chimerism for CD3+ cells at 1 and 2 years after transplantation

• To investigate the presence of donor antigen-specific T-cell clones before and after withdrawal of immune suppression.

• To compare the relapse profiles of patients with T-cell responses against CLL to those whose CLL cells are not reactive

• To prospectively examine the impact of high-risk genomic features and immune-based single nucleotide polymorphisms on response, toxicity, and 2-year PFS to reduced intensity allogeneic stem cell transplant

OUTLINE: This is a multicenter study.

• Preparative regimen: Patients receive 1 of 2 preparative regimens at the discretion of the participating institution.

• Preparative regimen 1: Patients receive rituximab IV on days -7, -1, 7, and 14 and fludarabine phosphate IV over 30 minutes and busulfan IV over 3 hours on days -5 to -2. .

• Preparative regimen 2: Patients receive rituximab IV on days -7, -1, 7, and 14, fludarabine phosphate IV over 30 minutes on days -5 to -2, and cyclophosphamide IV over 1-2 hours on days -5 to -3. Patients with matched unrelated donors also receive anti-thymocyte globulin IV over 4-6 hours on days -6 to -4.

• Graft-vs-host disease (GVHD) prophylaxis: Patients who receive preparative regimen 1 may receive either GVHD prophylaxis regimen 1 or 2; patients who receive preparative regimen 2 may only receive GVHD prophylaxis regimen 2.

• GVHD prophylaxis regimen 1: Patients receive tacrolimus either orally or IV and oral sirolimus beginning on day -2 and continuing until day 60, followed by a taper until day 180. Patients also receive methotrexate IV on days 1, 3, and 6.

• GVHD prophylaxis regimen 2: Patients receive tacrolimus either orally or IV beginning on day -2 and continuing until day 60, followed by a taper until day 180. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

• Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.

• Maintenance therapy: Patients receive rituximab IV at 3, 6, 9, and 12 months after transplantation.

Peripheral blood and bone marrow aspirate samples may be collected periodically for correlative laboratory studies.

Patients are followed up periodically for a maximum of 5 years from study entry.

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Reduced-Intensity Allogeneic Stem Cell Transplant for High-Risk Chronic Lymphocytic Leukemia (CLL)
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (Combination of chemotherapy and transplant) See detailed description	Biological: rituximab; Drug: busulfan; Drug: cyclophosphamide; Drug: fludarabine phosphate; Drug: methotrexate; Drug: sirolimus; Drug: tacrolimus; Procedure: allogeneic stem cell transplant

Outcome Measures

Primary Outcome Measures

1. 2-year Progression-free Survival in Early Disease Participants [2 years post-registration]

   Percentage of participants who were alive and progression free at 2 years for participants with early disease stage. The 2 year progression free survival, with 95% confidence interval, was estimated using the Kaplan Meier method. A progression is defined as one of the following events: >= 50% increase in the products of at least two lymph nodes on two consecutive determinations two weeks apart (at least one lymph node must be >= 2 cm); appearance of new palpable lymph nodes. >= 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin; appearance of palpable hepatomegaly or splenomegaly, which was not previously present. > 50% increase in peripheral blood lymphocytes with an absolute increase > 5000/μL. Transformation to a more aggressive histology (i.e., Richter's syndrome or prolymphocytic leukemia with >= 56% prolymphocytes).

Secondary Outcome Measures

1. Response [5 years post-registration]

2. Acute Graft-vs-host Disease (GVHD) [5 years post-registration]

3. Chronic GVHD [5 years post-registration]

4. Treatment-related Mortality [6 months post-transplant]

5. Overall Survival [5 years post-registration]

6. Chimerism for CD3 [5 years post-registration]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 69 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Patient Eligibility:

1. Diagnosis of B-cell chronic lymphocytic leukemia or B-cell small lymphocytic lymphoma.

Diagnosis should be according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria

1. Early Disease Cohort - Patients in the early disease cohort must include one or more of the following:

• FISH showing deletion 17p in ≥ 20% of cells (either at diagnosis or any time prior to study entry) either alone or in combination with other cytogenetic abnormalities

• FISH showing del 11q in ≥ 20% of cells (either at diagnosis or any time prior to study entry) either alone or in combination with other cytogenetic abnormalities, unless the patient has achieved a complete remission by IWCLL 2008 which includes CT scan, bone marrow morphology and flow cytometry

• Failure to achieve a partial response with initial chemotherapy, but with lack of progression. These patients may receive a second therapy to improve their response prior to transplant.

• Patients who, at the time of first progression, have a 17p deletion by FISH in ≥ 20% of cells, either alone or in combination with other cytogenetic abnormalities.

The duration of the first progression is not specified.

• In addition, patients in the early disease cohort must have all of the following:

• Received at least 2 cycles of induction therapy. It is expected that most patients will receive at least 4 months of therapy prior to enrollment, but this is not required. Suggested regimens include but are not limited to the following: fludarabine plus rituximab, fludarabine, cyclophosphamide plus rituximab, pentostatin, cyclophosphamide plus rituximab, bendumustine plus rituximab, or alemtuzumab alone or in combination with other agents. Patients may receive no more than 2 different regimens prior to proceeding to transplantation.

• Nodes ≤ 5 cm

1. Advanced Disease Cohort - Patients in the advanced disease cohort must include one or more of the following:

• FISH showing deletion 17p in ≥ 20% of cells (regardless of interval from initial therapy) either alone or in combination with other cytogenetic abnormalities

• First progression < 24 months after completing therapy. This includes progression on initial therapy.

• Second or subsequent progression

• In addition, patients in the advanced disease cohort must have all of the following:

• Stable disease or better by the Revised IWCLL 2008 NCI Criteria to their most recent chemotherapy

• Nodes ≤ 5 cm

1. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

2. Age Requirement - Patients must be between ≥ 18 and < 70 years of age

3. Cytotoxic Chemotherapy or Alemtuzamab - There must be at least 4 weeks after day 1 of the last cycle of cytotoxic chemotherapy, or alemtuzamab.

4. Human Immunodeficiency Virus (HIV) Status - Patients must have no HIV infection.

Allogeneic transplantation in the HIV patient population is not well-defined and there are likely to be requirements for concomitant anti-HIV therapy and anti-GVHD therapy that would create potentially dangerous pharmacokinetic interactions among the different agents that could constrain therapeutic options for controlling both HIV and GVHD.

1. Hepatitis B and C - Patients must have no Hepatitis B sAg, anti-HBc or HCV.

2. Diffusion capacity of carbon monoxide DLCO must be ≥ 40% predicted

3. Left ventricular ejection fraction (LVEF) by Echocardiogram (ECHO) or Multiple gated acquisition (MUGA) must be ≥ 30%

4. Diabetes or Serious Infection - Patients must have no uncontrolled diabetes mellitus or active uncontrolled serious infections

5. Pregnancy and Nursing Status - Patients must be non-pregnant and non-nursing. Treatment under this protocol would expose a fetus to significant risks. Women of childbearing potential should have a negative pregnancy test prior to study entry.

Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include oral contraceptives, implantable hormonal contraceptives (Norplant®), or double barrier method (diaphragm plus condom).

1. Richter's Transformation - Patients must have no history of Richter's transformation.

2. Initial Required Laboratory Values:

• Serum Creatinine < 2 mg/dL

• Calculated Creatinine Clearance ≥ 40 mL/min

• AST < 3 x ULN

• Total Bilirubin < 2 mg/dL (except for Gilbert's syndrome)

Donor Eligibility:

1. Donors may be either a 6/6 HLA-matched related donor by low-resolution typing at HLA A, B, DR.

2. Donors may be an 8/8 HLA-matched unrelated donor at HLA A, B, C, DR. Unrelated donors will be analyzed by molecular typing at both HLA Class I and Class II (A, B, C, DR loci).

3. Syngeneic donors are not eligible

4. Donors must be healthy and must be an acceptable donor as per institutional standards for stem cell donation.

5. There will be no donor age restriction.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010-3000
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	Florida Hospital Cancer Institute at Florida Hospital Orlando	Orlando	Florida	United States	32803-1273
5	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida	United States	33612-9497
6	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637-1470
7	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa	United States	52242-1002
8	Union Hospital of Cecil County	Elkton	Maryland	United States	21921
9	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
10	Dana-Farber/Brigham and Women's Cancer Center	Boston	Massachusetts	United States	02115
11	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
12	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
13	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-6805
14	Cancer Institute of New Jersey at Cooper - Voorhees	Voorhees	New Jersey	United States	08043
15	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
16	Monter Cancer Center of the North Shore-LIJ Health System	Lake Success	New York	United States	11042
17	CCOP - North Shore University Hospital	Manhasset	New York	United States	11030
18	Don Monti Comprehensive Cancer Center at North Shore University Hospital	Manhasset	New York	United States	11030
19	Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
20	New York Weill Cornell Cancer Center at Cornell University	New York	New York	United States	10021
21	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
22	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
23	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
24	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210-1240
25	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma	United States	73104

Sponsors and Collaborators

• Alliance for Clinical Trials in Oncology
• National Cancer Institute (NCI)
• Genentech, Inc.
• Biologics, Inc.

Investigators

• Study Chair: Edwin P. Alyea, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alliance for Clinical Trials in Oncology
• ClinicalTrials.gov Identifier: NCT01027000
• Other Study ID Numbers: CALGB 100701; CDR0000660555; U10CA031946; NCI-2011-01995
• First Posted: Dec 7, 2009
• Last Update Posted: Aug 18, 2021
• Last Verified: Aug 1, 2021

• Keywords provided by Alliance for Clinical Trials in Oncology: refractory chronic lymphocytic leukemia; stage I chronic lymphocytic leukemia; stage II chronic lymphocytic leukemia; stage III chronic lymphocytic leukemia; stage IV chronic lymphocytic leukemia; B-cell chronic lymphocytic leukemia; contiguous stage II small lymphocytic lymphoma; noncontiguous stage II small lymphocytic lymphoma; recurrent small lymphocytic lymphoma; stage I small lymphocytic lymphoma; stage III small lymphocytic lymphoma; stage IV small lymphocytic lymphoma
• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Sirolimus; Cyclophosphamide; Busulfan; Rituximab; Methotrexate; Fludarabine; Fludarabine phosphate; Tacrolimus

Study Results

Participant Flow

Recruitment Details	Between February 2010 and January 2014, 68 participants were recruited.

Arm/Group Title	Treatment (Combination of Chemotherapy and Transplant)
Arm/Group Description	Preparative: Patients receive 1 of 2 preparative regimens (Reg) chosen by the treating institution Reg1: Rituximab (RTX) 500 mg/m^2 IV on days -7, -1, 7, and 14 & fludarabine phosphate (FP) 30 mg/m^2 IV & busulfan 0.8 mg/kg IV on days -5 to -2 Reg 2: RTX 500 mg/m^2 IV on days -7, -1, 7, and 14 & FP 30 mg/m^2 IV on days -5 to -2 & cyclophosphamide 1 g/m^2 IV on days -5 to -3 Graft-vs-host disease (GVHD) prophylaxis: Patients treated with preparative regimen 1 received either GVHD prophylaxis regimen 1 or 2; those given preparative regimen 2 received regimen 2 Reg 1: Tacrolimus PO or IV & oral sirolimus 12 mg on day -2 through day 60, followed by taper until day 180 & methotrexate (MTX) 5 mg/m^2 IV on days 1, 3, and 6. Reg 2: Tacrolimus PO or IV on day -2 through day 60, followed by taper until day 180 & MTX 5mg/m^2 IV on days 1, 3, 6, & 11 Transplantation: allogeneic peripheral blood transplant on day 0 Maintenance: RTX 500 mg/m^2 IV at 3, 6, 9, & 12 months post-transplant
Period Title: Overall Study
STARTED	68
COMPLETED	68
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Combination of Chemotherapy and Transplant)
Arm/Group Description	Preparative: Patients receive 1 of 2 preparative regimens (Reg) chosen by the treating institution Reg1: Rituximab (RTX) 500 mg/m^2 IV on days -7, -1, 7, and 14 & fludarabine phosphate (FP) 30 mg/m^2 IV & busulfan 0.8 mg/kg IV on days -5 to -2 Reg 2: RTX 500 mg/m^2 IV on days -7, -1, 7, and 14 & FP 30 mg/m^2 IV on days -5 to -2 & cyclophosphamide 1 g/m^2 IV on days -5 to -3 Graft-vs-host disease (GVHD) prophylaxis: Patients treated with preparative regimen 1 received either GVHD prophylaxis regimen 1 or 2; those given preparative regimen 2 received regimen 2 Reg 1: Tacrolimus PO or IV & oral sirolimus 12 mg on day -2 through day 60, followed by taper until day 180 & methotrexate (MTX) 5 mg/m^2 IV on days 1, 3, and 6. Reg 2: Tacrolimus PO or IV on day -2 through day 60, followed by taper until day 180 & MTX 5mg/m^2 IV on days 1, 3, 6, & 11 Transplantation: allogeneic peripheral blood transplant on day 0 Maintenance: RTX 500 mg/m^2 IV at 3, 6, 9, & 12 months post-transplant
Overall Participants	68
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56
Sex: Female, Male (Count of Participants)
Female	22 32.4%
Male	46 67.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 2.9%
Not Hispanic or Latino	62 91.2%
Unknown or Not Reported	4 5.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 1.5%
White	66 97.1%
More than one race	0 0%
Unknown or Not Reported	1 1.5%
Region of Enrollment (participants) [Number]
United States	68 100%
Disease stage (participants) [Number]
Early Disease	14 20.6%
Advanced Disease	50 73.5%
Not reported	4 5.9%

Outcome Measures

1. Primary Outcome

Title	2-year Progression-free Survival in Early Disease Participants
Description	Percentage of participants who were alive and progression free at 2 years for participants with early disease stage. The 2 year progression free survival, with 95% confidence interval, was estimated using the Kaplan Meier method. A progression is defined as one of the following events: >= 50% increase in the products of at least two lymph nodes on two consecutive determinations two weeks apart (at least one lymph node must be >= 2 cm); appearance of new palpable lymph nodes. >= 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin; appearance of palpable hepatomegaly or splenomegaly, which was not previously present. > 50% increase in peripheral blood lymphocytes with an absolute increase > 5000/μL. Transformation to a more aggressive histology (i.e., Richter's syndrome or prolymphocytic leukemia with >= 56% prolymphocytes).
Time Frame	2 years post-registration

Outcome Measure Data

Analysis Population Description

Participants with early disease stage were analyzed. Two participants, who did not start protocol therapy, were excluded from this analysis.

Arm/Group Title	Treatment (Combination of Chemotherapy and Transplant)
Arm/Group Description	Preparative: Patients receive 1 of 2 preparative regimens (Reg) chosen by the treating institution Reg1: Rituximab (RTX) 500 mg/m^2 IV on days -7, -1, 7, and 14 & fludarabine phosphate (FP) 30 mg/m^2 IV & busulfan 0.8 mg/kg IV on days -5 to -2 Reg 2: RTX 500 mg/m^2 IV on days -7, -1, 7, and 14 & FP 30 mg/m^2 IV on days -5 to -2 & cyclophosphamide 1 g/m^2 IV on days -5 to -3 Graft-vs-host disease (GVHD) prophylaxis: Patients treated with preparative regimen 1 received either GVHD prophylaxis regimen 1 or 2; those given preparative regimen 2 received regimen 2 Reg 1: Tacrolimus PO or IV & oral sirolimus 12 mg on day -2 through day 60, followed by taper until day 180 & methotrexate (MTX) 5 mg/m^2 IV on days 1, 3, and 6. Reg 2: Tacrolimus PO or IV on day -2 through day 60, followed by taper until day 180 & MTX 5mg/m^2 IV on days 1, 3, 6, & 11 Transplantation: allogeneic peripheral blood transplant on day 0 Maintenance: RTX 500 mg/m^2 IV at 3, 6, 9, & 12 months post-transplant
Measure Participants	12
Median (95% Confidence Interval) [percentage of participants]	79.5 116.9%

2. Secondary Outcome

Title	Response
Time Frame	5 years post-registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Acute Graft-vs-host Disease (GVHD)
Time Frame	5 years post-registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Chronic GVHD
Time Frame	5 years post-registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Treatment-related Mortality
Time Frame	6 months post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Overall Survival
Time Frame	5 years post-registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Chimerism for CD3
Time Frame	5 years post-registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Adverse Event Reporting Description	Adverse event data is available for 59 participants . The remaining 9 participants cancelled before beginning treatment or withdrew consent for follow-up.
Arm/Group Title	Treatment (Combination of Chemotherapy and Transplant)
Arm/Group Description	Preparative: Patients receive 1 of 2 preparative regimens (Reg) chosen by the treating institution Reg1: Rituximab (RTX) 500 mg/m^2 IV on days -7, -1, 7, and 14 & fludarabine phosphate (FP) 30 mg/m^2 IV & busulfan 0.8 mg/kg IV on days -5 to -2 Reg 2: RTX 500 mg/m^2 IV on days -7, -1, 7, and 14 & FP 30 mg/m^2 IV on days -5 to -2 & cyclophosphamide 1 g/m^2 IV on days -5 to -3 Graft-vs-host disease (GVHD) prophylaxis: Patients treated with preparative regimen 1 received either GVHD prophylaxis regimen 1 or 2; those given preparative regimen 2 received regimen 2 Reg 1: Tacrolimus PO or IV & oral sirolimus 12 mg on day -2 through day 60, followed by taper until day 180 & methotrexate (MTX) 5 mg/m^2 IV on days 1, 3, and 6. Reg 2: Tacrolimus PO or IV on day -2 through day 60, followed by taper until day 180 & MTX 5mg/m^2 IV on days 1, 3, 6, & 11 Transplantation: allogeneic peripheral blood transplant on day 0 Maintenance: RTX 500 mg/m^2 IV at 3, 6, 9, & 12 months post-transplant
All Cause Mortality
	Treatment (Combination of Chemotherapy and Transplant)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Combination of Chemotherapy and Transplant)
	Affected / at Risk (%)	# Events
Total	6/59 (10.2%)
Blood and lymphatic system disorders
Anemia	5/59 (8.5%)	8
Ear and labyrinth disorders
Vertigo	1/59 (1.7%)	3
Eye disorders
Corneal ulcer	1/59 (1.7%)	1
Eye disorders - Other, specify	1/59 (1.7%)	1
Keratitis	1/59 (1.7%)	1
Gastrointestinal disorders
Diarrhea	1/59 (1.7%)	1
Mucositis oral	1/59 (1.7%)	1
Nausea	1/59 (1.7%)	3
Vomiting	1/59 (1.7%)	3
General disorders
Edema limbs	1/59 (1.7%)	1
Fatigue	3/59 (5.1%)	3
Infections and infestations
Infections and infestations - Other, specify	1/59 (1.7%)	1
Lung infection	2/59 (3.4%)	2
Sepsis	1/59 (1.7%)	1
Skin infection	1/59 (1.7%)	1
Urinary tract infection	2/59 (3.4%)	2
Vaginal infection	1/59 (1.7%)	1
Investigations
Alanine aminotransferase increased	2/59 (3.4%)	2
Aspartate aminotransferase increased	1/59 (1.7%)	1
Blood bilirubin increased	2/59 (3.4%)	2
Cholesterol high	1/59 (1.7%)	1
Creatinine increased	4/59 (6.8%)	5
Investigations - Other, specify	1/59 (1.7%)	1
Lymphocyte count decreased	3/59 (5.1%)	5
Neutrophil count decreased	4/59 (6.8%)	6
Platelet count decreased	6/59 (10.2%)	7
White blood cell decreased	3/59 (5.1%)	4
Metabolism and nutrition disorders
Anorexia	1/59 (1.7%)	1
Glucose intolerance	1/59 (1.7%)	2
Hyperglycemia	5/59 (8.5%)	6
Hypertriglyceridemia	1/59 (1.7%)	1
Hypoalbuminemia	2/59 (3.4%)	2
Hypocalcemia	2/59 (3.4%)	2
Hypokalemia	1/59 (1.7%)	1
Hypomagnesemia	1/59 (1.7%)	1
Hyponatremia	1/59 (1.7%)	1
Nervous system disorders
Dizziness	1/59 (1.7%)	3
Dysphasia	1/59 (1.7%)	1
Edema cerebral	1/59 (1.7%)	1
Intracranial hemorrhage	2/59 (3.4%)	2
Nervous system disorders - Other, specify	2/59 (3.4%)	4
Stroke	1/59 (1.7%)	1
Tremor	1/59 (1.7%)	1
Psychiatric disorders
Psychiatric disorders - Other, specify	1/59 (1.7%)	1
Renal and urinary disorders
Chronic kidney disease	1/59 (1.7%)	1
Reproductive system and breast disorders
Genital edema	1/59 (1.7%)	1
Skin and subcutaneous tissue disorders
Pruritus	1/59 (1.7%)	1
Rash maculo-papular	4/59 (6.8%)	4
Vascular disorders
Hypertension	3/59 (5.1%)	3
Hypotension	2/59 (3.4%)	2
Thromboembolic event	1/59 (1.7%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Combination of Chemotherapy and Transplant)
	Affected / at Risk (%)	# Events
Total	58/59 (98.3%)
Blood and lymphatic system disorders
Anemia	48/59 (81.4%)	161
Blood and lymphatic system disorders - Other, specify	2/59 (3.4%)	4
Febrile neutropenia	6/59 (10.2%)	7
Hemolysis	1/59 (1.7%)	1
Leukocytosis	5/59 (8.5%)	5
Cardiac disorders
Atrioventricular block first degree	1/59 (1.7%)	1
Palpitations	1/59 (1.7%)	1
Restrictive cardiomyopathy	1/59 (1.7%)	1
Sinus bradycardia	2/59 (3.4%)	2
Sinus tachycardia	4/59 (6.8%)	5
Supraventricular tachycardia	1/59 (1.7%)	1
Ear and labyrinth disorders
Ear pain	1/59 (1.7%)	4
Tinnitus	1/59 (1.7%)	1
Endocrine disorders
Cushingoid	3/59 (5.1%)	4
Endocrine disorders - Other, specify	1/59 (1.7%)	4
Eye disorders
Blurred vision	3/59 (5.1%)	3
Cataract	1/59 (1.7%)	1
Corneal ulcer	1/59 (1.7%)	2
Dry eye	6/59 (10.2%)	11
Eye disorders - Other, specify	5/59 (8.5%)	7
Eye pain	1/59 (1.7%)	1
Keratitis	1/59 (1.7%)	1
Papilledema	1/59 (1.7%)	1
Photophobia	1/59 (1.7%)	1
Scleral disorder	1/59 (1.7%)	1
Gastrointestinal disorders
Abdominal distension	4/59 (6.8%)	7
Abdominal pain	13/59 (22%)	21
Ascites	2/59 (3.4%)	6
Colonic ulcer	1/59 (1.7%)	1
Constipation	11/59 (18.6%)	14
Diarrhea	28/59 (47.5%)	54
Dry mouth	6/59 (10.2%)	16
Dyspepsia	3/59 (5.1%)	3
Dysphagia	1/59 (1.7%)	1
Enterocolitis	1/59 (1.7%)	1
Esophagitis	1/59 (1.7%)	1
Gastritis	3/59 (5.1%)	3
Gastrointestinal disorders - Other, specify	4/59 (6.8%)	4
Gastrointestinal pain	1/59 (1.7%)	3
Hemorrhoids	2/59 (3.4%)	2
Ileus	1/59 (1.7%)	1
Lip pain	1/59 (1.7%)	1
Malabsorption	1/59 (1.7%)	1
Mucositis oral	9/59 (15.3%)	9
Nausea	29/59 (49.2%)	64
Oral pain	3/59 (5.1%)	4
Pancreatitis	1/59 (1.7%)	1
Rectal pain	2/59 (3.4%)	2
Stomach pain	1/59 (1.7%)	1
Toothache	1/59 (1.7%)	1
Vomiting	17/59 (28.8%)	28
General disorders
Chills	8/59 (13.6%)	11
Edema face	5/59 (8.5%)	5
Edema limbs	17/59 (28.8%)	42
Fatigue	34/59 (57.6%)	105
Fever	17/59 (28.8%)	22
Infusion related reaction	2/59 (3.4%)	2
Injection site reaction	1/59 (1.7%)	1
Irritability	2/59 (3.4%)	2
Localized edema	1/59 (1.7%)	1
Malaise	3/59 (5.1%)	3
Neck edema	1/59 (1.7%)	1
Non-cardiac chest pain	2/59 (3.4%)	2
Pain	4/59 (6.8%)	8
Hepatobiliary disorders
Cholecystitis	2/59 (3.4%)	3
Hepatic failure	1/59 (1.7%)	1
Hepatobiliary disorders - Other, specify	5/59 (8.5%)	10
Immune system disorders
Allergic reaction	2/59 (3.4%)	2
Infections and infestations
Abdominal infection	1/59 (1.7%)	1
Bronchial infection	1/59 (1.7%)	1
Catheter related infection	2/59 (3.4%)	2
Eye infection	1/59 (1.7%)	1
Hepatic infection	1/59 (1.7%)	1
Infections and infestations - Other, specify	9/59 (15.3%)	14
Joint infection	1/59 (1.7%)	1
Lip infection	1/59 (1.7%)	1
Lung infection	8/59 (13.6%)	9
Meningitis	1/59 (1.7%)	1
Mucosal infection	2/59 (3.4%)	4
Rhinitis infective	1/59 (1.7%)	1
Sepsis	2/59 (3.4%)	2
Sinusitis	2/59 (3.4%)	9
Skin infection	1/59 (1.7%)	1
Upper respiratory infection	9/59 (15.3%)	15
Urinary tract infection	1/59 (1.7%)	1
Vaginal infection	1/59 (1.7%)	1
Injury, poisoning and procedural complications
Bruising	1/59 (1.7%)	3
Fall	1/59 (1.7%)	1
Fracture	2/59 (3.4%)	2
Hip fracture	1/59 (1.7%)	1
Intraoperative renal injury	1/59 (1.7%)	1
Investigations
Activated partial thromboplastin time prolonged	7/59 (11.9%)	8
Alanine aminotransferase increased	26/59 (44.1%)	65
Alkaline phosphatase increased	17/59 (28.8%)	37
Aspartate aminotransferase increased	25/59 (42.4%)	71
Blood bilirubin increased	21/59 (35.6%)	44
Cholesterol high	8/59 (13.6%)	12
Creatinine increased	36/59 (61%)	70
INR increased	1/59 (1.7%)	1
Investigations - Other, specify	13/59 (22%)	51
Lymphocyte count decreased	35/59 (59.3%)	97
Lymphocyte count increased	7/59 (11.9%)	9
Neutrophil count decreased	51/59 (86.4%)	137
Platelet count decreased	52/59 (88.1%)	143
Weight gain	1/59 (1.7%)	1
Weight loss	7/59 (11.9%)	9
White blood cell decreased	33/59 (55.9%)	80
Metabolism and nutrition disorders
Anorexia	10/59 (16.9%)	14
Dehydration	1/59 (1.7%)	1
Hypercalcemia	1/59 (1.7%)	1
Hyperglycemia	40/59 (67.8%)	153
Hyperkalemia	14/59 (23.7%)	22
Hypermagnesemia	4/59 (6.8%)	4
Hypernatremia	7/59 (11.9%)	9
Hypertriglyceridemia	14/59 (23.7%)	19
Hyperuricemia	1/59 (1.7%)	1
Hypoalbuminemia	19/59 (32.2%)	34
Hypocalcemia	26/59 (44.1%)	50
Hypoglycemia	4/59 (6.8%)	5
Hypokalemia	13/59 (22%)	18
Hypomagnesemia	25/59 (42.4%)	52
Hyponatremia	18/59 (30.5%)	39
Hypophosphatemia	12/59 (20.3%)	22
Metabolism and nutrition disorders - Other, specify	4/59 (6.8%)	9
Obesity	9/59 (15.3%)	27
Musculoskeletal and connective tissue disorders
Abdominal soft tissue necrosis	1/59 (1.7%)	1
Arthralgia	8/59 (13.6%)	12
Arthritis	4/59 (6.8%)	7
Back pain	15/59 (25.4%)	21
Bone pain	2/59 (3.4%)	2
Chest wall pain	1/59 (1.7%)	1
Flank pain	4/59 (6.8%)	4
Generalized muscle weakness	4/59 (6.8%)	6
Musculoskeletal and connective tissue disorder - Other, specify	4/59 (6.8%)	6
Myalgia	7/59 (11.9%)	9
Neck pain	3/59 (5.1%)	5
Osteoporosis	1/59 (1.7%)	1
Pain in extremity	5/59 (8.5%)	5
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/59 (1.7%)	3
Nervous system disorders
Ataxia	1/59 (1.7%)	1
Dizziness	7/59 (11.9%)	11
Dysesthesia	1/59 (1.7%)	1
Dysgeusia	3/59 (5.1%)	4
Headache	23/59 (39%)	31
Lethargy	1/59 (1.7%)	1
Nervous system disorders - Other, specify	1/59 (1.7%)	1
Neuralgia	2/59 (3.4%)	3
Paresthesia	2/59 (3.4%)	3
Peripheral motor neuropathy	3/59 (5.1%)	3
Peripheral sensory neuropathy	7/59 (11.9%)	14
Sinus pain	3/59 (5.1%)	5
Stroke	1/59 (1.7%)	2
Syncope	1/59 (1.7%)	1
Transient ischemic attacks	1/59 (1.7%)	1
Tremor	14/59 (23.7%)	25
Psychiatric disorders
Agitation	1/59 (1.7%)	4
Anxiety	7/59 (11.9%)	16
Confusion	1/59 (1.7%)	1
Delirium	1/59 (1.7%)	1
Depression	7/59 (11.9%)	12
Hallucinations	1/59 (1.7%)	1
Insomnia	8/59 (13.6%)	9
Libido decreased	2/59 (3.4%)	2
Psychiatric disorders - Other, specify	1/59 (1.7%)	1
Renal and urinary disorders
Acute kidney injury	2/59 (3.4%)	2
Cystitis noninfective	2/59 (3.4%)	2
Hematuria	2/59 (3.4%)	3
Renal and urinary disorders - Other, specify	2/59 (3.4%)	2
Urinary frequency	3/59 (5.1%)	6
Urinary urgency	1/59 (1.7%)	1
Urine discoloration	1/59 (1.7%)	2
Reproductive system and breast disorders
Erectile dysfunction	1/59 (1.7%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	2/59 (3.4%)	9
Apnea	2/59 (3.4%)	3
Aspiration	2/59 (3.4%)	3
Atelectasis	1/59 (1.7%)	2
Bronchopleural fistula	1/59 (1.7%)	1
Cough	22/59 (37.3%)	44
Dyspnea	15/59 (25.4%)	28
Epistaxis	4/59 (6.8%)	5
Hoarseness	1/59 (1.7%)	1
Hypoxia	4/59 (6.8%)	5
Nasal congestion	7/59 (11.9%)	8
Pharyngolaryngeal pain	2/59 (3.4%)	2
Pleural effusion	3/59 (5.1%)	3
Pleuritic pain	2/59 (3.4%)	3
Pneumonitis	6/59 (10.2%)	8
Postnasal drip	2/59 (3.4%)	3
Productive cough	3/59 (5.1%)	3
Respiratory failure	2/59 (3.4%)	2
Respiratory, thoracic and mediastinal disorders - Other, specify	5/59 (8.5%)	10
Sinus disorder	1/59 (1.7%)	1
Sleep apnea	2/59 (3.4%)	3
Sore throat	7/59 (11.9%)	7
Wheezing	1/59 (1.7%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/59 (1.7%)	2
Dry skin	5/59 (8.5%)	12
Erythema multiforme	1/59 (1.7%)	1
Pain of skin	1/59 (1.7%)	1
Periorbital edema	2/59 (3.4%)	2
Pruritus	11/59 (18.6%)	20
Rash maculo-papular	33/59 (55.9%)	68
Skin and subcutaneous tissue disorders - Other, specify	10/59 (16.9%)	12
Skin hyperpigmentation	4/59 (6.8%)	5
Skin hypopigmentation	1/59 (1.7%)	1
Skin ulceration	2/59 (3.4%)	2
Urticaria	1/59 (1.7%)	1
Surgical and medical procedures
Surgical and medical procedures - Other, specify	1/59 (1.7%)	2
Vascular disorders
Flushing	2/59 (3.4%)	2
Hot flashes	2/59 (3.4%)	4
Hypertension	25/59 (42.4%)	76
Hypotension	5/59 (8.5%)	5
Superficial thrombophlebitis	1/59 (1.7%)	1
Thromboembolic event	4/59 (6.8%)	4

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.