Pilot Study of Leuprolide to Improve Immune Function After Allogeneic Bone Marrow Transplantation
Condition: Myelodysplastic Syndrome; Acute Lymphocytic Leukemia; Acute Myelogenous Leukemia; Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia
MeSH terms: Leukemia; Preleukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): First Allogeneic Bone Marrow Transplant (BMT); Leuprolide; 18F FLT; Cyclophosphamide; Methotrexate; Tacrolimus; Total Body Irradiation; Busulfan; Fludarabine; Second Allogeneic Bone Marrow Transplantation
Intervention type(s): Procedure; Drug; Drug; Drug; Drug; Drug; Radiation; Drug; Drug; Procedure
Intervention description(s): First Allogeneic Bone Marrow Transplant; 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; 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); 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); Methotrexate:10 mg/m(2) intravenous (IV) on day +1, and 5 mg/m(2) IV Days + 3, 6, 11; Tacrolimus:0.02 mg/kg/day continuous intravenous infusion (CIV) on day -1.; Total Body Irradiation (TBI) 1200 cGy fractionate twice daily (lung block) Days -8, -7, -6, -5 (adult), -9, -8, -7, -6 (ped); Second choice is Busulfan (with goal steady state of 800-1000) with fludarabine or cyclophosphamide at myeloablative dosing or non-myeloablative dosing.; Given with Busulfan as alternative to cyclophosphamide in second transplant setting only; Second Allogeneic Bone Marrow Transplantation
Other intervention name(s): Lupron; [18F]fluorothymidine; Cytoxan; Trexall; Prograf; Busulfex; Fludara
Intervention MeSH terms: Alovudine; Cyclophosphamide; Busulfan; Methotrexate; Fludarabine; Leuprolide; Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: FLT; Leuprolide; Thymic Renewal; Stem Cell Transplant; Acute Lymphocytic Leukemia; Acute Myelogenous Leukemia; Myelodysplastic Syndrome