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

Multiple Myeloma Clinical Trial

— RLI  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00909948
• Other study ID #: Protocol 07-068
• Status: Terminated
• Phase: Phase 1
• First received: May 27, 2009
• Last updated: March 26, 2018
• Start date: November 2008
• Est. completion date: August 2012

Study information

• Verified date: March 2018
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Other known NCT identifiers

• NCT00981760

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 7
• Est. completion date: August 2012
• Est. primary completion date: August 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. 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

2. Non Hodgkin's lymphoma, or Hodgkin's lymphoma: primary refractory or refractory relapse

3. Multiple myeloma; primary refractory or refractory relapse

4. Patients with the above malignancies who have had a previous autologous or allogeneic bone marrow or stem cell transplant.

5. An estimated disease-free survival of less than one year.

6. Age 18 to age < 75 years

7. ECOG performance status of 0, 1, or 2.

Exclusion Criteria:

1. Patients whose life expectancy is limited by diseases other than their malignancy

2. 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

3. Cardiac disease: symptomatic congestive heart failure or RVG or echocardiogram determined LVEF ogf< 30%, active angina pectoris or uncontrolled hypertension

4. Pulmonary disease: severe chronic obstructive lung disease, or symptomatic restrictive lung disease, or corrected DLCO < 40% of predicted

5. Renal disease: serum creatinine > 3.0 mg/dl.

6. Hepatic disease: serum bilirubin > 3.0 mg/dl or alkaline phosphatase, SGOT or SGPT > 3 x ULN

7. 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)

8. Uncontrolled infection.

9. 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

10. 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

Related Conditions & MeSH terms

• Hodgkin Disease
• Lymphoma, Non-Hodgkin
• Multiple Myeloma
• Neoplasms, Plasma Cell
• Non Hodgkin's Lymphoma

Intervention

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.

Radiation:
• Total body irradiation
Patients will receive 200 cGy TBI on day 0,4-6 hours prior to HCT.

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Massachusetts General Hospital

Country where clinical trial is conducted

United States, 

References & Publications (10)

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	To evaluate the incidence of acute and chronic GVHD		Up to 2 years post transplant
Secondary	To evaluate the incidence of loss of donor grafts		Up to 2 years post transplant
Secondary	To evaluate progression-free and overall survival		Up to 2 years post transplant
Secondary	To evaluate antitumor responses following this transplant strategy		Up to 2 years post transplant