Combined Bone Marrow and Renal Transplantation for Hematologic Disorders With End Stage Renal Disease

Study Overview
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Brief Summary
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This pilot trial offers the unique opportunity for both the treatment of multiple myeloma or systemic AL amyloidosis for which hematopoietic stem cell transplantation would be ordinarily indicated and the reversal of end-stage renal failure, while avoiding the risks associated with long-term standard anti-rejection therapy used in renal transplantation. The primary objectives of this study are to assess renal allograft tolerance (that is, the acceptance of the kidney without the need for anti-rejection therapy), assess anti-tumor response rates in multiple myeloma and AL amyloidosis, and assess complication rates for genetically (HLA) matched related donor combined bone marrow and kidney transplantation using a low dose total body irradiation based preparative regimen.

Detailed Description
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The induction of transplantation tolerance involves the specific elimination of the immune response to the transplant but not to other antigens. In the realm of kidney transplantation, tolerance means that the recipient is unable to detect the donor transplant kidney as foreign, and therefore the recipient is unable to reject the kidney. Donor bone marrow engraftment leads to kidney graft tolerance in animal models. Renal failure is a major complication of multiple myeloma and AL amyloidosis for which the only known cure is allogeneic bone marrow transplantation. Standard bone marrow transplantation is associated with prohibitive toxicities in patients with end stage renal disease, and is generally not considered an option for those patients. Patients with multiple myeloma and AL amyloidosis are excluded from conventional renal transplantation protocols because of their underlying malignancy. A less toxic bone marrow transplantation protocol, utilizing low dose total body irradiation and anti-thymocyte globulin, combined with renal transplantation, could provide an opportunity for cure of the myeloma or amyloidosis and correction of end stage renal disease. In addition, successful marrow engraftment may be expected to lead to a state of tolerance. Successful implementation of tolerance would be a major benefit to transplant recipients. The significance of developing tolerance is that the patient could be spared the disabling complications of indefinite immunosuppression, which include infections, cataracts, osteoporosis, diabetes, atherosclerosis, hypertension, and malignancy.

Official Title
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Combined HLA-Matched Bone Marrow and Kidney Transplantation for Multiple Myeloma or Other Hematologic Disorders With End Stage Renal Disease

Conditions
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Amyloidosis, Multiple Myeloma

Intervention / Treatment
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* Drug: Tacrolimus
* Drug: Equine Anti-thymocyte globulin
* Procedure: Kidney transplant from a related donor
* Drug: Bone marrow transplant from a related donor
* Radiation: Total body irradiation 400 centigray (200 cGy X 2)


Participation Criteria
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Eligibility Criteria
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Participant Inclusion Criteria Participants with end-stage renal failure due to or in association with multiple myeloma or systemic AL amyloidosis which hematopoietic cell transplantation is appropriate and a ≥ 50% five-year survival probability with transplantation is expected. This includes, but is not limited to: Multiple myeloma (MM), ISS stage II or III in complete or very good partial remission AL amyloidosis without significant cardiac disease Males or females 18 - 65 years of age. Participants must have an HLA-matched or one of six HLA A, B, or DR antigen-mismatched related donor, with high resolution molecular class I and II allele typing. Men and women of reproductive potential must agree to use a reliable method of birth control during the treatment, and women should do so for a period of 2 years following the transplant. Participants should be on dialysis or have a CrCl <20 ml/min. Patients should not have evidence of renal recovery of their renal failure over a 90 day period of therapy for their underlying malignancy or other blood disorder. . Patients with a history of other malignancies excluding basal cell carcinoma of the skin and carcinoma in situ of the cervix with a disease-free survival interval of >2 years. Patients with the following malignancies must demonstrate a 5 year disease-free survival: Breast cancer with positive nodes Malignant melanoma (other than in situ) Colorectal cancer (other than Dukes Stage A or B1) Patients with multiple myeloma must have received previous treatment with a bortezomib-based regimen. Patients with AL amyloidosis must have received previous treatment with a bortezomib-based regimen and/or autologous stem cell transplantation Patients with a history of malignant melanoma must be reviewed by an independent oncologist prior to enrollment. Recipient ability to understand and provide informed consent. Participant Exclusion Criteria Evidence of active infection as defined by: a) clinical syndrome consistent with viral or bacterial infection (e.g., influenza, URI, UTI) or b) fever with a clinical site of infection identified, or c) microbiologically documented infection, including, but not limited to, bacteremia or septicemia. Participation in other investigational drug use at the time of enrollment. Contraindication to therapy with any one of the proposed agents (e.g., history of allergy to horse serum in ATG). Serologic positivity to HIV or HCV. Women of childbearing age in whom adequate contraception cannot be maintained. AST/ALT > 3 x normal or bilirubin > 1.5 x normal (unless due to Gilbert's syndrome). Pregnancy or uncontrolled serious medical illness not related to underlying myeloma. Cardiac ejection fraction < 40% by echocardiogram. FEV1 < 50% predicted or corrected DLCO < 50% predicted. ABO blood group incompatibility in the host-vs-graft direction. Diagnosis of myelodysplastic syndrome Donor Inclusion Criteria HLA-matched or one of six HLA A, B, or DR antigen-mismatched related male or female donor 18-65 years of age. ECOG performance status 0 or 1. Excellent health per conventional pre-donor history (medical and psychosocial evaluation). Acceptable laboratory parameters (hematology in normal or near-normal range; liver function < 2 times the upper limit of normal and normal creatinine). Compatible ABO blood group. Negative donor lymphocyte crossmatch. No positive testing for viral infection (HbsAg, HIV, HCV, HTLV-1). Cardiac/Pulmonary evaluation within normal limits (CXR, EKG). Donor ability to understand and provide informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bone Marrow and Kidney RECIPIENTS<br>combined bone marrow and kidney transplantation | Drug: Tacrolimus<br>* Tacrolimus starting on Day -1<br>Drug: Equine Anti-thymocyte globulin<br>* 20 mg/kg IV on Days -3, -1, +1, +3<br>Procedure: Kidney transplant from a related donor<br>* On Day 0 the renal transplant is performed according to standard surgical techniques.<br>Drug: Bone marrow transplant from a related donor<br>* Donor bone marrow (> 2 x 10e8 nucleated cells/kg of recipient body weight) is prepared for infusion according to the standard procedure. The infusion begins in the operating room as soon as the vascular anastomosis of the renal allograft has been completed.<br>Radiation: Total body irradiation 400 centigray (200 cGy X 2)<br>* On transplant day -1<br>|
| Other: Bone Marrow and Kidney DONORS<br>Donors who donate bone marrow and kidney | Procedure: Kidney transplant from a related donor<br>* On Day 0 the renal transplant is performed according to standard surgical techniques.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Without Renal Allograft Rejection at 6 Months Post-transplant | The Primary Outcome is: the incidence of renal allograft rejection at 6 months post-transplant | 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-Tumor Response Rate | This is measurement is summarized via bone marrow biopsy results and blood assays through 3 years. Anti-tumor response is assessed according to Center for International Blood and Marrow Transplant Research (CIBMTR.org) criteria. For multiple myeloma, based on assessment of serum and urine immunofixation, the presence or absence of soft tissue plasmacytomas and analyses of bone marrow aspirate and biopsy samples, response categories include stringent complete remission (sCR), complete remission (CR), near CR (nCR) very good partial response (VGPR), partial response (PR), stable disease (SD), and progressive disease (PD). For AL amyloidosis, based on assessment of serum and urine immunofixation and serum free light chain ratio, hematologic response categories include complete response, very good partial response, partial response, no response/stable disease and progressive disease. Organ responses are also assessed according to organ specific criteria. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HLA matched, bone marrow transplantation, kidney transplantation