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
Intervention: First Allogeneic Bone Marrow Transplant (BMT); Leuprolide; 18F FLT; Cyclophosphamide; Methotrexate; Tacrolimus; Total Body Irradiation; Busulfan; Fludarabine; Second Allogeneic Bone Marrow Transplantation
Intervention description: 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
Intervention MeSH terms: Alovudine; Cyclophosphamide; Busulfan; Methotrexate; Fludarabine; Leuprolide; Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 76.0
Sex: All
Minimum age: 4 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: FLT; Leuprolide; Thymic Renewal; Stem Cell Transplant; Acute Lymphocytic Leukemia; Acute Myelogenous Leukemia; Myelodysplastic Syndrome

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.
    

Eligibility criteria:

        -  ELIGIBILITY CRITERIA:

        INCLUSION CRITERIA: TRANSPLANT RECIPIENT

          1. At National Institutes of Health (NIH). Age greater than or equal to 15 years old
             and/or greater than or equal to 9 years old and pubertal and less than or equal to 55
             years for recipient. Pubertal is defined by: prior menses at any time (females),
             documentation of clinical Tanner stage greater than 2 at some point pre-chemotherapy
             or at the current visit. (At this point, sex steroids have been produced for a few
             years which have driven initial pubertal development). Tanner 2 is defined as: breast
             buds for females with coarse pubic hair, and coarse pubic hair and testes > 2.5cm for
             males.

          2. At Children's National Medical Center only: age > 4 years old and < 24.

          3. At University of Oklahoma: Age greater than or equal to 17 years old and less than or
             equal to 55 years for recipient.

          4. A diagnosis of a hematologic malignancy for which stem cell transplant is standard of
             care:

        4.1. Acute Lymphocytic Leukemia (ALL)

        Adult: (greater than or equal to 22 years) greater than or equal to compete remission 2
        (CR2) OR complete remission 1 (CR1) with:

          -  Matched sibling donor for recipient treated on adult leukemia regimen

          -  t(9:22) or bcr-abl+; t(4:11), t(1:19), t(8:14), 11q23 (MLL rearrangements) complex
             cytogenetics (5 or more chromosomal abnormalities), hypodiploidy (<44 chromosomes).
             Note that patients with ALL blast crisis who emerge from chronic myeloid leukemia
             (CML) are also eligible

          -  Primary induction failure, defined as failure to achieve CR with primary induction
             chemotherapy

          -  High white blood cell (WBC) (>30,000 for B-cell ALL and >100,000 for T-cell ALL) at
             diagnosis

          -  Persistence of minimal residual disease despite induction chemotherapy

        Pediatric (< 22 years): greater than or equal to CR2 OR CR1 with high risk features

          -  Matched sibling donor for recipient treated on adult leukemia regimen

          -  Primary induction failure (M3 (>25% with greater 200 cells counted) marrow at day 29),
             M2 (5-25% blasts with greater than 200 cells counted) bone marrow or minimal residual
             disease (MRD) > 1% at day 29 who then fail at day 43 with either an M2 or M3 BM or MRD
             > 1%

          -  Persistent leukemia and t(9;22) (MRD >1% day 29 or MRD > 0.01% end consolidation)

          -  11q23 (MLL) rearrangements detected by cytogenetic or polymerase chain reaction (PCR)
             at initial diagnosis who are slow early responders (M2/M3 at day 14 or MRD> 0.01% at
             day 29)

          -  Extreme hypodiploidy (< 44 chromosomes or deoxyribonucleic acid (DNA) index of <0.81)
             detected by cytogenetic/ploidy analysis

        4.2 Acute Myelogenous Leukemia

        Adult: (greater than or equal to 22 years) greater than or equal to CR2 OR CR1 with high
        one of the following risk features

        -Adverse or intermediate-risk cytogenetics including:

          1. Normal cytogenetics

          2. complex karyotype (>2 abnormalities)

          3. inv (3) or t (3;3); t(11;19)(q23;p13.1); +13; -17/17p-; -18; -20; (t(6;9); t(6;11);
             -7, 7q-; -5, 5q-; trisomy 8; t(3;5); t(9:11)(p22q23)

          4. monosomy karyotype (presence of an autosomal monosomy in conjunction with at least one
             other autosomal monosomy or structural abnormality.

          5. Any other karyotype EXCEPT t(8;21), t(9;11), inv(16), or t (16;16), and M3 (17; 17)
             unless ckit mutation present and then eligible.

          6. AML emerging from CML (blast crisis) are eligible

             -Primary induction failure, defined as failure to achieve CR with primary induction
             chemotherapy

               -  Secondary AML, defined as AML related to antecedent myelodysplastic syndrome
                  (MDS), myeloproliferative neoplasms (MPN), or cytotoxic chemotherapy

               -  Hyperleukocytosis (White blood cell (WBC) > 100,000 at diagnosis)

               -  Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene (FLT3-LM; FLT-ITDs)

               -  Bilineage or biphenotypic leukemias are high risk features and eligible.

             Pediatric (< 22 years): greater than or equal to CR2 OR CR1 with a high risk feature
             including:

             -Primary induction failure (greater than or equal to 5% blasts in marrow after
             induction)

               -  Persistent leukemia (>15% after first course of chemotherapy)

               -  Complex karyotype, monosomy 7, or -5/-5q, FLT3 ITD-AR (>0.4) EXCEPT if also
                  inv(16)/t(16;16), t(8,21)

               -  Normal cytogenetics or abnormal cytogenetics EXCEPT if also inv(16)/t(16;16),
                  t(8,21) are eligible for SIBLING transplant only

               -  Bilineage or biphenotypic leukemias are high risk features and eligible.

             4.3. Myelodysplastic Syndrome Refractory Anemia with Excess Blasts (RAEB) 1 or 2;
             cytogenetics showing complex karyotype (3 or more abnormalities), monosomy 7/del(7q),
             or inv(3)/t(3q)/del(3q); or transfusion dependent.

             4.4. Chronic Myelomonocytic Leukemia

             4.5. Chronic Myelogenous Leukemia who have failed 2G- tyrosine kinase inhibitors (TKI)

             4.6. Standard pediatric indications for myeloablative transplantation for patients
             undergoing bone marrow transplant at Children's National Medical Center per
             institutional guidelines

             5. Disease status

             If patients are found to not be in remission at screening, then the patient may be
             returned to their primary hematologist/oncologist or may receive chemotherapy as per
             standard of care for the malignant disease. Patients for whom this would be their
             first allogeneic transplant must be in remission (< 5% malignant blasts in marrow and
             peripheral blood and no evidence of extramedullary disease) for transplant. Patients
             enrolled on this protocol for their second transplant do not need to have attained
             remission prior to transplant.

             6. Performance status: Karnofsky or Lansky performance status greater than or equal to
             60% AND life expectance of greater than 3 months.

             7. Ability to give informed consent. For recipients and donors < 18 years of age,
             their legal guardian must give informed consent. Pediatric patients will be included
             in an age appropriate discussion in accordance with institutional guidelines.

             8 Hepatic function: Patients must have evidence of adequate liver function prior to
             enrollment defined by total bilirubin < 2.5 mg/dL (unless documented Gilbert's
             syndrome) AND transaminases less than or equal to 5 x the upper limit of normal for
             age appropriate indices.

             9. Renal function: Patients must have evidence of adequate renal function to proceed
             with stem cell transplant, creatinine clearance > 60 ml/min/1.73 m(2). Glomerular
             filtration rate (GFR) may also demonstrate adequate renal function.

             10. Left ventricular ejection fraction greater than or equal to 50% OR shortening
             fraction of greater than or equal to 27% demonstrated on 2-dimension (2D)
             echocardiogram or multi-gated acquisition scan (MUGA).

             11. Pulmonary function of Diffusing Capacity of the Lung for Carbon Monoxide (DLC0)
             adj/alveolar volume (VA) and forced expiratory volume 1 (FEV1) greater than or equal
             to 60% of normal indices for age and height unless the patient has a likely acute
             reversible etiology of decline and then DLCO adj/VA greater than or equal to 30% of
             normal. Pediatric patients unable to complete pulmonary function tests (PFTs) may be
             enrolled as per enrolling institution Standard Operating Procedure (SOP) for recipient
             guidelines.

             12. Patients with prior autologous stem cell transplants will be included. Patients
             with prior allogeneic stem cell transplants will be eligible for 2nd BMT if not
             previously transplanted with FLT on this study.

             13. Prior experimental systemic therapies must have been completed greater than 2
             weeks prior to study entry.

             EXCLUSION CRITERIA: TRANSPLANT RECIPIENT

               1. History of psychiatric disorder which may compromise compliance with transplant
                  protocol, or which does not allow for appropriate informed consent.

               2. Active infections not responding to therapy. All efforts should be made to clear
                  the infection prior to enrollment.

               3. Clinically significant systemic illness with manifestations of significant organ
                  dysfunction which in the judgment principal investigator (PI) or associate
                  investigator (AI) would render the patient unlikely to tolerate the protocol
                  therapy or complete the study.

               4. Presence of active malignancy from an organ system other than hematopoietic.

               5. Human immunodeficiency virus (HIV) infection.

               6. Chronic active hepatitis B infection. Patients may be hepatitis B core antibody
                  positive but must be surface antigen negative and without active evidence of
                  disease.

               7. Pregnant or lactating females will be excluded from this trial due to unknown
                  risks to the developing fetus. Patients of child-bearing potential must use an
                  effective form of contraception while on study.

               8. Sexually active individuals capable of becoming pregnant who are unable or
                  unwilling to use effective form(s) of contraception during time enrolled on study
                  and for 1 year post-transplant.

               9. History of prior Leuprolide intolerance. Note: patients ARE eligible if prior or
                  current leuprolide exposure.

             INCLUSION CRITERIA: MATCHED RELATED TRANSPLANT DONOR

               1. Age greater than or equal to 2 and less than or equal to 60 years old and able to
                  give consent or assent. For donors < 18 years old, the legal guardian must be
                  able to provide informed consent and an evaluation by a Licensed Social Worker
                  (LSW) or psychiatric personnel will be needed to determine willingness to
                  participate. Pediatric patients will be included in an age appropriate discussion
                  in accordance with institutional guidelines.

               2. Human leukocyte antigen (HLA)-matched related donor, excluding identical twins.
                  Donors must be matched at least 7 loci out of 8 at the allele or antigen level
                  excluding antigen DRB1 mismatch.

               3. Donor selection will be in accordance with National Institutes of Health
                  (NIH)/Clinical Center (CC) Department of Transfusion Medicine criteria and must
                  be able to medically endure stem cell collection or as per local institutional
                  guidelines.

               4. Donors must be HIV negative, human T-cell leukemia-lymphoma virus (HTLV)
                  negative, hepatitis B surface antigen (HBsA) negative.

               5. Donors must be physically able to and willing to tolerate marrow harvest
                  collection preferably, or in the absence of this option, able and willing to
                  donate via peripheral blood pheresis.

             EXCLUSION CRITERIA: MATCHED RELATED TRANSPLANT DONOR

               1. History of medical illness that in the estimation of the PI or Department of
                  Transfusion Medicine (DTM) physician precludes donation of marrow.

               2. Anemia (Hemoglobin (Hb) < 10 gm/dl) or thrombocytopenia (< 100,000/ ul).

               3. Pregnant females (due to risk to fetus).

               4. Current psychiatric diagnosis that would compromise compliance with transplant
                  protocol or precludes appropriate informed consent.

               5. Presence of any blood transmissible infectious disease that cannot be cleared
                  prior to stem cell collection and poses an unacceptable risk for the recipient
                  (excludes cytomegalovirus (CMV)).

               6. Active malignancy will exclude the donor. Any malignancy less than five years
                  postremission will exclude the donor. Non-hematologic malignancies greater than 5
                  years ago will not exclude the donor. Any history of hematologic malignancy will
                  be considered on a case by case basis.

               7. Any medical contraindication to anesthesia or marrow donation will exclude the
                  donor.

               8. Donors receiving experimental therapy or investigational agents.

               9. Active autoimmune disease that in the opinion of the PI or AI would compromise
                  the success of the transplant.

             INCLUSION CRITERIA- MATCHED UNRELATED DONOR

               1. Unrelated donor matched at HLA-A, B, C, and DR loci by high resolution typing (at
                  8/8 or 7/8 antigen/allele match) are acceptable donors.

               2. The evaluation of donors shall be in accordance with existing National Marrow
                  Donor Program (NMDP) Standard Policies and Procedures at all institutions.

             INCLUSION CRITERIA- (18F) FLT CANDIDATE TRANSPLANT RECIPIENT

               1. Meets criteria for Transplant Recipient

               2. Age greater than or equal to 18 years old at National Cancer Institute (NCI), and
                  age > 4 years and < 24 years at Children's National Medical Center

               3. Donor who is willing to undergo bone marrow or stem cell harvest.

             EXCLUSION CRITERIA- (18F) FLT CANDIDATE TRANSPLANT RECIPIENT

             1. History of prior fluorothymidine allergy or intolerance.