Efficacy Study of T Cell Depleted Allogeneic Non-myeloablative Stem Cell Transplant

• ClinicalTrials.gov Identifier: NCT00597714
• Recruitment Status: Completed
• First Posted: January 18, 2008
• Results First Posted: June 2, 2014
• Last Update Posted: June 2, 2014
• Sponsor: David Rizzieri, MD
• Information provided by (Responsible Party): David Rizzieri, MD, Duke University

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
Hodgkin's Disease; Non Hodgkin's Lymphoma; Myeloma; Leukemia; Myelodysplasia	Drug: Non-myeloablative Stem Cell Transplantation	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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 264 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy Study of T Cell Depleted Allogeneic Non-myeloablative Stem Cell Transplantation
• Study Start Date: February 2008
• Actual Primary Completion Date: July 2013
• Actual Study Completion Date: November 2013

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 Name: Allogeneic Stem Cell Transplant
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 Name: Allogeneic Stem Cell Transplant
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 :

1. Disease Free Survival [ Time Frame: 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 :

1. Immune Recovery [ Time Frame: 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.
2. Progression Free Survival [ Time Frame: 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.
3. Overall Survival [ Time Frame: 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.
4. Graft Failure [ Time Frame: 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:

1. Graft Versus Host Disease [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

1. 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.

2. Donor must not have any medical condition which would make mobilization or apheresis more than a minimal risk, and should have the following:

   1. 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
   2. Adequate hematopoietic function with hematocrit ≥ 30%, white blood cell count of 3000, and platelets 100,000.
3. 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

United States, North Carolina

Duke University Health System

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

David Rizzieri, MD

Investigators

• Principal Investigator: David Rizzieri, MD; Duke University Health System

More Information

Publications of Results:

Kanda J, Long GD, Gasparetto C, Horwitz ME, Sullivan KM, Chute JP, Morris A, Shafique M, Li Z, Chao NJ, Rizzieri DA. Reduced-intensity allogeneic transplantation using alemtuzumab from HLA-matched related, unrelated, or haploidentical related donors for patients with hematologic malignancies. Biol Blood Marrow Transplant. 2014 Feb;20(2):257-63. doi: 10.1016/j.bbmt.2013.11.010. Epub 2013 Nov 20.

• Responsible Party: David Rizzieri, MD, Associate Professor of Medicine, Duke University
• ClinicalTrials.gov Identifier: NCT00597714
• Other Study ID Numbers: Pro00003567
• First Posted: January 18, 2008
• Results First Posted: June 2, 2014
• Last Update Posted: June 2, 2014
• Last Verified: February 2014

Keywords provided by David Rizzieri, MD, Duke University:

Stem Cell Transplantation, Non-myeloablative

Additional relevant MeSH terms:

Hodgkin Disease; Preleukemia; Myelodysplastic Syndromes; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions