NCT01338987

Pilot Study of Leuprolide to Improve Immune Function After Allogeneic Bone Marrow Transplantation

Multi-Institutional Prospective Pilot Study of Lupron to Enhance Lymphocyte Immune Reconstitution Following Allogeneic Bone Marrow Transplantation in Post-Pubertal Children and Adults With Molecular Imaging Evaluation

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 76 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 4 Years – 55 Years
• Healthy volunteers: Not accepted

Summary

Background: * One way to treat certain cancers of the blood and immune system is to give a patient stem cells from the bone marrow of a donor whose genes are very similar but not identical to the patients. One problem with these transplants is that the new immune cells may not work as well in the recipient as they did in the donor. The result may be that the immune system will not work as well. This can increase the risk of severe infections and other complications. * Researchers are studying the use of drugs that lower hormone levels and may allow the immune system to recover in a way that improves white blood cell function. In this study they will be looking at the drug leuprolide, a drug that lowers estrogen or testosterone levels, to see if it might improve the function of the newly transplanted cells. Objectives: * To determine whether leuprolide improves immune system function after bone marrow transplant from a donor with similarities in their immune cells (matched to each other). * To evaluate the effectiveness of a nuclear medicine test with a radiotracer drug 3-deoxy-3 18F-fluorothymidine (FLT) in imaging studies. FLT will be used to image the immune system function in patients who have received bone marrow from the donor. Eligibility: * People between 15 (or as young as 9 in those who have gone through puberty) and 55 years of age. These patients must have acute myelogenous leukemia, acute lymphocytic leukemia, high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or chronic myeloid leukemia. They must also be eligible for a bone marrow transplant. * Genetically similar donors for the patients who are eligible for a transplant. Design: * People taking part in the study will be screened with a physical examination, medical history, blood and urine tests, and imaging studies. Patients who are not in remission or who require a bone marrow donor search may receive chemotherapy first. * Donors will provide bone marrow for transplant according to standard bone marrow transplant (BMT) procedures. * All women and half of the men will receive regular leuprolide doses 2 weeks before BMT to suppress hormone function. * All recipients will receive 4 days of radiation followed by 2-4 days of chemotherapy before the bone marrow transplant (depending on age). Recipients will also receive other drugs to prevent transplant rejection and other complications of transplantation. * Recipients will be monitored in the hospital for 4 weeks after transplant with blood tests and other studies. * Some recipients will have an imaging study with FLT during the protocol. These imaging studies will take place before the transplant, on days 5 and 28 after transplant, and at a later time to be determined by the study researchers. * Following discharge, participants will be monitored closely for up to 6 months, with regular but less frequent followup visits for at least 5 years. Study-related medications, including vaccinations for the new immune system, will be provided by the National Institutes of Health during the hospital stay and after discharge.

Detailed description

Background: * Impaired lymphocyte immune reconstitution is associated with morbidity and mortality following allogeneic bone marrow transplant (BMT). * Data suggest that one of the limitations of immunity after BMT is the lack of thymus recovery and proper B cell development. * Androgen withdrawal has been shown to enhance T and B lymphopoiesis. * Leuprolide is an approved, safe, gonadotropin releasing hormone (GnRH) agonist/antagonist. * Noninvasive imaging modalities to study immune reconstitution would be invaluable to predict optimal or impaired immune recovery permitting early institution of therapies. * FLT is 3-deoxy-3 18F-fluorothymidine, a radiolabeled thymidine analogue that illustrates dividing hematopoietic cells and may predict immune recovery after allogeneic BMT. * FLT has been used safely in patients who have received intensive chemotherapy. Objectives: * Primary: To determine if leuprolide improves B lymphocyte reconstitution after first BMT. * Primary: To assess whether 18F FLT positron emission tomography (PET)/computed tomography (CT) could predict early engraftment/immune reconstitution in marrow and thymus after allogeneic BMT. * Primary: To assess safety of leuprolide after 2nd BMT evaluated in a separate arm. Eligibility: * Patients \> 9 years old and pubertal and/or \>15 year and less than or equal to 55 years, with aggressive leukemia (Acute Myelogenous Leukemia (AML), myelodysplastic syndromes (MDS) with high risk cytogenetics, Acute Lymphocytic Leukemia (ALL), CMML, certain CML) requiring BMT will be enrolled at National Cancer Institute (NCI). * At University of Oklahoma, Age \> 17 years old and less than or equal to 55 years for recipient. * Patients \> 4 and \< 24 years with the above diseases will be enrolled at Children's National Medical Center (CNMC). Design: * This is a prospective pilot study, the primary aims of which are: 1) to assess whether leuprolide enhances lymphocyte recovery after first BMT, 2) whether FLT imaging can be used to predict engraftment/immune reconstitution after first transplant, and 3) whether leuprolide and FLT are tolerable for second HSCT. * At NCI and Univ of Oklahoma, post-pubertal pediatric male patients (\<18 years) will be randomized to receive a 3 month (11.25 mg) injection and adult male patients will be randomized to receive 4-month preparation of leuprolide (30 mg) or placebo two weeks before the preparative regimen for first BMT. Women and all individuals undergoing 2nd BMT will receive leuprolide at these doses per age and be evaluated in the treated cohort. At Children's National Medical Center, the patients will not receive leuprolide outside of the context of clinical care and will receive myeloablative BMT as per standard of care with FLT imaging for engraftment as the only primary endpoint. * A target of 68 evaluable adult patients will be enrolled on this trial, which may necessitate up to 118 patients (118 donors) enrolled to reach this target at NCI and University of Oklahoma. A total of 10 pediatric patients will be enrolled at Children's National Medical Center for FLT imaging only. Sixteen patients will be enrolled to undergo second BMT. * At NCI, adults greater than 18 years old both female and adult male patients undergoing 2nd BMT will receive 4-month preparation of leuprolide (30 mg) two weeks before the preparative regimen. All patients will undergo FLT imaging to evaluate whether this may predict BMT response or failure (relapse). This will be a pilot arm of 16 patients total. * The planned length of this trial is 7 years with interim analyses at day 100 and day 365. * Some of the patients are anticipated to be evaluated using FLT (to include only patients needed for the immunological primary endpoint, not increasing total patient numbers). 23 adult NCI patients in total will undergo FLT PET/CT imaging on day -1, at day +5 or day +9, at 4 weeks, and at a future point to include evidence of graft-versus-host disease (GVHD) relapse, or immune recovery. An estimated 50 patients (including subset of the 23 patients undergoing serial scanning) will be imaged approximately at 1 year for evaluation of thymus reconstitution. The total possible numbers will include no more than 118 patients to achieve the 68 evaluable adults for the immunological primary endpoint. However, all 23 FLT PET/CT imaged NCI patients will undergo a single 1 year FLT for evaluation of thymus reconstitution. Up to 10 pediatric patients at CNMC will undergo FLT PET/CT imaging on Day -1, day+9, and day +28 (if possible). Initial images will be correlated with engraftment and other secondary endpoints.

Conditions

• Myelodysplastic Syndrome
• Acute Lymphocytic Leukemia
• Acute Myelogenous Leukemia
• Chronic Myelogenous Leukemia
• Chronic Myelomonocytic Leukemia

Interventions

Type	Name	Description
PROCEDURE	First Allogeneic Bone Marrow Transplant (BMT)	First Allogeneic Bone Marrow Transplant
DRUG	Leuprolide	Leuprolide: 30 mg intramuscular injection(for adult) or 11.25 mg (for patients \<18 years) between day -13 and day -20 pre-bone marrow transplant but definitely prior to initiation of preparative regimen as a 4 month intramuscular injection for patients \> 18 years and as a 3 month injection (adult preparation) for patients \< 18 years
DRUG	18F FLT	For the first 23 patients undergoing 1st bone marrow transplant (BMT):\[18F\]fluorothymidine (18F FLT): 0.07 mCi/kg with a maximum of 3 mCi On day + 28 (+/- 5 days) For 2nd BMT: 18F FLT: 0.07 mCi/kg with a maximum of 3 mCi On day -1, + 28, day 60 and at relapse (+/- 5 days)
DRUG	Cyclophosphamide	Cyclophosphamide: 60 mg/kg intravenous (IV) on days -4 and -3 (for Adults \> 22 years) or Cyclophosphamide: cyclophosphamide 50 mg/kg IV, Days -5, -4, -3, -2. (For Pediatric \</= 22 years)
DRUG	Methotrexate	Methotrexate:10 mg/m(2) intravenous (IV) on day +1, and 5 mg/m(2) IV Days + 3, 6, 11
DRUG	Tacrolimus	Tacrolimus:0.02 mg/kg/day continuous intravenous infusion (CIV) on day -1.
RADIATION	Total Body Irradiation	Total Body Irradiation (TBI) 1200 cGy fractionate twice daily (lung block) Days -8, -7, -6, -5 (adult), -9, -8, -7, -6 (ped)
DRUG	Busulfan	Second choice is Busulfan (with goal steady state of 800-1000) with fludarabine or cyclophosphamide at myeloablative dosing or non-myeloablative dosing.
DRUG	Fludarabine	Given with Busulfan as alternative to cyclophosphamide in second transplant setting only
PROCEDURE	Second Allogeneic Bone Marrow Transplantation	Second Allogeneic Bone Marrow Transplantation

Timeline

• Start date: 2011-04-19
• Primary completion: 2017-12-01
• Completion: 2020-11-19
• First posted: 2011-04-20
• Last updated: 2021-03-18
• Results posted: 2019-04-23

Locations

3 sites across 1 country: United States

Regulatory

• FDA-regulated drug study