A Phase 2 interventional study of Non-myeloablative Stem Cell Transplantation in Hodgkin's Disease, Non Hodgkin's Lymphoma and Myeloma, sponsored by David Rizzieri, MD. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2014-06-02.
Sponsored by David Rizzieri, MD · Phase 2, Interventional, and Treatment
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.
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.
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Recipient Inclusion Criteria:
Specific populations:
Recipient Exclusion Criteria:
Donor Inclusion Criteria:
Donor must not have any medical condition which would make mobilization or apheresis more than a minimal risk, and should have the following:
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
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
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.
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.
Also known as: Allogeneic Stem Cell Transplant
Disease Free Survival
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
Immune Recovery
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
Progression Free Survival
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
Overall Survival
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
Graft Failure
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
Graft Versus Host Disease
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
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.
| Milestone | Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease | Donor |
|---|---|---|---|
| Started | 80 | 57 | 94 |
| Completed | 24 | 11 | 84 |
| Not completed | 56 | 46 | 10 |
| Withdrew: Death | 56 | 46 | 0 |
| Withdrew: Recipient death | 0 | 0 | 10 |
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.
| percentage of participants | Cohort A & B- Lymphoid & Myeloid Disease |
|---|---|
| Matched Related Donors (MRD); n=38 | 47 (29 to 63) |
| Matched Unrelated Donors (MUD); n=53 | 23 (12 to 36) |
| Haploidentical related (HAPLO) donors; n=33 | 16 (5 to 33) |
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.
| T cells/μL | Cohort A & B- Lymphoid & Myeloid Disease |
|---|---|
| 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 |
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.
| percentage of participants | Cohort A & B - Lymphoid & Myeloid Disease |
|---|---|
| Matched Related Donors (MRD) n=38 | 43 (26 to 59) |
| Matched Unrelated Donors (MUD) n=53 | 22 (11 to 34) |
| Haploidentical related (HAPLO) donor n=33 | 15 (5 to 30) |
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.
| percentage of participants | Cohort A & B - Lymphoid & Myeloid Disease |
|---|---|
| Matched Related Donors (MRD) n=38 | 51 (33 to 66) |
| Matched Unrelated Donors (MUD) n=53 | 22 (12 to 35) |
| Haploidentical related (HAPLO) donors n=33 | 23 (10 to 39) |
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.
| percentage of participants | Cohort A & B - Lymphoid & Myeloid Disease |
|---|---|
| Grade II-IV GvHD (MRD n=38) | 16 (7 to 30) |
| Grade II-IV GvHD (MUD n=53) | 26 (14 to 39) |
| Grade II-IV GvHD (HAPLO n=33) | 46 (24 to 65) |
| Grade III-IV GvHD (MRD n=38) | 3 (0.2 to 12) |
| Grade III-IV GvHD (MUD=53) | 13 (5 to 25) |
| Grade III-IV GvHD (HAPLO n=33) | 27 (11 to 47) |
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.
| number of participants | Cohort A & B - Lymphoid & Myeloid Disease |
|---|---|
| Graft Failure (MRD n=38) | 1 |
| Graft Failure (MUD n=53) | 3 |
| Graft Failure (HAPLO n=33) | 10 |
Collected over 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.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Cohort A - Lymphoid Disease | — | 16/80 (20%) | 77/80 (96.3%) |
| Cohort B - Myeloid Disease | — | 10/57 (17.5%) | 52/57 (91.2%) |
| Event | Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease |
|---|---|---|
| Death - NOSGeneral disorders | 9/80 | 6/57 |
| Infection - OtherInfections and infestations | 3/80 | 3/57 |
| Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L)Infections and infestations | 2/80 | 3/57 |
| Supraventricular and nodal arrhythmiaCardiac disorders | 2/80 | 0/57 |
| Infection with grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L)Infections and infestations | 2/80 | 0/57 |
| Cardiac Ischemia/InfarctionCardiac disorders | 0/80 | 1/57 |
| Febrile neutropeniaInfections and infestations | 1/80 | 1/57 |
| Altered Mental StatusNervous system disorders | 1/80 | 1/57 |
| CNS - Cerebrovascular IschemiaNervous system disorders | 0/80 | 1/57 |
| Renal FailureRenal and urinary disorders | 1/80 | 1/57 |
| Event | Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease |
|---|---|---|
| Infection with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L)Infections and infestations | 53/80 | 41/57 |
| Infection with normal ANC or grade 1 or 2 neutrophilsInfections and infestations | 42/80 | 18/57 |
| Febrile neutropeniaInfections and infestations | 40/80 | 22/57 |
| Failure to EngraftBlood and lymphatic system disorders | 3/80 | 13/57 |
| DiarrheaGastrointestinal disorders | 17/80 | 4/57 |
| Infection - OtherInfections and infestations | 14/80 | 4/57 |
| CreatinineMetabolism and nutrition disorders | 8/80 | 1/57 |
| HypoxiaRespiratory, thoracic and mediastinal disorders | 6/80 | 5/57 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 7/80 | 1/57 |
| Renal/Genitourinary - OtherRenal and urinary disorders | 7/80 | 2/57 |
Participants who proceeded to therapy and transplant.
| Age, Categorical(Participants) | Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 73 | 40 | 113 |
| >=65 years | 7 | 17 | 24 |
| Sex: Female, Male(Participants) | Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease | Total |
|---|---|---|---|
| Female | 35 | 24 | 59 |
| Male | 45 | 33 | 78 |
| Race (NIH/OMB)(Participants) | Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 1 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 9 | 6 | 15 |
| White | 70 | 51 | 121 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Ethnicity (NIH/OMB)(Participants) | Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease | Total |
|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 |
| Not Hispanic or Latino | 80 | 57 | 137 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Cohort A - Lymphoid Disease | Cohort B - Myeloid Disease | Total |
|---|---|---|---|
| United States | 80 | 57 | 137 |
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David Rizzieri, MD