Efficacy Study of T Cell Depleted Allogeneic Non-myeloablative Stem Cell Transplant
Study Details
Study Description
Brief Summary
The central hypothesis of this study is that use of a less toxic chemotherapy preparative regimen for allogeneic hematopoietic stem cell transplantation in combination with T cell depletion with alemtuzumab for patients with high risk hematologic malignancies will allow effective control of disease and improved disease free and overall survival compared with historical expectations. Specifically, the objectives are to estimate toxicity, disease free, progression free, event free, and overall survival rates in patients treated with alemtuzumab T cell depleted, reduced intensity preparative regimen followed by allogeneic hematopoietic transplantation; evaluate immune recovery following this reduced intensity allogeneic immunotherapy; develop an in vitro assay to allow patient individualized targeted dosing.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
The central hypothesis of this study is that use of a less toxic chemotherapy preparative regimen for allogeneic hematopoietic stem cell transplantation in combination with T cell depletion with alemtuzumab for patients with high risk hematologic malignancies will allow effective control of disease and improved disease free and overall survival compared with historical expectations. Specifically, the objectives are to estimate toxicity, disease free, progression free, event free and overall survival rates in patients treated with an alemtuzumab T cell depleted, reduced intensity preparative regimen followed by allogeneic hematopoietic transplantation; evaluate immune recovery following this reduced intensity allogeneic immunotherapy; develop an in vitro assay to allow patient individualized targeted dosing. The study population is HIV negative, adult patients who are not pregnant but have confirmed diagnosis of disease; must have Cancer and Leukemia Group B (CALGB) performance status (PS) 0, 1, or 2; must have a 3-6/6 human leukocyte antigen (HLA)-matched related donor or 8/8 (A, B, C, DRB1, DQ are the primary determinants) or better HLA-matched unrelated donor who is evaluated and deemed able to provide peripheral blood stem cells (PBPCs) and/or marrow by the transplant team. The target population of patients is those with a high chance of progressive lymphoid or myelomatous diseases, progressive myeloid diseases, marrow failure syndromes or myeloproliferative disorders.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort A - Lymphoid Disease Group A: Patients with a high chance of progressive lymphoid or myelomatous disease undergo Non-myeloablative Stem Cell Transplantation. |
Drug: Non-myeloablative Stem Cell Transplantation
The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. Group B's prep regimen will begin on day -5 or day -4 and busulfan 130mg/m2/d for 2 days over 3 hours. The peripheral blood stem cells (PBSCs) will be infused over 2-4 days. Patient evaluations will occur 2 times per week by physical exam for toxicity through day 45.
Other Names:
|
| Experimental: Cohort B - Myeloid Disease Group B: Patients with a high chance of progressive myeloid diseases, marrow failure syndromes or myeloproliferative disorders undergo Non-myeloablative Stem Cell Transplantation. |
Drug: Non-myeloablative Stem Cell Transplantation
The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. Group B's prep regimen will begin on day -5 or day -4 and busulfan 130mg/m2/d for 2 days over 3 hours. The peripheral blood stem cells (PBSCs) will be infused over 2-4 days. Patient evaluations will occur 2 times per week by physical exam for toxicity through day 45.
Other Names:
|
| No Intervention: Donor Donor priming and apheresis will include filgrastim 8 mcg/kg subcutaneously twice daily for 4 days prior to stem cell collection and continuing until pheresis is completed. Alternative mobilization strategies may be employed at the investigator's discretion. |
Outcome Measures
Primary Outcome Measures
- Disease Free Survival [2 years]
Estimate disease free survival rates in participants treated with an alemtuzumab T cell depleted, reduced intensity preparative regimen followed by allogeneic hematopoietic transplantation. Disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) rates after SCT were estimated using the Kaplan-Meier method. We performed univariate comparisons by using the log-rank test. DFS was defined as the period of time between the day of transplantation and either disease relapse or death due to the disease. The following variables were considered as confounders: recipient age, recipient sex, disease (myeloid or lymphoid), disease risk (standard or high), and donor type (MRD, MUD, or HAPLO donor). The percentage of participants who were disease free at 2 years is reported by donor type.
Secondary Outcome Measures
- Immune Recovery [1 year]
Evaluate immune recovery following this reduced intensity allogeneic immunotherapy. Quantification of CD3+, CD4+, and CD8+ T cells was performed by flow cytometry on fresh peripheral blood at approximately 1 month before transplantation and then 1.5, 3, 6, and 12 months after transplantation. The immune recovery rates of the CD3+, CD4+, and CD8+ T cells in the MRD, MUD, and HAPLO groups were compared by performing an analysis of variance at each time point after transplantation. The median T cell counts at 12 months for each type of cell are reported by donor type.
- Progression Free Survival [2 years]
Progression-free survival (PFS) rates after stem cell transplant were estimated using the Kaplan-Meier method. We performed univariate comparisons by using the log-rank test. PFS was defined as the period of time between the day of transplantation and either the day underlying disease progression was documented or death occurred by any cause. The following variables were considered as confounders: recipient age, recipient sex, disease (myeloid or lymphoid), disease risk (standard or high), and donor type (MRD, MUD, or HAPLO donor). The percentage of participants progression free at 2 years is reported by donor type. Progression = > 25% increase of serum M-protein and/or urine M-protein. Also, an absolute increase in bone marrow plasma cells > 10%, new bone lesions or soft tissue plasmacytomas or increase in the size of existing bone lesions or soft tissue plasmacytomas or development of hypercalcemia that can be attributed solely to the plasma cell proliferative disorder.
- Overall Survival [2 years]
Estimate overall survival rates in participants treated with an alemtuzumab T cell depleted, reduced intensity preparative regimen followed by allogeneic hematopoietic transplantation. Disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) rates after SCT were estimated using the Kaplan-Meier method. We performed univariate comparisons by using the log-rank test. OS was defined as the period of time between the day of transplantation and death. The following variables were considered as confounders: recipient age, recipient sex, disease (myeloid or lymphoid), disease risk (standard or high), and donor type (MRD, MUD, or HAPLO donor). The percentage of participants surviving 2 years by donor type is reported.
- Graft Failure [180 days]
Estimate toxicity including graft-versus-host disease (GVHD) in participants treated with an alemtuzumab T cell depleted, reduced intensity preparative regimen followed by allogeneic hematopoietic transplantation. Bone marrow aspiration and/or biopsy were performed 3-5 weeks after transplant to assess donor-cell engraftment. Primary Graft Failure was defined as a neutrophil count below 500/μL or the absence of donor-derived hematopoiesis (<5%donor cells) before relapse, death, or re-transplantation. Secondary Graft Failure was defined as the achievement of primary engraftment and a subsequent decrease in neutrophils to 3 consecutive counts of less than 100/μL or the absence of donor-derived hematopoiesis (<5% donor cells) before relapse, death, or re-transplantation.
Other Outcome Measures
- Graft Versus Host Disease [180 days]
Estimate toxicity including graft-versus-host disease (GVHD) in participants treated with an alemtuzumab T cell depleted, reduced intensity preparative regimen followed by allogeneic hematopoietic transplantation. Bone marrow aspiration and/or biopsy were performed 3-5 weeks after transplant to assess donor-cell engraftment. Acute or chronic GVHD was diagnosed and graded according to standard criteria. Toxicity was formally graded using the National Cancer Institute Common Toxicity Criteria version 3.0.
Eligibility Criteria
Criteria
Recipient Inclusion Criteria:
-
Subjects must have their diagnosis confirmed at the transplant center.
-
Performance status must be Cancer and Leukemia Group B (CALGB) = 0, 1, or 2.
-
Subjects must have a 3-6/6 human leukocyte antigen (HLA)-matched related donor or 8/8 or better allele level match matched unrelated donor (MUD) (at A,B, C, DRB1, DQ).
-
HIV negative.
-
Women of child bearing potential must have a negative pregnancy test within 1 week of starting therapy.
-
Subjects > or equal to 18 years of age are eligible.
-
Subjects must have a Multi Gated Acquisition Scan (MUGA) and/or Echocardiography (ECHO) or cardiac magnetic resonance (MR) and or diffusing capacity testing of the lung for carbon monoxide (DLCO) performed before transplant.
-
Specific populations:
-
Group A) Subjects with a high chance of progressive lymphoid or myelomatous diseases.
-
Group B) Subjects with a high chance of progressive myeloid diseases, marrow failure syndromes or myeloproliferative disorders
Recipient Exclusion Criteria:
-
Pregnant or lactating women.
-
Subjects with other major medical or psychiatric illnesses which the treating physician feels could seriously compromise tolerance to this protocol.
-
Subjects with uncontrolled, progressive infections.
-
Subjects who are good candidates for long term disease control with standard chemotherapy or radiation or high dose therapy and autologous support.
-
Subjects with active central nervous system (CNS) disease.
Donor Inclusion Criteria:
-
Donor must be capable of providing informed consent. If 14-17 years of age, a 'single patient exemption' from the local Institutional Review Board must be obtained.
-
Donor must not have any medical condition which would make mobilization or apheresis more than a minimal risk, and should have the following:
-
Adequate cardiac function by history and physical examination. Those with a history of cardiac failure or infarction should be evaluated by a cardiologist prior to donation
-
Adequate hematopoietic function with hematocrit ≥ 30%, white blood cell count of 3000, and platelets 100,000.
-
Females should not be pregnant or lactating and have a negative serum pregnancy test within 1 week of beginning mobilization if of child bearing potential.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Duke University Health System | Durham | North Carolina | United States | 27710 |
Sponsors and Collaborators
- David Rizzieri, MD
Investigators
- Principal Investigator: David Rizzieri, MD, Duke Health
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Pro00003567
Study Results
Participant Flow
| Recruitment Details | 170 transplant recipients were recruited through the Adult Bone Marrow Transplant Program at Duke University Medical Center. Recruitment began in February, 2008 and ended in June, 2013. 33 recipients were screen failures. 94 donors were consented for leukapheresis. |
|---|---|
| Pre-assignment Detail | Recipients had history and exam, labs, x-ray, and possible bone marrow aspirate. Radiation therapy may be used prior to transplant for minimal active disease. Donor selection included a 5-6/6 matched sibling as the first choice, a matched unrelated donor as the second choice, or a 3-5/6 partially matched family member as the third choice. |
| Arm/Group Title | Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease | Donor |
|---|---|---|---|
| Arm/Group Description | Non-myeloablative stem cell transplant (SCT): Donor will receive Granulocyte colony-stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily for 4 days, until pheresis is completed or until white blood cells > 100,000. Recipients will be premedicated with Benadryl 50 mg intravenously (IV) or orally (PO), and acetaminophen 650 mg PO (or hydrocortisone 50-100 mg IV on first day). The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. The PBSCs will be infused over 2-4 days. Participant evaluations will occur 2 times per week by physical exam for toxicity through day 45. | Non-myeloablative stem cell transplant (SCT): Donor will receive granulocyte colony stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily for 4 days, until pheresis is completed or until white blood cells > 100,000. Recipients will be premedicated with Benadryl 50 mg intravenously (IV) or orally (PO), and acetaminophen 650 mg PO (or hydrocortisone 50-100 mg IV on first day). The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. The prep regimen will begin on day -5 or day -4 and busulfan 130mg/m2/d for 2 days over 3 hours. The PBSCs will be infused over 2-4 days. Participant evaluations will occur 2 times per week by physical exam for toxicity through day 45. | 5-6/6 matched sibling who meets the other donor criteria is the first choice, Matched Unrelated Donor (MUD) is the second choice*, and 3-5/6 partially matched family member (if 5/6 then this donor is not a sibling as that would be first choice) is the third choice for donor type. Multiple choices for 3-5/6 human leukocyte antigen (HLA) matched family member donors order of choice will be best match, then cytomegalovirus (CMV) negativity, then Killer-cell immunoglobulin-like receptors (KIR) mismatching (for natural killer [NK] cell activity), then history of pregnancy. All subjects without an available matched sibling must have a donor search initiated with the national bank. If potential high resolution matches are found but not utilized, the reason for proceeding with a partially matched family member should be documented (i.e. donor not available, not enough time to allow MUD donor work up and collection due to high risk nature of the subject's disease, etc). |
| Period Title: Overall Study | |||
| STARTED | 80 | 57 | 94 |
| COMPLETED | 24 | 11 | 84 |
| NOT COMPLETED | 56 | 46 | 10 |
Baseline Characteristics
| Arm/Group Title | Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease | Total |
|---|---|---|---|
| Arm/Group Description | Non-myeloablative stem cell transplant (SCT): Donor will receive Granulocyte colony-stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily for 4 days, until pheresis is completed or until white blood cells > 100,000. Recipients will be premedicated with Benadryl 50 mg intravenously (IV) or orally (PO), and acetaminophen 650 mg PO (or hydrocortisone 50-100 mg IV on first day). The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. The PBSCs will be infused over 2-4 days. Participant evaluations will occur 2 times per week by physical exam for toxicity through day 45. | Non-myeloablative stem cell transplant (SCT): Donor will receive granulocyte colony stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily for 4 days, until pheresis is completed or until white blood cells > 100,000. Recipients will be premedicated with Benadryl 50 mg intravenously (IV) or orally (PO), and acetaminophen 650 mg PO (or hydrocortisone 50-100 mg IV on first day). The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. The prep regimen will begin on day -5 or day -4 and busulfan 130mg/m2/d for 2 days over 3 hours. The PBSCs will be infused over 2-4 days. Participant evaluations will occur 2 times per week by physical exam for toxicity through day 45. | Total of all reporting groups |
| Overall Participants | 80 | 57 | 137 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
73
91.3%
|
40
70.2%
|
113
82.5%
|
| >=65 years |
7
8.8%
|
17
29.8%
|
24
17.5%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
35
43.8%
|
24
42.1%
|
59
43.1%
|
| Male |
45
56.3%
|
33
57.9%
|
78
56.9%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
1
1.3%
|
0
0%
|
1
0.7%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
9
11.3%
|
6
10.5%
|
15
10.9%
|
| White |
70
87.5%
|
51
89.5%
|
121
88.3%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
80
100%
|
57
100%
|
137
100%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
80
100%
|
57
100%
|
137
100%
|
Outcome Measures
| Title | Disease Free Survival |
|---|---|
| Description | Estimate disease free survival rates in participants treated with an alemtuzumab T cell depleted, reduced intensity preparative regimen followed by allogeneic hematopoietic transplantation. Disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) rates after SCT were estimated using the Kaplan-Meier method. We performed univariate comparisons by using the log-rank test. DFS was defined as the period of time between the day of transplantation and either disease relapse or death due to the disease. The following variables were considered as confounders: recipient age, recipient sex, disease (myeloid or lymphoid), disease risk (standard or high), and donor type (MRD, MUD, or HAPLO donor). The percentage of participants who were disease free at 2 years is reported by donor type. |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects with complete response. Cohort A (n=62) had acute or chronic leukemia (ALL or CLL), lymphoma, or myeloma. Cohort B (n=62) had acute or chronic myeloid leukemia (AML or CML), myelodysplastic disorder or myeloproliferative disorder. DFS was analyzed by type of donor (Matched Unrelated Donor; Matched Related Donor; Haplo-identical). |
| Arm/Group Title | Cohort A & B- Lymphoid & Myeloid Disease |
|---|---|
| Arm/Group Description | Non-myeloablative Stem Cell Transplant (SCT): Donor will receive Granulocyte colony-stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily for 4 days, until pheresis is completed or until white blood cells > 100,000. Recipients will be premedicated with Benadryl 50 mg intravenously (IV) or orally (PO), and acetaminophen 650 mg PO (or hydrocortisone 50-100 mg IV on first day). The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. The prep regimen for myeloid disease will begin on day -5 or day -4 and busulfan 130mg/m2/d for 2 days over 3 hours. The Peripheral Blood Stem Cells (PBSCs) will be infused over 2-4 days. Participant evaluations will occur 2 times per week by physical exam for toxicity through day 45. |
| Measure Participants | 124 |
| Matched Related Donors (MRD); n=38 |
47
58.8%
|
| Matched Unrelated Donors (MUD); n=53 |
23
28.8%
|
| Haploidentical related (HAPLO) donors; n=33 |
16
20%
|
| Title | Immune Recovery |
|---|---|
| Description | Evaluate immune recovery following this reduced intensity allogeneic immunotherapy. Quantification of CD3+, CD4+, and CD8+ T cells was performed by flow cytometry on fresh peripheral blood at approximately 1 month before transplantation and then 1.5, 3, 6, and 12 months after transplantation. The immune recovery rates of the CD3+, CD4+, and CD8+ T cells in the MRD, MUD, and HAPLO groups were compared by performing an analysis of variance at each time point after transplantation. The median T cell counts at 12 months for each type of cell are reported by donor type. |
| Time Frame | 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects with complete response. Cohort A (n=62) had acute or chronic leukemia (ALL or CLL), lymphoma, or myeloma. Cohort B (n=62) had acute or chronic myeloid leukemia (AML or CML), myelodysplastic disorder or myeloproliferative disorder. Analysis by type of donor (Matched Unrelated Donor; Matched Related Donor; Haplo-identical). |
| Arm/Group Title | Cohort A & B- Lymphoid & Myeloid Disease |
|---|---|
| Arm/Group Description | Non-myeloablative Stem Cell Transplant (SCT): Donor will receive Granulocyte colony-stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily for 4 days, until pheresis is completed or until white blood cells > 100,000. Recipients will be premedicated with Benadryl 50 mg intravenously (IV) or orally (PO), and acetaminophen 650 mg PO (or hydrocortisone 50-100 mg IV on first day). The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. The Peripheral Blood Stem Cells (PBSCs) will be infused over 2-4 days. Participant evaluations will occur 2 times per week by physical exam for toxicity through day 45. |
| Measure Participants | 124 |
| Matched Related Donors (MRD) n=38 - CD3+ Tcells/uL |
700
(100)
|
| Matched Unrelated Donors(MUD) n=53 - CD3+Tcells/uL |
550
(150)
|
| Haploidentical related (HAPLO) n=33 -CD3+Tcells/uL |
500
(200)
|
| Matched Related Donors (MRD) n=38 - CD4+ Tcells/uL |
225
(30)
|
| Matched Unrelated Donors (MUD) n=53 -CD4+Tcells/uL |
140
(20)
|
| Haploidentical related (HAPLO) n=33 -CD4+Tcells/uL |
150
(55)
|
| Matched Related Donors (MRD) n=38 - CD8+ Tcells/uL |
420
(100)
|
| Matched Unrelated Donors (MUD) n=53 -CD8+Tcells/uL |
350
(150)
|
| Haploidentical related (HAPLO) n=33 -CD8+Tcells/uL |
300
(150)
|
| Title | Progression Free Survival |
|---|---|
| Description | Progression-free survival (PFS) rates after stem cell transplant were estimated using the Kaplan-Meier method. We performed univariate comparisons by using the log-rank test. PFS was defined as the period of time between the day of transplantation and either the day underlying disease progression was documented or death occurred by any cause. The following variables were considered as confounders: recipient age, recipient sex, disease (myeloid or lymphoid), disease risk (standard or high), and donor type (MRD, MUD, or HAPLO donor). The percentage of participants progression free at 2 years is reported by donor type. Progression = > 25% increase of serum M-protein and/or urine M-protein. Also, an absolute increase in bone marrow plasma cells > 10%, new bone lesions or soft tissue plasmacytomas or increase in the size of existing bone lesions or soft tissue plasmacytomas or development of hypercalcemia that can be attributed solely to the plasma cell proliferative disorder. |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants who received transplant. Cohort A (n=62) had acute or chronic leukemia (ALL or CLL), lymphoma, or myeloma. Cohort B (n=62) had acute or chronic myeloid leukemia (AML or CML), myelodysplastic disorder or myeloproliferative disorder. Analysis by type of donor (Matched Unrelated Donor; Matched Related Donor; Haplo-identical). |
| Arm/Group Title | Cohort A & B - Lymphoid & Myeloid Disease |
|---|---|
| Arm/Group Description | Non-myeloablative Stem Cell Transplant (SCT): Donor will receive Granulocyte colony-stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily for 4 days, until pheresis is completed or until white blood cells > 100,000. Recipients will be premedicated with Benadryl 50 mg intravenously (IV) or orally (PO), and acetaminophen 650 mg PO (or hydrocortisone 50-100 mg IV on first day). The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. For the myeloid group, the prep regimen will begin on day -5 or day -4 and busulfan 130mg/m2/d for 2 days over 3 hours. The Peripheral Blood Stem Cells (PBSCs) will be infused over 2-4 days. Participant evaluations will occur 2 times per week by physical exam for toxicity through day 45. |
| Measure Participants | 124 |
| Matched Related Donors (MRD) n=38 |
43
53.8%
|
| Matched Unrelated Donors (MUD) n=53 |
22
27.5%
|
| Haploidentical related (HAPLO) donor n=33 |
15
18.8%
|
| Title | Overall Survival |
|---|---|
| Description | Estimate overall survival rates in participants treated with an alemtuzumab T cell depleted, reduced intensity preparative regimen followed by allogeneic hematopoietic transplantation. Disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) rates after SCT were estimated using the Kaplan-Meier method. We performed univariate comparisons by using the log-rank test. OS was defined as the period of time between the day of transplantation and death. The following variables were considered as confounders: recipient age, recipient sex, disease (myeloid or lymphoid), disease risk (standard or high), and donor type (MRD, MUD, or HAPLO donor). The percentage of participants surviving 2 years by donor type is reported. |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants who received transplant. Cohort A (n=62) had acute or chronic leukemia (ALL or CLL), lymphoma, or myeloma. Cohort B (n=62) had acute or chronic myeloid leukemia (AML or CML), myelodysplastic disorder or myeloproliferative disorder. Analysis by type of donor (Matched Unrelated Donor; Matched Related Donor; Haplo-identical). |
| Arm/Group Title | Cohort A & B - Lymphoid & Myeloid Disease |
|---|---|
| Arm/Group Description | Non-myeloablative Stem Cell Transplant (SCT): Donor will receive Granulocyte colony-stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily for 4 days, until pheresis is completed or until white blood cells > 100,000. Recipients will be premedicated with Benadryl 50 mg intravenously (IV) or orally (PO), and acetaminophen 650 mg PO (or hydrocortisone 50-100 mg IV on first day). The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. The prep regimen for myeloid disease will begin on day -5 or day -4 and busulfan 130mg/m2/d for 2 days over 3 hours. The Peripheral Blood Stem Cells (PBSCs) will be infused over 2-4 days. Participant evaluations will occur 2 times per week by physical exam for toxicity through day 45. |
| Measure Participants | 124 |
| Matched Related Donors (MRD) n=38 |
51
63.8%
|
| Matched Unrelated Donors (MUD) n=53 |
22
27.5%
|
| Haploidentical related (HAPLO) donors n=33 |
23
28.8%
|
| Title | Graft Versus Host Disease |
|---|---|
| Description | Estimate toxicity including graft-versus-host disease (GVHD) in participants treated with an alemtuzumab T cell depleted, reduced intensity preparative regimen followed by allogeneic hematopoietic transplantation. Bone marrow aspiration and/or biopsy were performed 3-5 weeks after transplant to assess donor-cell engraftment. Acute or chronic GVHD was diagnosed and graded according to standard criteria. Toxicity was formally graded using the National Cancer Institute Common Toxicity Criteria version 3.0. |
| Time Frame | 180 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants who received transplant. Cohort A (n=62) had acute or chronic leukemia (ALL or CLL), lymphoma, or myeloma. Cohort B (n=62) had acute or chronic myeloid leukemia (AML or CML), myelodysplastic disorder or myeloproliferative disorder. Analysis by occurrence of Graft versus Host Disease (GvHD) and Graft Failure and donor type. |
| Arm/Group Title | Cohort A & B - Lymphoid & Myeloid Disease |
|---|---|
| Arm/Group Description | Non-myeloablative Stem Cell Transplant (SCT): Donor will receive Granulocyte colony-stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily for 4 days, until pheresis is completed or until white blood cells > 100,000. Recipients will be premedicated with Benadryl 50 mg intravenously (IV) or orally (PO), and acetaminophen 650 mg PO (or hydrocortisone 50-100 mg IV on first day). The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. The prep regimen for myeloid disease will begin on day -5 or day -4 and busulfan 130mg/m2/d for 2 days over 3 hours.The Peripheral Blood Stem Cells (PBSCs) will be infused over 2-4 days. Participant evaluations will occur 2 times per week by physical exam for toxicity through day 45. |
| Measure Participants | 124 |
| Grade II-IV GvHD (MRD n=38) |
16
20%
|
| Grade II-IV GvHD (MUD n=53) |
26
32.5%
|
| Grade II-IV GvHD (HAPLO n=33) |
46
57.5%
|
| Grade III-IV GvHD (MRD n=38) |
3
3.8%
|
| Grade III-IV GvHD (MUD=53) |
13
16.3%
|
| Grade III-IV GvHD (HAPLO n=33) |
27
33.8%
|
| Title | Graft Failure |
|---|---|
| Description | Estimate toxicity including graft-versus-host disease (GVHD) in participants treated with an alemtuzumab T cell depleted, reduced intensity preparative regimen followed by allogeneic hematopoietic transplantation. Bone marrow aspiration and/or biopsy were performed 3-5 weeks after transplant to assess donor-cell engraftment. Primary Graft Failure was defined as a neutrophil count below 500/μL or the absence of donor-derived hematopoiesis (<5%donor cells) before relapse, death, or re-transplantation. Secondary Graft Failure was defined as the achievement of primary engraftment and a subsequent decrease in neutrophils to 3 consecutive counts of less than 100/μL or the absence of donor-derived hematopoiesis (<5% donor cells) before relapse, death, or re-transplantation. |
| Time Frame | 180 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects who received transplant. Cohort A (n=62) had acute or chronic leukemia (ALL or CLL), lymphoma, or myeloma. Cohort B (n=62) had acute or chronic myeloid leukemia (AML or CML), myelodysplastic disorder or myeloproliferative disorder. Analysis by occurrence of Graft versus Host Disease (GvHD) and donor type. |
| Arm/Group Title | Cohort A & B - Lymphoid & Myeloid Disease |
|---|---|
| Arm/Group Description | Non-myeloablative Stem Cell Transplant (SCT): Donor will receive Granulocyte colony-stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily for 4 days, until pheresis is completed or until white blood cells > 100,000. Recipients will be premedicated with Benadryl 50 mg intravenously (IV) or orally (PO), and acetaminophen 650 mg PO (or hydrocortisone 50-100 mg IV on first day). The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. The prep regimen for myeloid disease will begin on day -5 or day -4 and busulfan 130mg/m2/d for 2 days over 3 hours.The Peripheral Blood Stem Cells (PBSCs) will be infused over 2-4 days. Participant evaluations will occur 2 times per week by physical exam for toxicity through day 45. |
| Measure Participants | 124 |
| Graft Failure (MRD n=38) |
1
1.3%
|
| Graft Failure (MUD n=53) |
3
3.8%
|
| Graft Failure (HAPLO n=33) |
10
12.5%
|
Adverse Events
| Time Frame | Participants will be evaluated at a minimum of 2 times per week by physical exam for toxicity following Version 3 of the NCI expanded common toxicity criteria through day 45 following the first infusion. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Graft versus Host Disease (GVHD) and other toxicity was graded per NCI's common terminology criteria for adverse events (CTCAE) (3.0). | |||
| Arm/Group Title | Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease | ||
| Arm/Group Description | Non-myeloablative stem cell transplant (SCT): Donor will receive Granulocyte colony-stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily for 4 days, until pheresis is completed or until white blood cells > 100,000. Recipients will be premedicated with Benadryl 50 mg intravenously (IV) or orally (PO), and acetaminophen 650 mg PO (or hydrocortisone 50-100 mg IV on first day). The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. The peripheral blood stem cells (PBSCs) will be infused over 2-4 days. Participant evaluations will occur 2 times per week by physical exam for toxicity through day 45. | Non-myeloablative stem cell transplant (SCT): Donor will receive granulocyte colony stimulating factor (G-CSF) 8 mcg/kg/d subcutaneously twice daily for 4 days, until pheresis is completed or until white blood cells > 100,000. Recipients will be premedicated with Benadryl 50 mg intravenously (IV) or orally (PO), and acetaminophen 650 mg PO (or hydrocortisone 50-100 mg IV on first day). The preparative regimen is 4 days of daily fludarabine at 40 mg/m2/d infused over 30 minutes; melphalan 140 mg/m2/d for 1 day administered over 15 minutes; 4 days of Alemtuzumab at 20 mg/d in 250 ml of normal saline infused over 3 hours. The prep regimen will begin on day -5 or day -4 and busulfan 130mg/m2/d for 2 days over 3 hours. The peripheral blood stem cells (PBSCs) will be infused over 2-4 days. Participant evaluations will occur 2 times per week by physical exam for toxicity through day 45. | ||
All Cause Mortality |
||||
| Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 16/80 (20%) | 10/57 (17.5%) | ||
| Cardiac disorders | ||||
| Supraventricular and nodal arrhythmia | 2/80 (2.5%) | 2 | 0/57 (0%) | 0 |
| Cardiac Ischemia/Infarction | 0/80 (0%) | 0 | 1/57 (1.8%) | 1 |
| Gastrointestinal disorders | ||||
| Diarrhea | 1/80 (1.3%) | 1 | 0/57 (0%) | 0 |
| Nausea | 1/80 (1.3%) | 1 | 0/57 (0%) | 0 |
| General disorders | ||||
| Death - NOS | 9/80 (11.3%) | 9 | 6/57 (10.5%) | 6 |
| Hepatobiliary disorders | ||||
| Hepatobiliary/Pancreas | 1/80 (1.3%) | 1 | 0/57 (0%) | 0 |
| Pancreatitis | 1/80 (1.3%) | 1 | 0/57 (0%) | 0 |
| Liver dysfunction/failure | 0/80 (0%) | 0 | 1/57 (1.8%) | 1 |
| Infections and infestations | ||||
| Febrile neutropenia | 1/80 (1.3%) | 1 | 1/57 (1.8%) | 2 |
| Infection - Other | 3/80 (3.8%) | 3 | 3/57 (5.3%) | 3 |
| Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L) | 2/80 (2.5%) | 2 | 3/57 (5.3%) | 5 |
| Infection with grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L) | 2/80 (2.5%) | 3 | 0/57 (0%) | 0 |
| Infection with unknown ANC | 1/80 (1.3%) | 1 | 0/57 (0%) | 0 |
| Nervous system disorders | ||||
| Altered Mental Status | 1/80 (1.3%) | 1 | 1/57 (1.8%) | 2 |
| CNS - Cerebrovascular Ischemia | 0/80 (0%) | 0 | 1/57 (1.8%) | 1 |
| Renal and urinary disorders | ||||
| Renal Failure | 1/80 (1.3%) | 1 | 1/57 (1.8%) | 1 |
| Cystitis | 1/80 (1.3%) | 1 | 0/57 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Adult Respiratory Distress Syndrome (ARDS) | 1/80 (1.3%) | 1 | 0/57 (0%) | 0 |
| Cough | 1/80 (1.3%) | 1 | 0/57 (0%) | 0 |
| Dyspnea | 1/80 (1.3%) | 1 | 0/57 (0%) | 0 |
| Vascular disorders | ||||
| Hemorrhage | 0/80 (0%) | 0 | 1/57 (1.8%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 77/80 (96.3%) | 52/57 (91.2%) | ||
| Blood and lymphatic system disorders | ||||
| Failure to Engraft | 3/80 (3.8%) | 3 | 13/57 (22.8%) | 13 |
| Hemorrhage/Bleeding | 5/80 (6.3%) | 6 | 3/57 (5.3%) | 3 |
| Gastrointestinal disorders | ||||
| Diarrhea | 17/80 (21.3%) | 20 | 4/57 (7%) | 4 |
| Mucositis/Stomatitis | 5/80 (6.3%) | 5 | 2/57 (3.5%) | 2 |
| Nausea | 5/80 (6.3%) | 5 | 2/57 (3.5%) | 2 |
| General disorders | ||||
| Fever without neutropenia | 4/80 (5%) | 7 | 0/57 (0%) | 0 |
| Infections and infestations | ||||
| Febrile neutropenia | 40/80 (50%) | 46 | 22/57 (38.6%) | 23 |
| Infection - Other | 14/80 (17.5%) | 14 | 4/57 (7%) | 5 |
| Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L) | 53/80 (66.3%) | 118 | 41/57 (71.9%) | 90 |
| Infection with normal ANC or grade 1 or 2 neutrophils | 42/80 (52.5%) | 101 | 18/57 (31.6%) | 37 |
| Infection with unknown ANC | 5/80 (6.3%) | 12 | 1/57 (1.8%) | 1 |
| Metabolism and nutrition disorders | ||||
| Creatinine | 8/80 (10%) | 8 | 1/57 (1.8%) | 1 |
| Renal and urinary disorders | ||||
| Renal/Genitourinary - Other | 7/80 (8.8%) | 8 | 2/57 (3.5%) | 3 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Dyspnea | 7/80 (8.8%) | 8 | 1/57 (1.8%) | 2 |
| Hypoxia | 6/80 (7.5%) | 7 | 5/57 (8.8%) | 5 |
| Skin and subcutaneous tissue disorders | ||||
| Rash/desquamation | 2/80 (2.5%) | 2 | 4/57 (7%) | 5 |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | David Rizzieri, MD |
|---|---|
| Organization | Duke University Medical Center |
| Phone | 919-668-1040 |
| david.rizzieri@duke.edu |
- Pro00003567