Intentional Rejection of the Donor Graft Using Recipient Leukocyte Infusion(s) Following Nonmyeloablative Allogeneic Stem Cell Transplant (RLI)

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ClinicalTrials.gov Identifier: NCT00909948

Recruitment Status : Terminated (Slow Accrual)

First Posted : May 29, 2009

Last Update Posted : March 29, 2018

Sponsor:

Information provided by (Responsible Party):

Bimalangshu Dey, Massachusetts General Hospital

Study Description

Brief Summary:

The proposed study is based on our observation of paradoxical tumor regression after rejection of the donor graft in conjunction with the results of our murine experiments. We hypothesize that clinically meaningful responses can be achieved in patients with advanced malignancies with a transplant strategy using nonmyeloablative conditioning and related mismatched donor stem cell transplant where the intention will be to initially achieve mixed chimerism which will be followed by recipient lymphocyte infusion (RLI) in an attempt to deliberately reject the donor graft. This will lead to the development of novel transplant strategies for achieving antitumor effects without the risk of graft versus host disease (GVHD). This proposed protocol is a Pilot Study that will evaluate the safety of this outpatient transplant strategy, i.e., establishment of initial mixed chimerism followed by RLI for donor graft rejection, in patients with advanced lymphomas, and multiple myeloma.

In addition, because RLI have been reported to reverse ongoing GVHD, this approach might potentially reverse GVHD while achieving antitumor responses if this complication unexpectedly occurs.

Condition or disease	Intervention/treatment	Phase
Non Hodgkin's Lymphoma Hodgkin Disease Multiple Myeloma	Other: Fludarabine and total body irradiation Radiation: Total body irradiation	Phase 1

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	7 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Intentional Rejection of the Donor Graft Using Recipient Leukocyte Infusion(s) Following Nonmyeloablative Allogeneic Stem Cell Transplant
Study Start Date :	November 2008
Actual Primary Completion Date :	August 2012
Actual Study Completion Date :	August 2012

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Multiple myeloma

Drug Information available for: Fludarabine Fludarabine phosphate

Genetic and Rare Diseases Information Center resources: Lymphosarcoma Multiple Myeloma Hodgkin Lymphoma

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Fludarabine The patients in this cohort will receive fludarabine 30 mg/m2/day on days -4 to -2 and 200 cGy TBI on day 0.	Other: Fludarabine and total body irradiation The patients in the second cohort will receive fludarabine 30 mg/m2/day on days -4 to -2 and 200 cGy TBI on day 0.
Active Comparator: TBI only Patients will be given 200 centiGray (cGy) total body irradiation (TBI) in one fraction. TBI will be given on day 0, 4 to 6 hours prior to HCT.	Radiation: Total body irradiation Patients will receive 200 cGy TBI on day 0,4-6 hours prior to HCT.

Outcome Measures

Primary Outcome Measures :

To determine the safety at ≤100 days of a non myeloablative mismatched related HCT when followed by recipient leukocyte infusion to induce deliberate rejection of the donor graft. [ Time Frame: 100 days post transplant ]

Secondary Outcome Measures :

To evaluate the incidence of acute and chronic GVHD [ Time Frame: Up to 2 years post transplant ]
To evaluate the incidence of loss of donor grafts [ Time Frame: Up to 2 years post transplant ]
To evaluate progression-free and overall survival [ Time Frame: Up to 2 years post transplant ]
To evaluate antitumor responses following this transplant strategy [ Time Frame: Up to 2 years post transplant ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients with chemorefractory non-Hodgkin's or Hodgkin's lymphoma or multiple myeloma.

Criteria for consideration of enrollment will include:
1. primary refractory or refractory relapsed disease for which autologous HCT is unlikely to be beneficial;
2. relapse after autologous HCT
3. ineligibility for standard myeloablative or nonmyeloablative allo-HCT because of either lack of a donor or patient considerations
Non Hodgkin's lymphoma, or Hodgkin's lymphoma: primary refractory or refractory relapse
Multiple myeloma; primary refractory or refractory relapse
Patients with the above malignancies who have had a previous autologous or allogeneic bone marrow or stem cell transplant.
An estimated disease-free survival of less than one year.
Age 18 to age < 75 years
ECOG performance status of 0, 1, or 2.

Exclusion Criteria:

Patients whose life expectancy is limited by diseases other than their malignancy
Patients who have a 5/6 or better matched related donor or a 4/6 or better umbilical cord blood donor and who are medically eligible for conventional myeloablative or non-myeloablative transplant will be excluded
Cardiac disease: symptomatic congestive heart failure or RVG or echocardiogram determined LVEF ogf< 30%, active angina pectoris or uncontrolled hypertension
Pulmonary disease: severe chronic obstructive lung disease, or symptomatic restrictive lung disease, or corrected DLCO < 40% of predicted
Renal disease: serum creatinine > 3.0 mg/dl.
Hepatic disease: serum bilirubin > 3.0 mg/dl or alkaline phosphatase, SGOT or SGPT > 3 x ULN
Neurologic disease: symptomatic leukoencephalopathy, active CNS malignancy or other neuropsychiatric abnormalities believed to preclude transplantation (pervious CNS malignancy presently in CR is not an exclusion)
Uncontrolled infection.
Recipient leukocyte infusion (RLI) might involve the infusion of circulating tumor cells to the patients. To minimize this risk patients who have evidence of circulating tumor cells by light microscopy and flow cytometry will be excluded
Patients with acute leukemia will be excluded because they will likely have much greater circulating tumor burden, which would increase the risk of infusion of clonal tumor cells

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00909948

Locations

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United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114

Sponsors and Collaborators

Massachusetts General Hospital

Investigators

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Principal Investigator:	Bimalangshu R Dey, MD, PhD	MGH

More Information

Publications:

Bortin MM, Rimm AA, Saltzstein EC. Graft versus leukemia: quantification of adoptive immunotherapy in murine leukemia. Science. 1973 Feb 23;179(4075):811-3.

Hill GR, Krenger W, Ferrara JL. The role of cytokines in acute graft-versus-host disease. Cytokines Cell Mol Ther. 1997 Dec;3(4):257-66. Review.

Dey BR, McAfee S, Colby C, Sackstein R, Saidman S, Tarbell N, Sachs DH, Sykes M, Spitzer TR. Impact of prophylactic donor leukocyte infusions on mixed chimerism, graft-versus-host disease, and antitumor response in patients with advanced hematologic malignancies treated with nonmyeloablative conditioning and allogeneic bone marrow transplantation. Biol Blood Marrow Transplant. 2003 May;9(5):320-9.

Sykes M, Romick ML, Sachs DH. Interleukin 2 prevents graft-versus-host disease while preserving the graft-versus-leukemia effect of allogeneic T cells. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5633-7.

Mapara MY, Kim YM, Wang SP, Bronson R, Sachs DH, Sykes M. Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras: a critical role for host antigen-presenting cells. Blood. 2002 Sep 1;100(5):1903-9.

Kraus AB, Shaffer J, Toh HC, Preffer F, Dombkowski D, Saidman S, Colby C, George R, McAfee S, Sackstein R, Dey B, Spitzer TR, Sykes M. Early host CD8 T-cell recovery and sensitized anti-donor interleukin-2-producing and cytotoxic T-cell responses associated with marrow graft rejection following nonmyeloablative allogeneic bone marrow transplantation. Exp Hematol. 2003 Jul;31(7):609-21.

Spitzer TR, McAfee S, Sackstein R, Colby C, Toh HC, Multani P, Saidman S, Weyouth DW, Preffer F, Poliquin C, Foley A, Cox B, Andrews D, Sachs DH, Sykes M. Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood Marrow Transplant. 2000;6(3A):309-20.

Rubio MT, Kim YM, Sachs T, Mapara M, Zhao G, Sykes M. Antitumor effect of donor marrow graft rejection induced by recipient leukocyte infusions in mixed chimeras prepared with nonmyeloablative conditioning: critical role for recipient-derived IFN-gamma. Blood. 2003 Sep 15;102(6):2300-7. Epub 2003 Jun 5.

Ballen KK, Becker PS, Emmons RV, Fitzgerald TJ, Hsieh CC, Liu Q, Heyes C, Clark Y, Levy W, Lambert JF, Chiafari F, Szymanski I, Rososhansky S, Popovsky MA, Stewart FM, Quesenberry PJ. Low-dose total body irradiation followed by allogeneic lymphocyte infusion may induce remission in patients with refractory hematologic malignancy. Blood. 2002 Jul 15;100(2):442-50.

Colby C, Sykes M, Sachs DH, Spitzer TR. Cellular modulation of acute graft-vs.-host disease. Biol Blood Marrow Transplant. 1997 Dec;3(6):287-93. Review.

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Responsible Party:	Bimalangshu Dey, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier:	NCT00909948
Obsolete Identifiers:	NCT00981760
Other Study ID Numbers:	Protocol 07-068
First Posted:	May 29, 2009 Key Record Dates
Last Update Posted:	March 29, 2018
Last Verified:	March 2018

Keywords provided by Bimalangshu Dey, Massachusetts General Hospital:


Related stem cell transplant, TBI, Mismatched stem cell transplant Fludarabine	Non-myeloablative Lymphoma Multiple myeloma

Additional relevant MeSH terms:

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Multiple Myeloma Hodgkin Disease Lymphoma Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Neoplasms, Plasma Cell	Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders Hematologic Diseases Hemorrhagic Disorders Fludarabine Antineoplastic Agents

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