Clinical trial NCT01338987: Pilot Study of Leuprolide to Improve Immune Function After Allogeneic Bone Marrow Transplantation
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myelodysplastic Syndrome
Acute Lymphocytic Leukemia
Acute Myelogenous Leukemia
Chronic Myelogenous Leukemia
Chronic Myelomonocytic Leukemia
Keywords: FLT
Leuprolide
Thymic Renewal
Stem Cell Transplant
Acute Lymphocytic Leukemia
Acute Myelogenous Leukemia
Myelodysplastic Syndrome
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2011-04-20
Enrollment: 76
Sex: ALL
Minimum age (years): 4
Maximum age (years): 55
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage of B Cells at One Year Post-transplant in Participants Who Did/Did Not Receive Leuprolide Following Bone Marrow Transplant (BMT)
timeFrame: after first Bone Marrow Transplant, approximately 12 months post-transplant
measure: 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
timeFrame: 18F FLT scan done between days +5 to +12 and then time from that scan to engraftment measured
measure: Number of Adverse Events Related to Study Drug Experienced by Participants After Second Bone Marrow Transplant (BMT)
timeFrame: 12 months after second BMT
Secondary outcomes:
measure: Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)
timeFrame: Date treatment consent signed to date off study, approximately 79 months and 11 days.
Other outcomes:
Locations:
city: Washington
country: United States
facility: Childrens National Medical Center
state: District of Columbia
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
Study officials:
affiliation: National Cancer Institute (NCI)
name: Christopher G Kanakry, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hakim FT, Cepeda R, Kaimei S, Mackall CL, McAtee N, Zujewski J, Cowan K, Gress RE. Constraints on CD4 recovery postchemotherapy in adults: thymic insufficiency and apoptotic decline of expanded peripheral CD4 cells. Blood. 1997 Nov 1;90(9):3789-98.
citation: Hazenberg MD, Otto SA, de Pauw ES, Roelofs H, Fibbe WE, Hamann D, Miedema F. T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events. Blood. 2002 May 1;99(9):3449-53. doi: 10.1182/blood.v99.9.3449.
citation: Storek J, Gooley T, Witherspoon RP, Sullivan KM, Storb R. Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol. 1997 Feb;54(2):131-8. doi: 10.1002/(sici)1096-8652(199702)54:23.0.co;2-y.
citation: Williams KM, Holter-Chakrabarty J, Lindenberg L, Duong Q, Vesely SK, Nguyen CT, Havlicek JP, Kurdziel K, Gea-Banacloche J, Lin FI, Avila DN, Selby G, Kanakry CG, Li S, Scordino T, Adler S, Bollard CM, Choyke P, Gress RE. Imaging of subclinical haemopoiesis after stem-cell transplantation in patients with haematological malignancies: a prospective pilot study. Lancet Haematol. 2018 Jan;5(1):e44-e52. doi: 10.1016/S2352-3026(17)30215-6. Epub 2017 Dec 14.