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

NCT00909948 | Terminated Phase 1 DMC

• 1 other identifier: Protocol 07-068
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

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.

Conditions

Non Hodgkin's Lymphoma; Hodgkin Disease; Multiple Myeloma

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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.

  100 days post transplant

Secondary Outcomes (4)

• To evaluate the incidence of acute and chronic GVHD

  Up to 2 years post transplant

• To evaluate the incidence of loss of donor grafts

  Up to 2 years post transplant

• To evaluate progression-free and overall survival

  Up to 2 years post transplant

• To evaluate antitumor responses following this transplant strategy

  Up to 2 years post transplant

Study Arms (2)

Fludarabine

ACTIVE COMPARATOR

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

TBI only

ACTIVE COMPARATOR

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

Interventions

Fludarabine and total body irradiation OTHER

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.

Fludarabine

Total body irradiation RADIATION

Patients will receive 200 cGy TBI on day 0,4-6 hours prior to HCT.

TBI only

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with chemorefractory non-Hodgkin's or Hodgkin's lymphoma or multiple myeloma.
• Criteria for consideration of enrollment will include:
• primary refractory or refractory relapsed disease for which autologous HCT is unlikely to be beneficial;
• relapse after autologous HCT
• 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.

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Related Publications (10)

• Bortin MM, Rimm AA, Saltzstein EC. Graft versus leukemia: quantification of adoptive immunotherapy in murine leukemia. Science. 1973 Feb 23;179(4075):811-3. doi: 10.1126/science.179.4075.811.

  PMID: 4405359 BACKGROUND

• 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.

  PMID: 9740354 BACKGROUND

• 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. doi: 10.1016/s1083-8791(03)00077-6.

  PMID: 12766882 BACKGROUND

• 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. doi: 10.1073/pnas.87.15.5633.

  PMID: 2377601 BACKGROUND

• 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. doi: 10.1182/blood-2002-01-0023.

  PMID: 12176915 BACKGROUND

• 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. doi: 10.1016/s0301-472x(03)00082-1.

  PMID: 12842706 BACKGROUND

• 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. doi: 10.1016/s1083-8791(00)70056-5.

  PMID: 10905768 BACKGROUND

• 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. doi: 10.1182/blood-2002-12-3949. Epub 2003 Jun 5.

  PMID: 12791660 BACKGROUND

• 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. doi: 10.1182/blood.v100.2.442.

  PMID: 12091334 BACKGROUND

• 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.

  PMID: 9502295 BACKGROUND

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Hodgkin Disease; Multiple Myeloma; Lymphoma

Interventions

fludarabine; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Investigative Techniques

Study Officials

• Bimalangshu R Dey, MD, PhD

  MGH

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: May 27, 2009
• First Posted: May 29, 2009
• Study Start: November 1, 2008
• Primary Completion: August 1, 2012
• Study Completion: August 1, 2012
• Last Updated: March 29, 2018

Record last verified: 2018-03

Locations

US (1)