Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant For Hematological Cancer

• Sponsor: City of Hope Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00589563
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 32
• Locations: 2
• Arms: 3
• Duration (Months): 57.1
• Patients Per Site: 16
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

RATIONALE: Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem 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, antithymocyte globulin, and methotrexate before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well sirolimus, tacrolimus, and antithymocyte globulin work in preventing graft-versus-host disease in patients undergoing a donor stem cell transplant for hematological cancer .

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloproliferative Disorders; Graft Versus Host Disease; Infection; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Precancerous Condition; Secondary Myelofibrosis; Small Intestine Cancer	Biological: anti-thymocyte globulin; Drug: cyclophosphamide; Drug: etoposide; Drug: fludarabine phosphate; Drug: melphalan; Drug: methotrexate; Drug: sirolimus; Drug: tacrolimus; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: hematopoietic stem cell transplantation; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Radiation: total-body irradiation	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To determine the incidence and severity of acute- and chronic-graft-versus-host disease (GVHD) after HLA-matched or -mismatched unrelated donor hematopoietic peripheral blood transplantation in patients with hematologic malignancies scheduled to receive immunosuppressive combination of sirolimus, tacrolimus, and anti-thymocyte globulin as GVHD prophylaxis.

• To determine the safety of this combination in the first six months post-transplant.

Secondary

• To determine the time-to-engraftment, non-relapse mortality rate, overall and disease-free survival, incidence of disease relapse, and incidence of opportunistic infections with this GVHD prophylaxis.

OUTLINE: Patients are stratified according to conditioning regimen (fludarabine phosphate and melphalan vs fractionated total-body irradiation [FTBI] and etoposide vs FTBI and cyclophosphamide) and degree of donor/recipient HLA mismatch (high-risk vs low-risk).

• Conditioning regimen: Patients receive 1 of 3 standard conditioning regimens beginning on day -9 or -8 and continuing to day -1 or 0.

• Peripheral blood stem cell transplantation: Patients receive HLA-matched or mismatched unrelated donor peripheral blood stem cells on day 0.

• Graft-versus-host disease prophylaxis: Patients receive tacrolimus IV continuously beginning on day -3 and then orally when tolerated, oral sirolimus on days -3 and -2, anti-thymocyte globulin IV over 4-8 hours on days -3 to 0, and methotrexate* IV on days 1, 3, and 6. Tacrolimus and sirolimus continue for 3-6 months (with taper).

NOTE: *Only patients with high-risk HLA mismatch receive treatment with methotrexate.

After completion of study therapy, patients are followed periodically for up to 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: A Phase II Study of Sirolimus, Tacrolimus and Thymoglobulin, as Graft-versus-Host Prophylaxis in Patients Undergoing Unrelated Donor Hematopoietic Cell Transplantation
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fludarabine/Melphalan Conditioning Fludarabine/Melphalan Conditioning with Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis	Biological: anti-thymocyte globulin; 0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant; Drug: fludarabine phosphate; Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant; Drug: melphalan; Melphalan 140 mg/m2 on day -4 from stem cell transplant; Drug: methotrexate; For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant; Drug: sirolimus; Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose. Pediatric Patients <40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose; Drug: tacrolimus; 0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant; Procedure: allogeneic hematopoietic stem cell transplantation; The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight; Procedure: hematopoietic stem cell transplantation; The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant; Procedure: peripheral blood stem cell transplantation; The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight; Radiation: total-body irradiation; 1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant
Experimental: FTBI/Cytoxan Conditioning FTBI/Cytoxan Conditioning with Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis	Biological: anti-thymocyte globulin; 0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant; Drug: cyclophosphamide; 60mg/kg on days -5 and -4 from stem cell transplant; Drug: methotrexate; For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant; Drug: sirolimus; Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose. Pediatric Patients <40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose; Drug: tacrolimus; 0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant; Procedure: allogeneic hematopoietic stem cell transplantation; The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight; Procedure: hematopoietic stem cell transplantation; The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant; Procedure: peripheral blood stem cell transplantation; The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight; Radiation: total-body irradiation; 1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant
Experimental: FTBI/Etoposide Conditioning FTBI/Etoposide Conditioning with Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis	Biological: anti-thymocyte globulin; 0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant; Drug: etoposide; 60mg/kg on day -4 from stem cell transplant; Drug: methotrexate; For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant; Drug: sirolimus; Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose. Pediatric Patients <40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose; Drug: tacrolimus; 0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant; Procedure: allogeneic hematopoietic stem cell transplantation; The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight; Procedure: hematopoietic stem cell transplantation; The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant; Procedure: peripheral blood stem cell transplantation; The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight; Radiation: total-body irradiation; 1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant

Outcome Measures

Primary Outcome Measures

1. Cumulative Incidence of Grade II-IV Acute Graft-Versus-Host Disease (GVHD) at Day 100 [100 Days Post Hematopoietic Stem Cell Transplant (HSCT)]

   Patients were evaluated for the development of acute GVHD within the first 100 days post HSCT. The cumulative incidence of grade II-IV acute GVHD was determined using competing risk analysis. Competing risks for acute GVHD were death and nonengraftment.

2. Severity of Acute GVHD [100 Days Post HSCT]

   All patients were considered for the evaluation of the severity of acute GVHD.

3. Cumulative Incidence of Chronic GVHD [2 year point estimate was provided.]

   Patients were evaluated for the development of chronic GVHD from 101 days post HSCT to last contact or documented evidence of the disease. The cumulative incidence of chronic GVHD was determined using competing risk analysis. Competing risks for GVHD were death and nonengraftment.

4. Severity of Chronic GVHD [Patients were evaluated until they developed chronic GVHD, a median of 130 days post HSCT]

   All Patients were considered for the evaluation of chronic GVHD severity.

Secondary Outcome Measures

1. Time to Absolute Neutrophil Count Recovery (Engraftment) [Patients were evaluated until neutrophil recovery, a median of 15 days post HSCT]

   Absolute neutrophil count (ANC) recovery is defined as an ANC of ≥ 0.5 x 10^9/L (500/mm3) for three consecutive laboratory values obtained on different days

2. Time to Platelet Count Recovery (Engraftment) [Patients were evaluated until platelet recovery, a median of 14 days]

   Platelet recovery is defined as the first date of three consecutive laboratory values ≥ 25 x 10^9 L obtained on different days.

3. Occurence of Infections Including Cytomegalovirus and Epstein-Barr Virus Reactivation [Median Follow Up: 28 months (Range: 1-49 months)]

   Participants were monitored throughout the trial (median of 28 months) for various infections/complications.

4. Occurrence of Thrombotic Microangiopathy [Median Follow Up: 28 Months (Range: 1-49 months)]

   Participants were monitored throughout the trial (median of 28 months) for various infections/complications. This is the number of participants who developed TMA.

5. Occurence of Sinusoidal Obstructive Syndrome (SOS) [Median Follow Up: 28 Months (Range: 1-49 Months)]

   Participants were monitored throughout the trial (median of 28 months) for various infections/complications. This is the number of participants who developed SOS.

6. Non-relapse Mortality at 100 Days Post HSCT [100 day point estimate was provided]

   Patients were evaluated for non-relapse mortality (NRM) throughout the study. Non-relapse mortality was considered any death not attributable to relapse or disease progression. The cumulative incidence of NRM was determined using competing risk analysis. Competing risks for NRM were death due to disease progression, relapse and nonengraftment.

7. Non-relapse Mortality at Two Years Post HSCT [2 year point estimate was provided.]

   Patients were evaluated for non-relapse mortality (NRM) throughout the study. Non-relapse mortality was considered any death not attributable to relapse or disease progression. The cumulative incidence of NRM was determined using competing risk analysis. Competing risks for NRM were death due to disease progression, relapse and nonengraftment.

8. Overall Survival at Two Years Post HSCT [2 year point estimate was provided.]

   Patients were evaluated for survival (OS) throughout the study. Kaplan Meier estiamtes were calculated for overall survival using time from HSCT to death of any cause or for surviving patients last contact date.

9. Event Free Survival at Two Years Post HSCT [2 year point estimate was provided.]

   Patients were evaluated for event free survival (EFS) throughout the study. Events were defined as death, relapse, progression, or nonengraftment. Kaplan Meier estimates were calculated as time from HSCT to event.

10. Incidence of Disease Relapse/Progression at 2 Years Post HSCT [2 year point estimate was provided.]

    Patients were evaluated for relapse/progression post transplant throughout the study. The cumulative incidence of relapse/progression was determined using competing risk analysis. Competing risks for relapse were non-relapse mortality and nonengraftment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of hematological malignancy including any of the following:

• Non-Hodgkin lymphoma (NHL) in any complete remission (CR) or partial response (PR)

• Hodgkin lymphoma in any CR or PR

• Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in any CR

• Bone marrow blasts < 20% within 4 weeks of transplant and peripheral blood absolute blast count < 500/µL on the day of initiation of conditioning for patients with non-CR AML or ALL

• Myelodysplastic syndromes (MDS) treated or untreated

• Chronic myelogenous leukemia (CML) in chronic or accelerated phase

• Multiple myeloma in any CR or PR

• Chronic lymphocytic leukemia in CR or PR 2 or greater

• Myelofibrosis and other myeloproliferative disorders

• Bone marrow blasts < 20% within 4 weeks of transplant and peripheral blood absolute blast count < 500/µL on the day of initiation

• High-risk disease defined as AML or ALL > CR1, accelerated phase CML, recurrent aggressive lymphoma, or active lymphoproliferative disease at transplant

• Low-risk disease defined as AML or ALL in CR1, chronic phase CML, or low-grade lymphoproliferative disorder with controlled disease at transplant

• Must be planning to receive 1 of the following conditioning regimens at City of Hope:

• Fludarabine phosphate and melphalan for patients with hematological malignancies and contraindications for conventional myeloablative regimens due to age, co-morbidity, or previous transplant

• Fractionated total-body irradiation (FTBI) and etoposide for patients with AML and ALL or CML in accelerated phase

• FTBI and cyclophosphamide for patients with NHL, AML, CML, and MDS

• Suitable unrelated donor available

• HLA-matched or mismatched

• Peripheral blood stem cells available

• No bone marrow or ex vivo-engineered or processed graft (e.g., CD34-positive, T-cell depletion)

• No uncontrolled CNS disease

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) 70-100% or ECOG PS 0-2

• Creatinine < 1.3 mg/dL or creatinine clearance ≥ 70 mL/min

• Ejection fraction > 45%

• Direct bilirubin < 3 times upper limit of normal (ULN)

• ALT and AST < 3 times ULN

• Forced vital capacity, FEV1, and DLCO > 45% of predicted

• Able to cooperate with oral medication intake

• No active donor or recipient serology positive for HIV

• No known contraindication to administration of sirolimus, tacrolimus, or anti-thymocyte globulin

• No active hepatitis B or C

• Negative pregnancy test

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Concurrent participation in other clinical trials for prevention or treatment of viral, bacterial, or fungal disease allowed provided agents do not interact with agents used in the current study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner Good Samaritan Medical Center	Phoenix	Arizona	United States	85006
2	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010-3000

Sponsors and Collaborators

• City of Hope Medical Center
• National Cancer Institute (NCI)

Investigators

• Study Chair: Ryotaro Nakamura, MD, City of Hope Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT00589563
• Other Study ID Numbers: 06141; P30CA033572; CHNMC-06141; CDR0000579340
• First Posted: Jan 9, 2008
• Last Update Posted: Sep 10, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by City of Hope Medical Center: graft versus host disease; infection; adult favorable prognosis Hodgkin lymphoma; adult unfavorable prognosis Hodgkin lymphoma; childhood favorable prognosis Hodgkin lymphoma; childhood unfavorable prognosis Hodgkin lymphoma; cutaneous B-cell non-Hodgkin lymphoma; recurrent adult Hodgkin lymphoma; recurrent cutaneous T-cell non-Hodgkin lymphoma; recurrent/refractory childhood Hodgkin lymphoma; stage I adult Hodgkin lymphoma; stage I childhood Hodgkin lymphoma; stage I cutaneous T-cell non-Hodgkin lymphoma; stage II adult Hodgkin lymphoma; stage II childhood Hodgkin lymphoma; stage II cutaneous T-cell non-Hodgkin lymphoma; stage III adult Hodgkin lymphoma; stage III childhood Hodgkin lymphoma; stage III cutaneous T-cell non-Hodgkin lymphoma; stage IV adult Hodgkin lymphoma; stage IV childhood Hodgkin lymphoma; stage IV cutaneous T-cell non-Hodgkin lymphoma; anaplastic large cell lymphoma; angioimmunoblastic T-cell lymphoma; Burkitt lymphoma; contiguous stage II adult Burkitt lymphoma; contiguous stage II adult diffuse large cell lymphoma; contiguous stage II adult diffuse mixed cell lymphoma; contiguous stage II adult diffuse small cleaved cell lymphoma; contiguous stage II adult immunoblastic large cell lymphoma; contiguous stage II adult lymphoblastic lymphoma; contiguous stage II grade 1 follicular lymphoma; contiguous stage II grade 2 follicular lymphoma; contiguous stage II grade 3 follicular lymphoma; contiguous stage II mantle cell lymphoma; contiguous stage II marginal zone lymphoma; contiguous stage II small lymphocytic lymphoma; extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue; nodal marginal zone B-cell lymphoma; noncontiguous stage II adult Burkitt lymphoma; noncontiguous stage II adult diffuse large cell lymphoma; noncontiguous stage II adult diffuse mixed cell lymphoma; noncontiguous stage II adult diffuse small cleaved cell lymphoma; noncontiguous stage II adult immunoblastic large cell lymphoma; noncontiguous stage II adult lymphoblastic lymphoma; noncontiguous stage II grade 1 follicular lymphoma; noncontiguous stage II grade 2 follicular lymphoma; noncontiguous stage II grade 3 follicular lymphoma; noncontiguous stage II mantle cell lymphoma; noncontiguous stage II marginal zone lymphoma; noncontiguous stage II small lymphocytic lymphoma; recurrent adult Burkitt lymphoma; recurrent adult diffuse large cell lymphoma; recurrent adult diffuse mixed cell lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent adult grade III lymphomatoid granulomatosis; recurrent adult immunoblastic large cell lymphoma; recurrent adult lymphoblastic lymphoma; recurrent adult T-cell leukemia/lymphoma; recurrent childhood anaplastic large cell lymphoma; recurrent childhood grade III lymphomatoid granulomatosis; recurrent childhood lymphoblastic lymphoma; recurrent childhood small noncleaved cell lymphoma; recurrent grade 1 follicular lymphoma; recurrent grade 2 follicular lymphoma; recurrent grade 3 follicular lymphoma; recurrent grade I lymphomatoid granulomatosis; recurrent grade II lymphomatoid granulomatosis; recurrent mantle cell lymphoma; recurrent marginal zone lymphoma; recurrent small lymphocytic lymphoma; small intestine lymphoma; splenic marginal zone lymphoma; stage I adult Burkitt lymphoma; stage I adult diffuse large cell lymphoma; stage I adult diffuse mixed cell lymphoma; stage I adult diffuse small cleaved cell lymphoma; stage I adult immunoblastic large cell lymphoma; stage I adult lymphoblastic lymphoma; stage I adult T-cell leukemia/lymphoma; stage III adult Burkitt lymphoma; stage III adult diffuse large cell lymphoma; stage III adult diffuse mixed cell lymphoma; stage III adult diffuse small cleaved cell lymphoma; stage III adult immunoblastic large cell lymphoma; stage III adult lymphoblastic lymphoma; stage III adult T-cell leukemia/lymphoma; stage III childhood anaplastic large cell lymphoma; stage III childhood lymphoblastic lymphoma; stage III childhood small noncleaved cell lymphoma; stage III grade 1 follicular lymphoma; stage III grade 2 follicular lymphoma; stage III grade 3 follicular lymphoma; stage III mantle cell lymphoma; stage III marginal zone lymphoma; stage III small lymphocytic lymphoma; stage IV adult Burkitt lymphoma; stage IV adult diffuse large cell lymphoma; stage IV adult diffuse mixed cell lymphoma; stage IV adult diffuse small cleaved cell lymphoma; stage IV adult immunoblastic large cell lymphoma; stage IV adult lymphoblastic lymphoma; stage IV adult T-cell leukemia/lymphoma; stage IV childhood anaplastic large cell lymphoma; stage IV childhood lymphoblastic lymphoma; stage IV childhood small noncleaved cell lymphoma; stage IV grade 1 follicular lymphoma; stage IV grade 2 follicular lymphoma; stage IV grade 3 follicular lymphoma; stage IV mantle cell lymphoma; stage IV marginal zone lymphoma; stage IV small lymphocytic lymphoma; adult acute myeloid leukemia in remission; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); childhood acute myeloid leukemia in remission; recurrent adult acute myeloid leukemia; recurrent childhood acute myeloid leukemia; secondary acute myeloid leukemia; adult acute lymphoblastic leukemia in remission; childhood acute lymphoblastic leukemia in remission; recurrent adult acute lymphoblastic leukemia; recurrent childhood acute lymphoblastic leukemia; accelerated phase chronic myelogenous leukemia; chronic phase chronic myelogenous leukemia; refractory chronic lymphocytic leukemia; relapsing chronic myelogenous leukemia; stage I chronic lymphocytic leukemia; stage II chronic lymphocytic leukemia; stage III chronic lymphocytic leukemia; stage IV chronic lymphocytic leukemia; stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma; childhood myelodysplastic syndromes; de novo myelodysplastic syndromes; myelodysplastic/myeloproliferative neoplasm, unclassifiable; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; atypical chronic myeloid leukemia, BCR-ABL negative; chronic myelomonocytic leukemia; juvenile myelomonocytic leukemia; primary myelofibrosis; secondary myelofibrosis
• Additional relevant MeSH terms: Lymphoma; Leukemia; Neoplasms; Multiple Myeloma; Neoplasms, Plasma Cell; Preleukemia; Neoplasm Metastasis; Plasmacytoma; Precancerous Conditions; Intestinal Neoplasms; Myelodysplastic Syndromes; Primary Myelofibrosis; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Graft vs Host Disease; Syndrome; Sirolimus; Cyclophosphamide; Melphalan; Methotrexate; Fludarabine; Fludarabine phosphate; Etoposide; Tacrolimus; Antilymphocyte Serum

Study Results

Participant Flow

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Period Title: Overall Study
STARTED	32
COMPLETED	32
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Overall Participants	32
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59.5
Sex: Female, Male (Count of Participants)
Female	19 59.4%
Male	13 40.6%
Region of Enrollment (participants) [Number]
United States	32 100%
Diagnosis (participants) [Number]
Acute Myeloid Leukemia	14 43.8%
Myelodysplastic Syndrome	6 18.8%
Acute Lymphoblastic Leukemia	3 9.4%
Chronic Myeloid Leukemia	3 9.4%
Non-Hodgkin Lymphoma	3 9.4%
Myeloproliferative Disorder	2 6.3%
Chronic Lymphocytic Leukemia	1 3.1%
Disease Status (American Society for Blood and Marrow Transplantation Guidelines) (participants) [Number]
Standard Risk	14 43.8%
High/Intermediate Risk	18 56.3%
Patient/Donor Cytomegalovirus (CMV) infection status (participants) [Number]
Positive/Negative	12 37.5%
Positive/Positive	12 37.5%
Negative/Negative	3 9.4%
Negative/Positive	5 15.6%
Human Leukocyte Antigen (HLA) Match Type (participants) [Number]
10/10 Matched	18 56.3%
1 Mismatch	12 37.5%
2 Mismatches	1 3.1%
3 Mismatches	1 3.1%
Conditioning Regimen (participants) [Number]
Fludarabine/Melphalan	23 71.9%
Fractionated Total Body Irradiation/Cytoxan	4 12.5%
Fractionated Total Body Irradiation/Etoposide	5 15.6%
Patient/donor sex match (participants) [Number]
Male patient/Female donor	3 9.4%
Others	29 90.6%

Outcome Measures

1. Primary Outcome

Title	Cumulative Incidence of Grade II-IV Acute Graft-Versus-Host Disease (GVHD) at Day 100
Description	Patients were evaluated for the development of acute GVHD within the first 100 days post HSCT. The cumulative incidence of grade II-IV acute GVHD was determined using competing risk analysis. Competing risks for acute GVHD were death and nonengraftment.
Time Frame	100 Days Post Hematopoietic Stem Cell Transplant (HSCT)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	32
Number (95% Confidence Interval) [Percentage of patients developing aGVHD]	37.3

2. Primary Outcome

Title	Severity of Acute GVHD
Description	All patients were considered for the evaluation of the severity of acute GVHD.
Time Frame	100 Days Post HSCT

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	32
No Acute GVHD	9 28.1%
Yes - Grade I	9 28.1%
Yes- Grade II	9 28.1%
Yes- Grade III	1 3.1%
Yes - Grade IV	0 0%
No- Inevaluable (graft failures)	4 12.5%

3. Secondary Outcome

Title	Time to Absolute Neutrophil Count Recovery (Engraftment)
Description	Absolute neutrophil count (ANC) recovery is defined as an ANC of ≥ 0.5 x 10^9/L (500/mm3) for three consecutive laboratory values obtained on different days
Time Frame	Patients were evaluated until neutrophil recovery, a median of 15 days post HSCT

Outcome Measure Data

Analysis Population Description

28 of the 32 patients had absolute neutrophil count recovery.

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	28
Median (Full Range) [Days]	14.5

4. Secondary Outcome

Title	Time to Platelet Count Recovery (Engraftment)
Description	Platelet recovery is defined as the first date of three consecutive laboratory values ≥ 25 x 10^9 L obtained on different days.
Time Frame	Patients were evaluated until platelet recovery, a median of 14 days

Outcome Measure Data

Analysis Population Description

27 of the 32 patients had platelet recovery.

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	27
Median (Full Range) [Days]	14

5. Secondary Outcome

Title	Occurence of Infections Including Cytomegalovirus and Epstein-Barr Virus Reactivation
Description	Participants were monitored throughout the trial (median of 28 months) for various infections/complications.
Time Frame	Median Follow Up: 28 months (Range: 1-49 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	32
Neither CMV or EBV	16 50%
CMV reactivation only	9 28.1%
EBV only	3 9.4%
Both CMV and EBV	4 12.5%

6. Secondary Outcome

Title	Occurrence of Thrombotic Microangiopathy
Description	Participants were monitored throughout the trial (median of 28 months) for various infections/complications. This is the number of participants who developed TMA.
Time Frame	Median Follow Up: 28 Months (Range: 1-49 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	32
Number [participants]	7 21.9%

7. Secondary Outcome

Title	Occurence of Sinusoidal Obstructive Syndrome (SOS)
Description	Participants were monitored throughout the trial (median of 28 months) for various infections/complications. This is the number of participants who developed SOS.
Time Frame	Median Follow Up: 28 Months (Range: 1-49 Months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	32
Number [participants]	1 3.1%

8. Secondary Outcome

Title	Non-relapse Mortality at 100 Days Post HSCT
Description	Patients were evaluated for non-relapse mortality (NRM) throughout the study. Non-relapse mortality was considered any death not attributable to relapse or disease progression. The cumulative incidence of NRM was determined using competing risk analysis. Competing risks for NRM were death due to disease progression, relapse and nonengraftment.
Time Frame	100 day point estimate was provided

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	32
Number (95% Confidence Interval) [Percentage of patients with a NRM]	9.4

9. Secondary Outcome

Title	Non-relapse Mortality at Two Years Post HSCT
Description	Patients were evaluated for non-relapse mortality (NRM) throughout the study. Non-relapse mortality was considered any death not attributable to relapse or disease progression. The cumulative incidence of NRM was determined using competing risk analysis. Competing risks for NRM were death due to disease progression, relapse and nonengraftment.
Time Frame	2 year point estimate was provided.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	32
Number (95% Confidence Interval) [Percentage of patients with a NRM]	15.6

10. Secondary Outcome

Title	Overall Survival at Two Years Post HSCT
Description	Patients were evaluated for survival (OS) throughout the study. Kaplan Meier estiamtes were calculated for overall survival using time from HSCT to death of any cause or for surviving patients last contact date.
Time Frame	2 year point estimate was provided.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	32
Number (95% Confidence Interval) [Percentage of patients who died]	65.6

11. Secondary Outcome

Title	Event Free Survival at Two Years Post HSCT
Description	Patients were evaluated for event free survival (EFS) throughout the study. Events were defined as death, relapse, progression, or nonengraftment. Kaplan Meier estimates were calculated as time from HSCT to event.
Time Frame	2 year point estimate was provided.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	32
Number (95% Confidence Interval) [Percentage of patients with an event]	61.3

12. Primary Outcome

Title	Cumulative Incidence of Chronic GVHD
Description	Patients were evaluated for the development of chronic GVHD from 101 days post HSCT to last contact or documented evidence of the disease. The cumulative incidence of chronic GVHD was determined using competing risk analysis. Competing risks for GVHD were death and nonengraftment.
Time Frame	2 year point estimate was provided.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	32
Number (95% Confidence Interval) [Percentage of patients developing cGVHD]	62.5

13. Primary Outcome

Title	Severity of Chronic GVHD
Description	All Patients were considered for the evaluation of chronic GVHD severity.
Time Frame	Patients were evaluated until they developed chronic GVHD, a median of 130 days post HSCT

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	32
No Chronic GVHD	4 12.5%
Yes- Limited	4 12.5%
Yes - Extensive	17 53.1%
No- Inevaluable (graft failure/died <day 100)	7 21.9%

14. Secondary Outcome

Title	Incidence of Disease Relapse/Progression at 2 Years Post HSCT
Description	Patients were evaluated for relapse/progression post transplant throughout the study. The cumulative incidence of relapse/progression was determined using competing risk analysis. Competing risks for relapse were non-relapse mortality and nonengraftment.
Time Frame	2 year point estimate was provided.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done.
Measure Participants	32
Number (95% Confidence Interval) [Percentage of patients who relapsed]	12.5

Adverse Events

Time Frame	180 days
Arm/Group Title	All Patients
Arm/Group Description	All patients were analyzed as a single population. Stratification by conditioning regimen was not done. One patient did not have adverse event data collected.
All Cause Mortality
	All Patients
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	9/31 (29%)
Blood and lymphatic system disorders
Blood disorder	1/31 (3.2%)	1
Cardiac disorders
Atrial flutter	1/31 (3.2%)	1
Myocardial ischemia	1/31 (3.2%)	1
Gastrointestinal disorders
Diarrhea	2/31 (6.5%)	2
General disorders
Ill-defined disorder	1/31 (3.2%)	1
Multi-organ failure	2/31 (6.5%)	2
Pain	1/31 (3.2%)	1
Hepatobiliary disorders
Portal hypertension	1/31 (3.2%)	1
Infections and infestations
Abdominal infection	1/31 (3.2%)	1
Catheter related infection	1/31 (3.2%)	1
Colitis, infectious (e.g., Clostridium difficile)	1/31 (3.2%)	1
Infection	1/31 (3.2%)	1
Opportunistic infection	2/31 (6.5%)	2
Pneumonia	1/31 (3.2%)	1
Sepsis	2/31 (6.5%)	2
Musculoskeletal and connective tissue disorders
Muscle weakness	1/31 (3.2%)	1
Renal and urinary disorders
Renal failure	2/31 (6.5%)	2
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/31 (3.2%)	1
Pulmonary hemorrhage	1/31 (3.2%)	1
Other (Not Including Serious) Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	31/31 (100%)
Blood and lymphatic system disorders
Blood disorder	2/31 (6.5%)	2
Febrile neutropenia	16/31 (51.6%)	16
Hemoglobin decreased	31/31 (100%)	31
Hemolysis	2/31 (6.5%)	2
Lymph node pain	1/31 (3.2%)	1
Lymphatic disorder	3/31 (9.7%)	3
Thrombotic microangiopathy	6/31 (19.4%)	6
Cardiac disorders
Atrial fibrillation	1/31 (3.2%)	1
Atrial flutter	1/31 (3.2%)	1
Cardiac disorder	1/31 (3.2%)	1
Left ventricular dysfunction	2/31 (6.5%)	2
Left ventricular failure	1/31 (3.2%)	1
Pericardial effusion	3/31 (9.7%)	3
Pericarditis	1/31 (3.2%)	1
Restrictive cardiomyopathy	1/31 (3.2%)	1
Sinus bradycardia	2/31 (6.5%)	2
Sinus tachycardia	23/31 (74.2%)	23
Supraventricular tachycardia	1/31 (3.2%)	1
Ventricular tachycardia	1/31 (3.2%)	1
Ear and labyrinth disorders
Ear disorder	1/31 (3.2%)	1
External ear inflammation	1/31 (3.2%)	1
Middle ear inflammation	1/31 (3.2%)	1
Endocrine disorders
Cushingoid	3/31 (9.7%)	3
Hyperthyroidism	1/31 (3.2%)	1
Eye disorders
Dry eye syndrome	3/31 (9.7%)	3
Eye disorder	4/31 (12.9%)	4
Eye pain	1/31 (3.2%)	1
Photophobia	1/31 (3.2%)	1
Vision blurred	3/31 (9.7%)	3
Watering eyes	1/31 (3.2%)	1
Gastrointestinal disorders
Abdominal distension	19/31 (61.3%)	19
Abdominal pain	23/31 (74.2%)	23
Anal pain	3/31 (9.7%)	3
Ascites	1/31 (3.2%)	1
Colonic hemorrhage	1/31 (3.2%)	1
Constipation	9/31 (29%)	9
Diarrhea	29/31 (93.5%)	29
Diarrhea associated with GVHD for BMT studies, if specified in the protocol.	1/31 (3.2%)	1
Dry mouth	7/31 (22.6%)	7
Dyspepsia	12/31 (38.7%)	12
Dysphagia	5/31 (16.1%)	5
Ear, nose and throat examination abnormal	22/31 (71%)	22
Esophageal pain	1/31 (3.2%)	1
Esophagitis	2/31 (6.5%)	2
Fecal incontinence	4/31 (12.9%)	4
Flatulence	4/31 (12.9%)	4
Gastritis	3/31 (9.7%)	3
Gastrointestinal disorder	2/31 (6.5%)	2
Gingival pain	1/31 (3.2%)	1
Hemorrhoids	4/31 (12.9%)	4
Mucositis oral	18/31 (58.1%)	18
Nausea	29/31 (93.5%)	29
Oral hemorrhage	1/31 (3.2%)	1
Oral pain	3/31 (9.7%)	3
Proctitis	1/31 (3.2%)	1
Rectal hemorrhage	2/31 (6.5%)	2
Rectal pain	3/31 (9.7%)	3
Upper gastrointestinal hemorrhage	1/31 (3.2%)	1
Vomiting	25/31 (80.6%)	25
General disorders
Chest pain	3/31 (9.7%)	3
Chills	25/31 (80.6%)	25
Edema	1/31 (3.2%)	1
Edema limbs	25/31 (80.6%)	25
Facial pain	4/31 (12.9%)	4
Fatigue	30/31 (96.8%)	30
Fever	19/31 (61.3%)	19
Flu-like symptoms	1/31 (3.2%)	1
Gait abnormal	2/31 (6.5%)	2
General symptom	3/31 (9.7%)	3
Ill-defined disorder	4/31 (12.9%)	4
Injection site reaction	11/31 (35.5%)	11
Irritability	1/31 (3.2%)	1
Localized edema	8/31 (25.8%)	8
Pain	17/31 (54.8%)	17
Immune system disorders
Cytokine release syndrome	1/31 (3.2%)	1
Hypersensitivity	3/31 (9.7%)	3
Infections and infestations
Bladder infection	3/31 (9.7%)	3
Bronchitis	1/31 (3.2%)	1
Catheter related infection	1/31 (3.2%)	1
Colitis, infectious (e.g., Clostridium difficile)	4/31 (12.9%)	4
Conjunctivitis infective	1/31 (3.2%)	1
Infection	8/31 (25.8%)	8
Infectious colitis	2/31 (6.5%)	2
Lip infection	1/31 (3.2%)	1
Opportunistic infection	11/31 (35.5%)	11
Pancreas infection	2/31 (6.5%)	2
Paranasal sinus infection	1/31 (3.2%)	1
Pneumonia	6/31 (19.4%)	6
Sepsis	15/31 (48.4%)	15
Sinusitis	1/31 (3.2%)	1
Skin infection	1/31 (3.2%)	1
Tracheitis	1/31 (3.2%)	1
Upper respiratory infection	4/31 (12.9%)	4
Urinary tract infection	3/31 (9.7%)	3
Injury, poisoning and procedural complications
Bruising	14/31 (45.2%)	14
Dermatitis radiation	2/31 (6.5%)	2
Intraoperative venous injury - Vein-portal vein	1/31 (3.2%)	1
Postoperative hemorrhage	1/31 (3.2%)	1
Radiation recall reaction (dermatologic)	2/31 (6.5%)	2
Vascular access complication	1/31 (3.2%)	1
Wound dehiscence	2/31 (6.5%)	2
Investigations
Activated partial thromboplastin time prolonged	1/31 (3.2%)	1
Alanine aminotransferase increased	29/31 (93.5%)	29
Alkaline phosphatase increased	23/31 (74.2%)	23
Amylase increased	2/31 (6.5%)	2
Aspartate aminotransferase increased	30/31 (96.8%)	30
Bilirubin increased	7/31 (22.6%)	7
Creatine phosphokinase increased	1/31 (3.2%)	1
Creatinine increased	21/31 (67.7%)	21
Gamma-glutamyltransferase increased	1/31 (3.2%)	1
Laboratory test abnormal	4/31 (12.9%)	4
Leukocyte count decreased	31/31 (100%)	31
Lipase increased	2/31 (6.5%)	2
Lymphocyte count decreased	26/31 (83.9%)	26
Neutrophil count decreased	31/31 (100%)	31
Neutrophils/granulocytes (ANC/AGC) for BMT studies, if specified in the protocol.	1/31 (3.2%)	1
Platelet count decreased	31/31 (100%)	31
Serum cholesterol increased	20/31 (64.5%)	20
Weight gain	11/31 (35.5%)	11
Weight loss	17/31 (54.8%)	17
Metabolism and nutrition disorders
Acidosis	4/31 (12.9%)	4
Alkalosis	5/31 (16.1%)	5
Anorexia	26/31 (83.9%)	26
Blood bicarbonate decreased	20/31 (64.5%)	20
Blood glucose increased	31/31 (100%)	31
Blood uric acid increased	1/31 (3.2%)	1
Dehydration	2/31 (6.5%)	2
Iron overload	1/31 (3.2%)	1
Serum albumin decreased	30/31 (96.8%)	30
Serum calcium decreased	31/31 (100%)	31
Serum calcium increased	7/31 (22.6%)	7
Serum glucose decreased	3/31 (9.7%)	3
Serum magnesium decreased	31/31 (100%)	31
Serum magnesium increased	6/31 (19.4%)	6
Serum phosphate decreased	28/31 (90.3%)	28
Serum potassium decreased	29/31 (93.5%)	29
Serum potassium increased	6/31 (19.4%)	6
Serum sodium decreased	31/31 (100%)	31
Serum sodium increased	1/31 (3.2%)	1
Serum triglycerides increased	28/31 (90.3%)	28
Musculoskeletal and connective tissue disorders
Back pain	16/31 (51.6%)	16
Bone pain	7/31 (22.6%)	7
Buttock pain	2/31 (6.5%)	2
Joint pain	11/31 (35.5%)	11
Muscle weakness	20/31 (64.5%)	20
Muscle weakness lower limb	6/31 (19.4%)	6
Muscle weakness upper limb	1/31 (3.2%)	1
Musculoskeletal disorder	3/31 (9.7%)	3
Myalgia	5/31 (16.1%)	5
Myositis	1/31 (3.2%)	1
Neck pain	9/31 (29%)	9
Osteoporosis	1/31 (3.2%)	1
Pain in extremity	19/31 (61.3%)	19
Nervous system disorders
Depressed level of consciousness	5/31 (16.1%)	5
Dizziness	16/31 (51.6%)	16
Encephalopathy	1/31 (3.2%)	1
Headache	27/31 (87.1%)	27
Memory impairment	4/31 (12.9%)	4
Neuralgia	2/31 (6.5%)	2
Neurological disorder NOS	2/31 (6.5%)	2
Nystagmus	1/31 (3.2%)	1
Peripheral motor neuropathy	3/31 (9.7%)	3
Peripheral sensory neuropathy	10/31 (32.3%)	10
Sinus pain	2/31 (6.5%)	2
Taste alteration	6/31 (19.4%)	6
Tremor	9/31 (29%)	9
Psychiatric disorders
Agitation	7/31 (22.6%)	7
Anxiety	25/31 (80.6%)	25
Confusion	6/31 (19.4%)	6
Depression	12/31 (38.7%)	12
Insomnia	24/31 (77.4%)	24
Psychosis	1/31 (3.2%)	1
Renal and urinary disorders
Bladder obstruction	1/31 (3.2%)	1
Bladder pain	3/31 (9.7%)	3
Bladder spasm	3/31 (9.7%)	3
Bladder stenosis	1/31 (3.2%)	1
Cystitis	1/31 (3.2%)	1
Hemorrhage urinary tract	7/31 (22.6%)	7
Protein urine positive	11/31 (35.5%)	11
Renal failure	1/31 (3.2%)	1
Urethral pain	5/31 (16.1%)	5
Urinary frequency	7/31 (22.6%)	7
Urinary incontinence	3/31 (9.7%)	3
Urinary retention	6/31 (19.4%)	6
Urogenital disorder	4/31 (12.9%)	4
Reproductive system and breast disorders
Pelvic pain	1/31 (3.2%)	1
Perineal pain	2/31 (6.5%)	2
Scrotal pain	1/31 (3.2%)	1
Vaginal discharge	1/31 (3.2%)	1
Vaginal dryness	1/31 (3.2%)	1
Vaginal hemorrhage	2/31 (6.5%)	2
Vaginal pain	2/31 (6.5%)	2
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	2/31 (6.5%)	2
Allergic rhinitis	4/31 (12.9%)	4
Atelectasis	8/31 (25.8%)	8
Bronchopulmonary hemorrhage	4/31 (12.9%)	4
Bronchospasm	2/31 (6.5%)	2
Cough	23/31 (74.2%)	23
Dyspnea	19/31 (61.3%)	19
Hemorrhage nasal	11/31 (35.5%)	11
Hiccough	4/31 (12.9%)	4
Hypoxia	8/31 (25.8%)	8
Nasal congestion	8/31 (25.8%)	8
Pharyngeal examination abnormal	1/31 (3.2%)	1
Pharyngeal mucositis	1/31 (3.2%)	1
Pharyngolaryngeal pain	2/31 (6.5%)	2
Pleural effusion	12/31 (38.7%)	12
Pneumonitis	11/31 (35.5%)	11
Respiratory disorder	5/31 (16.1%)	5
Voice alteration	3/31 (9.7%)	3
Skin and subcutaneous tissue disorders
Alopecia	18/31 (58.1%)	18
Decubitus ulcer	4/31 (12.9%)	4
Dry skin	15/31 (48.4%)	15
Hand-and-foot syndrome	1/31 (3.2%)	1
Petechiae	12/31 (38.7%)	12
Pruritus	19/31 (61.3%)	19
Rash desquamating	28/31 (90.3%)	28
Skin disorder	10/31 (32.3%)	10
Skin hyperpigmentation	11/31 (35.5%)	11
Skin ulceration	1/31 (3.2%)	1
Sweating	2/31 (6.5%)	2
Urticaria	1/31 (3.2%)	1
Vascular disorders
Flushing	14/31 (45.2%)	14
Hematoma	6/31 (19.4%)	6
Hemorrhage	4/31 (12.9%)	4
Hypertension	20/31 (64.5%)	20
Hypotension	17/31 (54.8%)	17
Peripheral ischemia	1/31 (3.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.