Selective T-Cell Depletion to Reduce GVHD (Patients) Receiving Stem Cell Tx to Treat Leukemia, Lymphoma or MDS

• ClinicalTrials.gov Identifier: NCT00025662
• Recruitment Status: Completed
• First Posted: January 27, 2003
• Results First Posted: January 13, 2012
• Last Update Posted: October 28, 2016
• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information

• First Submitted Date: October 11, 2001
• First Posted Date: January 27, 2003
• Results First Submitted Date: April 20, 2011
• Results First Posted Date: January 13, 2012
• Last Update Posted Date: October 28, 2016
• Study Start Date: May 2001
• Actual Primary Completion Date: February 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 9, 2011)

Treatment-related Mortality [ Time Frame: 100 days after stem cell infusion ]

Nonrelapse mortality in the first 100 days of transplant expressed as a percentage of the total subjects. This is different from outcome measure 3 (Cumulative Nonrelapse Mortality), which is cumulative non relapse mortality till December 2011.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: December 9, 2011)

• Overall Survival [ Time Frame: Dec 2011. ]
  Percent overall survival (actuarial) at analysis in Dec 2011.
• Cumulative Non Relapse Mortality [ Time Frame: Dec 2011. ]
  Percent non relapse mortality (actuarial) at analysis in Dec 2011

• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: December 9, 2011)

• Acute GVHD (Any Grade) Using the CIBMTR Grading System. [ Time Frame: 100 days from transplant ]
  Proportion of patients with acute GVHD, grade 1 to 4
• Acute GVHD (Grade 3 or 4) Using the CIBMTR Grading System. [ Time Frame: 100 days from transplant ]

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Selective T-Cell Depletion to Reduce GVHD (Patients) Receiving Stem Cell Tx to Treat Leukemia, Lymphoma or MDS
• Official Title: Ex Vivo Selective Depletion of Alloreactive Donor T-Lymphocytes Using "RFT5-SMPT-dgA": Reducing GVHD Risk Associated With Matched, Nonmyeloablative, Stem Cell Transplant for Hematologic Malignancies in Older Adults
• Brief Summary: This study will evaluate the safety and effectiveness of stem cell transplantation in which the donors T lymphocytes have undergone "selective depletion." Certain patients with cancers of the blood undergo transplantation of donated stem cells to generate new and normally functioning bone marrow. In addition to producing the new bone marrow, the donor's T-lymphocytes also fight any tumor cells that might have remained in the body. This attack on tumor cells is called a "graft-versus-leukemia" (GVL) effect. However, another type of T-lymphocyte from the donor may cause what is called "graft-versus-host-disease" (GVHD), in which the donor cells recognize the patient's cells as foreign and mount an immune response to reject them. Selective depletion is a technique that was developed to remove the T-lymphocytes that cause harmful GVHD, while keeping those that produce the desirable GVL effect.

Detailed Description

Despite improved prophylaxis and treatment, graft-versus-host disease (GVHD) remains a major complication after allogeneic stem cell transplantation. Although the most effective way to prevent GVHD is T cell depletion, this process results in poor immune function leading to increased rates of relapse, graft rejection, and post-transplant infections. Ideally, a method of removing GVHD- producing effector cells while retaining a broad T cell repertoire, including preservation of 3rd party, antiviral and anti-tumor responses would be desirable. Preclinical studies from our lab have demonstrated that alloreactive T cells can be selectively removed from the donor lymphocyte pool in vitro with the use of a specific immunotoxin directed against the interleukin-2 receptor.

To test this clinically, we will perform nonmyeloablative allogeneic stem cell transplants in older patients with hematologic malignancies. Although these patients can be cured with this approach, they have significant morbidity and mortality from GVHD. At our institution, nonmyeloablative transplantation is associated with an incidence of grade II-IV acute GVHD of approximately 50%. Although well tolerated in younger patients, patients over the age of 50 years have a transplant-related mortality (TRM) of approximately 35%, which is mostly related to GVHD. Through selective depletion of alloreactive donor lymphocytes, we hope to reduce GVHD mortality, while preserving the transplant efficacy.

Patients receive a reduced intensity preparative regimen, followed by a mobilized peripheral blood stem cell allograft from an HLA-identical sibling donor, containing "selectively-depleted" donor lymphocytes. To obtain such a graft, colony stimulating factor (G-CSF)-mobilized peripheral blood from the donor undergoes a positive cluster of differentiation (CD34) selection followed by a negative T cell selection using the "Nexell" Isolex 300i system. This stem cell-rich, T cell-depleted product will contain a CD34+ cell dose of at least 5x10(6)/kg. The unabsorbed fraction, remaining after the positive CD34 selection, is then co-cultured for 72 hours with irradiated lymphocytes from the patient. The immunotoxin, RFT5-SMPT-dgA, is added during the last 24 hours of culture to remove alloreacting cells. The washed T cell product (CD3+ cell dose of 1-4 x 10(8)/kg) is cryopreserved. Following the preparative regimen, the patient receives successive infusions of the stem cell product and selected lymphocytes. All patients receive standard post transplant immunosuppression with cyclosporine for a minimum of 30 days, followed by dose reduction depending on the degree of donor lymphocyte chimerism.

The primary end point of this study is the incidence and severity of acute GVHD. We will also examine the incidence of chronic GVHD, engraftment, degree of donor-host chimerism, transplant related morbidity and mortality, as well as disease-free and overall survival. Stopping rules will minimize the risk of untoward or unexpected side effects.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Graft vs Host Disease
• Myelodysplastic Syndromes
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Lymphocytic
• Lymphoma
• Lymphoma, Mantle-cell
• Lymphoma, Non-Hodgkin
• Hodgkin Disease

Intervention

• Drug: RFT5-SMPT-dgA
  A specific anti-interleukin-2 receptor immunotoxin
  Other Name: anti-interleukin-2 receptor immunotoxin
• Drug: Isolex system
  CD34 selection/ T cell depletion used this system
  Other Name: Nexell Isolex system

Study Arms

Experimental: RFT5-SMPT-dgA Isolex system

RFT5-SMPT-dgA, a specific anti-interleukin-2 receptor immunotoxin used in allogeneic stem cell transplantation (SCT) in older patients with hematologic malignancies using a graft manipulation process

Interventions:

• Drug: RFT5-SMPT-dgA
• Drug: Isolex system

Publications *

• Barrett J, Solomon S. The transition from bench to bedside: lessons learned in the creation of a new T-cell product for the clinic. Cytotherapy. 2004;6(6):593-5.
• Solomon SR, Tran T, Carter CS, Donnelly S, Hensel N, Schindler J, Bahceci E, Ghetie V, Michálek J, Mavroudis D, Read EJ, Vitetta ES, Barrett AJ. Optimized clinical-scale culture conditions for ex vivo selective depletion of host-reactive donor lymphocytes: a strategy for GvHD prophylaxis in allogeneic PBSC transplantation. Cytotherapy. 2002;4(5):395-406.
• Mielke S, Solomon SR, Barrett AJ. Selective depletion strategies in allogeneic stem cell transplantation. Cytotherapy. 2005;7(2):109-15. Review.
• Solomon SR, Mielke S, Savani BN, Montero A, Wisch L, Childs R, Hensel N, Schindler J, Ghetie V, Leitman SF, Mai T, Carter CS, Kurlander R, Read EJ, Vitetta ES, Barrett AJ. Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation. Blood. 2005 Aug 1;106(3):1123-9. Epub 2005 Apr 7.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 9, 2011): 23
• Original Enrollment: Not Provided
• Actual Study Completion Date: February 2008
• Actual Primary Completion Date: February 2008 (Final data collection date for primary outcome measure)

Eligibility Criteria

- INCLUSION CRITERIA: PATIENT

• Ages 50-75 years
• Relapsed CML in chronic or accelerated phase after therapy with STI-571 (Gleevec)
• Acute lymphoblastic leukemia (ALL), all patients in complete or partial remission. Exceptions: T cell ALL
• Acute myelogenous leukemia (AML): AML in first complete or partial remission including AML secondary to chemotherapy or prior hematological disease such as myelodysplastic syndrome, and myeloproliferative disorder.
• Myelodysplastic syndromes: (1) refractory anemia with excess of blasts (RAEB), (2) refractory anemia with excess blasts in transformation (RAEBT), (3) MDS with poor risk cytogenetics defined by a complex karyotype (greater than or equal to three anomalies) or chromosome 7 abnormalities, (4) secondary MDS after prior cytotoxic or radiation therapy, or (5) chronic myelomonocytic leukemia (CMML)
• Chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia, refractory to nucleoside analog therapy, with either progressive bulky disease or anemia (less than 10 g/dl) or thrombocytopenia (less than 100,000/microliter) not due to recent chemotherapy
• Mantle cell lymphoma
• Relapsed intermediate- or high-grade non-Hodgkin's lymphoma: (1) post autologous marrow or PBSC transplant, or (2) chemorefractory relapse. Exceptions: T cell NHL
• Relapse Hodgkin's disease: (1) post autologous marrow or PBSC transplant, or (2) chemorefractory relapse
• Low-grade follicular or small lymphocytic lymphoma: (1) relapsed following conventional chemotherapy, (2) relapsed following autologous marrow or PBSC transplant, or (3) chemoresistant disease
• Life expectancy greater than 3 months
• Ability to comprehend the investigational nature of the study and provide informed consent
• Availability of an HLA-identical family donor, 18 to 75 years old
• INCLUSION CRITERIA:

DONOR

• HLA identical family donor, 18 to 75 years old
• Fit to receive G-CSF and give peripheral blood stem cells (normal blood count, normotensive, no history of stroke, no history of severe heart disease)
• Ability to comprehend the investigational nature of the study and provide informed consent
• EXCLUSION CRITERIA:

RECIPIENT

• Pregnant or lactating
• Eastern Cooperative Oncology Group (ECOG) performance status of 3 or more
• Major anticipated illness or organ failure incompatible with survival from PBSC transplant
• Diffusion Capacity fir carbon monoxide (DLCO) less than 60% predicted
• Left ventricular ejection fraction less than 40%, or any angina.
• Absolute lymphocyte count less than 300/mm(3)
• Serum creatinine greater than 2.5 mg/dl
• Serum bilirubin greater than 4 mg/dl, transaminases greater than 5x upper limit of normal
• HIV positive
• Other malignant diseases liable to relapse or progress within 2 years
• EXCLUSION CRITERIA:

DONOR

• Pregnant or lactating
• HIV positive. Donors who are positive for Hepatitis B Virus, Hepatitis C Virus or human t-cell lymphoma virus (HTLV) will be used at the discretion of the investigator and with appropriate consent of the recipient
• Donor unfit to receive G-CSF and undergo apheresis (uncontrolled hypertension, history of heart failure or unstable angina, platelet count less than 90,000/cu mm)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00025662
• Other Study ID Numbers: 010162; 01-H-0162 ( Other Identifier: NIH )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
• Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: Not Provided

Investigators

• Study Chair: A. J Barrett, MD; NHLBI, NIH

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: September 2016