Pilot Study of Leuprolide to Improve Immune Function After Allogeneic Bone Marrow Transplantation
- Conditions
- Myelodysplastic SyndromeAcute Lymphocytic LeukemiaAcute Myelogenous LeukemiaChronic Myelogenous LeukemiaChronic Myelomonocytic Leukemia
- Interventions
- Procedure: First Allogeneic Bone Marrow Transplant (BMT)Drug: 18F FLTRadiation: Total Body IrradiationProcedure: Second Allogeneic Bone Marrow Transplantation
- Registration Number
- NCT01338987
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 76
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm1 First Transplt/males/leuprolide/+/-FLT Imaging First Allogeneic Bone Marrow Transplant (BMT) Males randomized to leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm1 First Transplt/males/leuprolide/+/-FLT Imaging Leuprolide Males randomized to leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm1 First Transplt/males/leuprolide/+/-FLT Imaging 18F FLT Males randomized to leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm1 First Transplt/males/leuprolide/+/-FLT Imaging Methotrexate Males randomized to leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm1 First Transplt/males/leuprolide/+/-FLT Imaging Tacrolimus Males randomized to leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm1 First Transplt/males/leuprolide/+/-FLT Imaging Total Body Irradiation Males randomized to leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging First Allogeneic Bone Marrow Transplant (BMT) Males not receiving leuprolide for first transplant \[18F\]fluorothymidine (FLT) imaging Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging 18F FLT Males not receiving leuprolide for first transplant \[18F\]fluorothymidine (FLT) imaging Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging Tacrolimus Males not receiving leuprolide for first transplant \[18F\]fluorothymidine (FLT) imaging Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging Total Body Irradiation Males not receiving leuprolide for first transplant \[18F\]fluorothymidine (FLT) imaging Arm3 First Transplt/females/leuprolide+/- FLT Imaging First Allogeneic Bone Marrow Transplant (BMT) Females receiving leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm3 First Transplt/females/leuprolide+/- FLT Imaging 18F FLT Females receiving leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm3 First Transplt/females/leuprolide+/- FLT Imaging Cyclophosphamide Females receiving leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm3 First Transplt/females/leuprolide+/- FLT Imaging Methotrexate Females receiving leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm3 First Transplt/females/leuprolide+/- FLT Imaging Tacrolimus Females receiving leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm4-Second Transplt/leuprolide and FLT Imaging Cyclophosphamide Second transplant with leuprolide and \[18F\]fluorothymidine (FLT) imaging Arm4-Second Transplt/leuprolide and FLT Imaging Total Body Irradiation Second transplant with leuprolide and \[18F\]fluorothymidine (FLT) imaging Arm3 First Transplt/females/leuprolide+/- FLT Imaging Total Body Irradiation Females receiving leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm4-Second Transplt/leuprolide and FLT Imaging Leuprolide Second transplant with leuprolide and \[18F\]fluorothymidine (FLT) imaging Arm4-Second Transplt/leuprolide and FLT Imaging 18F FLT Second transplant with leuprolide and \[18F\]fluorothymidine (FLT) imaging Arm4-Second Transplt/leuprolide and FLT Imaging Fludarabine Second transplant with leuprolide and \[18F\]fluorothymidine (FLT) imaging Arm4-Second Transplt/leuprolide and FLT Imaging Second Allogeneic Bone Marrow Transplantation Second transplant with leuprolide and \[18F\]fluorothymidine (FLT) imaging Arm1 First Transplt/males/leuprolide/+/-FLT Imaging Cyclophosphamide Males randomized to leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging Cyclophosphamide Males not receiving leuprolide for first transplant \[18F\]fluorothymidine (FLT) imaging Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging Methotrexate Males not receiving leuprolide for first transplant \[18F\]fluorothymidine (FLT) imaging Arm4-Second Transplt/leuprolide and FLT Imaging Busulfan Second transplant with leuprolide and \[18F\]fluorothymidine (FLT) imaging
- Primary Outcome Measures
Name Time Method Percentage of B Cells at One Year Post-transplant in Participants Who Did/Did Not Receive Leuprolide Following Bone Marrow Transplant (BMT) after first Bone Marrow Transplant, approximately 12 months post-transplant B cell percentage is defined as the percentage of lymphocytes that are B cells.
Time to Engraftment in First Transplant Recipients Only With Median Thoracic Spine Standardized Uptake Values (SUV) of 1.4 or Greater Than Those Patients With SUV's Less Than 1.4 18F FLT scan done between days +5 to +12 and then time from that scan to engraftment measured 18F-FLT imaging was performed serially on patients post transplant to identify the level of uptake of 18F-FLT at a day +5 to +12 scan and the day at which neutrophils recover to \>500 (i.e., subclinical bone-marrow recovery within 5 days of Bone Marrow Transplantation (BMT infusion)). On each image for each patient, the region of interest was drawn within each thoracic medullary space (n=12), generating the SUV for each space. The mean of these was calculated for each scan. The analysis was the median of the means of the SUV of the thorax values of the day 5-12 scan (averaged the SUV of the thorax for each patient and then took the medians of these).
Number of Adverse Events Related to Study Drug Experienced by Participants After Second Bone Marrow Transplant (BMT) 12 months after second BMT Serious and non-serious adverse events were assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
- Secondary Outcome Measures
Name Time Method Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) Date treatment consent signed to date off study, approximately 79 months and 11 days. Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Trial Locations
- Locations (3)
Childrens National Medical Center
🇺🇸Washington, District of Columbia, United States
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States
University of Oklahoma
🇺🇸Oklahoma City, Oklahoma, United States