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

Condition(s) targeted: Acute Lymphocytic Leukemia; Acute Myelogenous Leukemia; Myelodysplastic Syndrome RAEB 1

Intervention: Lupron (Drug); 18F FLT (Drug); Cyclophosphamide (Drug); Methotrexate (Drug); Tacrolimus (Drug); Total Body Irradiation (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Ronald E Gress, M.D., Principal Investigator, Affiliation: National Cancer Institute (NCI)

Overall contact:
Candice M Cottle-Delisle, R.N., Phone: (301) 496-5853, Email: cottlec@mail.nih.gov

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 patient's. 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 lupron, 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 lupron improves immune system function after bone marrow

transplantation 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 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 40

years of age. These patients must have acute myelogenous leukemia, acute lymphocytic leukemia, or high-risk myelodysplastic syndrome. 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 lupron 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.

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 design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

To determine if Lupron improves B lymphocyte reconstitution after HSCT.

To assess whether 18F FLT PET/CT could predict early engraftment/immune reconstitution in marrow and thymus after allogeneic HSCT.

Secondary outcome:

To investigate whether Lupron will decrease the incidence of acute or chronic GVHD without altering GVT after allogeneic HSCT.

To evaluate if Lupron decreases the incidence of infections after HSCT.

Detailed description: Background:

- Impaired lymphocyte immune reconstitution is associated with morbidity and mortality

following allogeneic hematopoietic stem cell transplantation (HSCT).

- Data suggest that one of the limitations of immunity after HSCT is the lack of thymus

recovery and proper B cell development.

- Androgen withdrawal has been shown to enhance T and B lymopoiesis.

- Lupron 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 HSCT.

- FLT has been used safely in patients who have received intensive chemotherapy.

Objectives:

- Primary: To determine if Lupron improves B lymphocyte reconstitution after HSCT.

- Primary: To assess whether 18F FLT PET/CT could predict early engraftment/immune

reconstitution in marrow and thymus after allogeneic HSCT.

- Secondary: To investigate whether Lupron will decrease the incidence of acute or

chronic GVHD without altering GVT after allogeneic HSCT.

- Secondary: To evaluate if Lupron decreases the incidence of infections after HSCT.

- Secondary: To evaluate if Lupron improves de novo lymphocyte immune reconstitution,

using T cell receptor excision circles (TREC), spectrotype, and peripheral total T cell subset numbers as measurements of T cell reconstitution after HSCT.

- Secondary: To evaluate the safety of 18F FLT in the peri-transplant period.

Eligibility:

- Patients > 9 years old and pubertal and/or > 15 year and less than 55 years with

aggressive leukemia (Acute Myelogenous Leukemia (AML), myelodysplastic syndromes (MDS) with high risk cytogenetics, Acute Lymphocytic Leukemia (ALL)) requiring HSCT.

Design:

- This is a prospective pilot study, the primary aims of which are to assess whether

Lupron enhances lymphocyte recovery after HSCT and whether FLT imaging can be used to predict engraftment/immune reconstitution.

- 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 Lupron (30 mg) or placebo two weeks before the preparative regimen. Women will receive Lupron at the proper dose per age and be evaluated in the treated cohort.

- A target of 64 evaluable patients will be enrolled on this trial, which may necessitate

up to 118 patients enrolled to reach this target.

- The planned length of this trial is 5 years with interim analyses at day 100 and day

365.

- 15 of these patients will be evaluated using FLT. They will undergo FLT PET/CT imaging

on day - 1, at 1 week, at 4 weeks, and at a future point to include evidence of either

GVHD or immune recovery. Images will be correlated with engraftment.

- Study endpoints to include: 1)safety of Lupron in the context of allogeneic BMT, 2)

lymphocyte reconstitution after Lupron administration, 3) the incidence of acute and chronic GVHD and infectious complications, 4) remission rates after HSCT

Minimum age: 9 Years. Maximum age: 40 Years. Gender(s): Both.

Criteria:

- ELIGIBILITY CRITERIA:

INCLUSION CRITERIA TRANSPLANT RECIPIENT:

- Age > 15 years old and/or > 9 years old and pubertal and < 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 has 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.

- A diagnosis of a hematologic malignancy for which stem cell transplant is standard of

care:

1. Acute Lymphocytic Leukemia:

A. Adult: (greater than or equal to 22 years) greater than or equal to CR2 OR CR1 with high risk features:

1. t(9: 22) or bcr-abl+; t(4: 11), t(1: 19), t(8: 14), 11q23 (MLL rearrangements). Note that patients with ALL blast crisis who emerge from CML are also eligible. Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy

2. Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy

B. Pediatric (< 22 years): greater than or equal to CR2 or CR1 with high risk features:

1. 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 MRD > 1% at day 29 who then fail at day 43 with either an M2 or M3 BM or MRD > 1%

2. Persistent leukemia and t(9;22) (MRD > 1% day 29 or MRD > 0. 01% end-consolidation)

3. 11q23 (MLL) rearrangements detected by cytogenetic or PCR at initial diagnosis who are slow early responders (M2/M3 at day 14 or MRD> 0. 01% at day 29)

4. Extreme hypodiploidy (< 44 chromosomes or DNA index of < 0. 81) detected by cytogenetic/ploidy analysis

2. Acute Myelogenous Leukemia:

A. Adult: (greater than or equal to 22 years) greater than or equal to CR2 OR CR1 with high risk features:

1. Adverse cytogenetics:

- Normal cytogenetics [52]

- complex karytoype (> 2 abnormalities) [53]

- 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)

[52, 53]

- monosomy karyotype (presence of an autosomal monosomy in conjunction

with at least one other autosomal monosomy or structural abnormality. [52]

- EXCEPT t(8;21), t(9;11), inv(16), or T(16;16), and M3 (17; 17) [53]

unless ckit mutation present and then eligible. [52]

- AML emerging from CML (blast crisis) are eligible

2. Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy

3. Secondary AML, defined as AML related to antecedent MDS, MPD, or cytotoxic chemotherapy

4. Hyperleukocytosis (WBC > 100,000 at diagnosis)

5. Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene (FLT3-LM; FLT-ITDs) [51-53]

6. Bilineage or biphenotypic leukemias are high risk features and eligible.

B. Pediatric (< 22 years): greater than or equal to CR2 or CR1 with high risk features:

1. Primary induction failure (greater than or equal to 5% blasts in marrow after induction)

2. Persistent leukemia (> 15% after first course of chemotherapy)

3. Monosomy 7, or - 5/-5q, FLT3 ITD-AR (> 0. 4) EXCEPT if also inv(16)/t(16;16),

t(8,21)

4. Normal cytogenetics or abnormal cytogenetics EXCEPT if also inv(16)/t(16;16), t(8,21) are eligible for SIBLING transplant only

5. Bilineage or biphenotypic leukemias are high risk features and eligible.

3. Myelodysplastic Syndrome RAEB 1 or 2, monosomy 7, or transfusion dependent.

- Disease status:

- -Patients with acute leukemia and MDS are to be referred in remission for

transplant. Should a patient screen for this protocol and protocol study evaluations reveal residual disease, the patient should return to the primary hematologist oncologist. If this is contraindicated or there are no other available options in the judgment of the PI/LAI, then the patient may receive chemotherapy as per standard of care for the malignant disease. However, the patient must be in remission (< 5% malignant blasts in marrow and peripheral blood) and no evidence of extramedullary disease for transplant.

- Performance status:

- -Karnofsky or Lansky performance status greater than or equal to 60% AND life

expectance of greater than 3 months.

- Ability to give informed consent. For 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 NIH guidelines.

- 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 times the upper limit of normal for age appropriate indices.

- 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).GFR may also demonstrate adequate renal function.

- Left ventricular ejection fraction greater than or equal to > 50% OR shortening

fraction of greater than or equal to 27% demonstrated on 2D echocardiogram or MUGA within 28 days of enrollment.

- Pulmonary function of DLC0 adj/VA and FEV1 greater than or equal to 60% of normal

indices for height and weight.

- Patients with prior autologous stem cell transplants will be included. However,

patients with prior allogeneic stem cell transplants will not be eligible.

- Prior systematic therapies must have been completed greater than 2 weeks prior to

study entry.(with exception of tyrosine kinase inhibitors).

EXCLUSION CRITERIA: TRANSPLANT RECIPIENT

- 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 PI or LAI 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.

- 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 Lupron intolerance. Note: patients ARE eligible if prior or current

lupron exposure.

INCLUSION CRITERIA: MATCHED RELATED TRANSPLANT DONOR

- Age > 8 and less than 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 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 NIH guidelines.

- 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 NIH/CC Department of Transfusion Medicine

criteria and must be able to medically endure stem cell collection.

- Donors must be HIV negative, HTLV negative, HBSag 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.

EXCLUSION CRITERIA: MATCHED RELATED TRANSPLANT DONOR

- History of medical illness that in the estimation of the PI or DTM physician

precludes donation of marrow.

- Anemia (Hb < 10 gm/dl) or thrombocytopenia (< 100,000/ microL).

- Pregnant females (due to risk to fetus).

- Current psychiatric diagnosis that would compromise compliance with transplant

protocol or precludes appropriate informed consent.

- Presence of any blood transmissible infectious disease that cannot be cleared prior

to stem cell collection and poses an unacceptable risk for the recipient (e. g. excludes CMV).

- Active malignancy will exclude the donor. Any malignancy less than five years

post-remission 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.

- Any medical contraindication to anesthesia or marrow donation will exclude the donor.

- Donors receiving experimental therapy or investigational agents.

- Active autoimmune disease that in the opinion of the PI or LAI would compromise the

success of the transplant.

INCLUSION CRITERIA: MATCHED UNRELATED DONOR

- Unrelated donor matched at HLA-A, B, C, and DR loci by high resolution typing (8/8

antigen/allele match) are acceptable donors.

- The evaluation of donors shall be in accordance with existing National Marrow Donor

Program (NMDP) Standard Policies and Procedures.

INCLUSION CRITERIA: (18F) FLT CANDIDATE TRANSPLANT RECIPIENT

- Meets criteria for Transplant Recipient sections

- Age > 18 years old

- Donor who is willing to undergo bone marrow harvest.

EXCLUSION CRITERIA: (18F) FLT CANDIDATE TRANSPLANT RECIPIENT

- History of prior fluorothymidine allergy or intolerance.

Candice M Cottle-Delisle, R.N., Phone: (301) 496-5853, Email: cottlec@mail.nih.gov

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting
For more information at the NIH Clinical Center contact National Cancer Institute Referral Office, Phone: (888) NCI-1937

University of Oklahoma, Oklahoma City, Oklahoma 73104, United States; Recruiting

NIH Clinical Center Detailed Web Page

Related publications:

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.

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.

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.

Starting date: March 2011
Last updated: December 8, 2012