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

NCT01338987 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 11013611-C-0136
• Study Type: interventional
• Target: 76
• Locations: 1 country
• Sites: 3

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.

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

Outcome Measures

Primary Outcomes (3)

• Percentage of B Cells at One Year Post-transplant in Participants Who Did/Did Not Receive Leuprolide Following Bone Marrow Transplant (BMT)

  B cell percentage is defined as the percentage of lymphocytes that are B cells.

  after first Bone Marrow Transplant, approximately 12 months post-transplant

• 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 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).

  18F FLT scan done between days +5 to +12 and then time from that scan to engraftment measured

• Number of Adverse Events Related to Study Drug Experienced by Participants After Second Bone Marrow Transplant (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.

  12 months after second BMT

Secondary Outcomes (1)

• 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.

Study Arms (5)

Arm1 First Transplt/males/leuprolide/+/-FLT Imaging

ACTIVE COMPARATOR

Males randomized to leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging

Procedure: First Allogeneic Bone Marrow Transplant (BMT); Drug: Leuprolide; Drug: 18F FLT; Drug: Cyclophosphamide; Drug: Methotrexate; Drug: Tacrolimus; Radiation: Total Body Irradiation

Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging

ACTIVE COMPARATOR

Males not receiving leuprolide for first transplant \[18F\]fluorothymidine (FLT) imaging

Procedure: First Allogeneic Bone Marrow Transplant (BMT); Drug: 18F FLT; Drug: Cyclophosphamide; Drug: Methotrexate; Drug: Tacrolimus; Radiation: Total Body Irradiation

Arm3 First Transplt/females/leuprolide+/- FLT Imaging

EXPERIMENTAL

Females receiving leuprolide for first transplant. \[18F\]fluorothymidine (FLT) imaging

Procedure: First Allogeneic Bone Marrow Transplant (BMT); Drug: 18F FLT; Drug: Cyclophosphamide; Drug: Methotrexate; Drug: Tacrolimus; Radiation: Total Body Irradiation

Arm4-Second Transplt/leuprolide and FLT Imaging

EXPERIMENTAL

Second transplant with leuprolide and \[18F\]fluorothymidine (FLT) imaging

Drug: Leuprolide; Drug: 18F FLT; Drug: Cyclophosphamide; Radiation: Total Body Irradiation; Drug: Busulfan; Drug: Fludarabine; Procedure: Second Allogeneic Bone Marrow Transplantation

Healthy Volunteer - Arm 5

NO INTERVENTION

Healthy Volunteer

Interventions

First Allogeneic Bone Marrow Transplant (BMT) PROCEDURE

First Allogeneic Bone Marrow Transplant

Arm1 First Transplt/males/leuprolide/+/-FLT Imaging; Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging; Arm3 First Transplt/females/leuprolide+/- FLT Imaging

Leuprolide DRUG

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

Also known as: Lupron

Arm1 First Transplt/males/leuprolide/+/-FLT Imaging; Arm4-Second Transplt/leuprolide and FLT Imaging

18F FLT DRUG

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)

Also known as: [18F]fluorothymidine

Arm1 First Transplt/males/leuprolide/+/-FLT Imaging; Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging; Arm3 First Transplt/females/leuprolide+/- FLT Imaging; Arm4-Second Transplt/leuprolide and FLT Imaging

Cyclophosphamide DRUG

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)

Also known as: Cytoxan

Arm1 First Transplt/males/leuprolide/+/-FLT Imaging; Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging; Arm3 First Transplt/females/leuprolide+/- FLT Imaging; Arm4-Second Transplt/leuprolide and FLT Imaging

Methotrexate DRUG

Methotrexate:10 mg/m(2) intravenous (IV) on day +1, and 5 mg/m(2) IV Days + 3, 6, 11

Also known as: Trexall

Arm1 First Transplt/males/leuprolide/+/-FLT Imaging; Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging; Arm3 First Transplt/females/leuprolide+/- FLT Imaging

Tacrolimus DRUG

Tacrolimus:0.02 mg/kg/day continuous intravenous infusion (CIV) on day -1.

Also known as: Prograf

Arm1 First Transplt/males/leuprolide/+/-FLT Imaging; Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging; Arm3 First Transplt/females/leuprolide+/- FLT Imaging

Total Body Irradiation RADIATION

Total Body Irradiation (TBI) 1200 cGy fractionate twice daily (lung block) Days -8, -7, -6, -5 (adult), -9, -8, -7, -6 (ped)

Arm1 First Transplt/males/leuprolide/+/-FLT Imaging; Arm2 First Transplt/males/No Leuprolide/+/- FLT Imaging; Arm3 First Transplt/females/leuprolide+/- FLT Imaging; Arm4-Second Transplt/leuprolide and FLT Imaging

Busulfan DRUG

Second choice is Busulfan (with goal steady state of 800-1000) with fludarabine or cyclophosphamide at myeloablative dosing or non-myeloablative dosing.

Also known as: Busulfex

Arm4-Second Transplt/leuprolide and FLT Imaging

Fludarabine DRUG

Given with Busulfan as alternative to cyclophosphamide in second transplant setting only

Also known as: Fludara

Arm4-Second Transplt/leuprolide and FLT Imaging

Second Allogeneic Bone Marrow Transplantation PROCEDURE

Second Allogeneic Bone Marrow Transplantation

Arm4-Second Transplt/leuprolide and FLT Imaging

Eligibility Criteria

• Age: 4 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• At Children's National Medical Center only: age \> 4 years old and \< 24.
• At University of Oklahoma: Age greater than or equal to 17 years old and less than or equal to 55 years for recipient.
• A diagnosis of a hematologic malignancy for which stem cell transplant is standard of care:
• 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)

You may not qualify if:

• History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.
• Active infections not responding to therapy. All efforts should be made to clear the infection prior to enrollment.
• 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.
• Presence of active malignancy from an organ system other than hematopoietic.
• Human immunodeficiency virus (HIV) infection.
• 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.
• 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.
• 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.
• History of prior Leuprolide intolerance. Note: patients ARE eligible if prior or current leuprolide exposure.
• 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.
• 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.
• 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.
• Donors must be HIV negative, human T-cell leukemia-lymphoma virus (HTLV) negative, hepatitis B surface antigen (HBsA) negative.
• 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.
• History of medical illness that in the estimation of the PI or Department of Transfusion Medicine (DTM) physician precludes donation of marrow.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (3)

Childrens National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

University of Oklahoma

Oklahoma City, Oklahoma, 73104, United States

Location

Related Publications (5)

• 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.

  PMID: 9345067 BACKGROUND

• 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.

  PMID: 11964316 BACKGROUND

• 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.

  PMID: 9034287 BACKGROUND

• 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.

  PMID: 29248669 RESULT

• Holter-Chakrabarty J, McNally L, Levine J, Ferrara J, Vesely SK, Kanakry CG, Garwe T, Han Z, Pandey M, Glover J, Wen Y, Gress R, Williams KM. 18F-FLT PET and Blood-based Biomarkers for Identifying Gastrointestinal Graft versus Host Disease after Allogeneic Cell Transplantation. Radiol Imaging Cancer. 2025 Jan;7(1):e240096. doi: 10.1148/rycan.240096.

  PMID: 39670843 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myelomonocytic, Chronic

Interventions

Leuprolide; alovudine; Cyclophosphamide; Methotrexate; Tacrolimus; Whole-Body Irradiation; Busulfan; fludarabine; fludarabine phosphate

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Myeloproliferative Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Myelodysplastic-Myeloproliferative Diseases

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Macrolides; Lactones; Radiotherapy; Therapeutics; Investigative Techniques; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Results Point of Contact

• Title: Dr. Christopher Kanakry
• Organization: National Cancer Institute

christopher.kanakry@nih.gov

240-760-6171

Study Officials

• Christopher G Kanakry, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 19, 2011
• First Posted: April 20, 2011
• Study Start: April 19, 2011
• Primary Completion: December 1, 2017
• Study Completion: November 19, 2020
• Last Updated: March 18, 2021
• Results First Posted: April 23, 2019

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)