Know Cancer

or
forgot password

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


Phase 2
8 Years
60 Years
Open (Enrolling)
Both
Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, Myelodysplastic Syndrome RAEB 1

Thank you

Trial Information

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


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), CMML, certain CML) 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.

- 23 of these patients will be evaluated using FLT. They 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 GVHD relapse, or immune recovery. Initial 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

Inclusion Criteria


- ELIGIBILITY CRITERIA:

INCLUSION CRITERIA TRANSPLANT RECIPIENT:

- 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 has driven
initial pubertal development). Tanner 2 is defined as: breast buds for females with
coarse pubic hair, and coarse pubic hair and testes greater than 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. Matched sibling donor for recipient treated on adult lukemia regimen.

2. 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

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

1. Matched sibling donor for recipient treated on adult leukemia regimen

2. Primary induction failure (M3 (greater than 25% with greater 200 cells
counted) marrow at day 29), M2 (5-25% blasts with greater than 200 cells
counted) bone marrow or MRD greater than 1% at day 29 who then fail at day
43 with either an M2 or M3 BM or MRD greater than 1%

3. Persistent leukemia and t(9;22) (MRD greater than1% day 29 or MRD greater
than 0.01% end-consolidation)

4. 11q23 (MLL) rearrangements detected by cytogenetic or PCR at initial
diagnosis who are slow early responders (M2/M3 at day 14 or MRD greater
than 0.01% at day 29)

5. Extreme hypodiploidy (less than 44 chromosomes or DNA index of less than
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

- complex karytoype (greater than 2 abnormalities)

- 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)

- monosomy karyotype (presence of an autosomal monosomy in conjunction with at
least one other autosomal monosomy or structural abnormality.

- EXCEPT t(8;21), t(9;11), inv(16), or T(16;16), and M3 (17; 17) unless ckit
mutation present and then eligible.

- 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 greater than 100,000 at diagnosis)

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

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

B. Pediatric (less than 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 (greater than 15% after first course of chemotherapy)

3. Monosomy 7, or -5/-5q, FLT3 ITD-AR (greater than 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.

4. Chronic Myelomonocytic Leukemia

5. Chronic Myelogenous Leukemia who fail 2G-TKI

6. 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/AI, then the patient may receive
chemotherapy as per standard of care for the malignant disease. However, the
patient must be in remission (less than 5% malignant blasts in marrow and
peripheral blood) and no evidence of extramedullary disease for transplant.

7. Performance status: Karnofsky or Lansky performance status greater than or
equal to 60% AND life expectance of greater than 3 months.

8. Ability to give informed consent. For donors less than 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.

9. Hepatic function: Patients must have evidence of adequate liver function
prior to enrollment defined by total bilirubin less than 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.

10. Renal function: Patients must have evidence of adequate renal function to
proceed with stem cell transplant, creatinine clearance greater than 60
ml/min/1.73 m(2).GFR may also demonstrate adequate renal function.

11. 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.

12. Pulmonary function of DLC0 adj/VA and 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.

13. Patients with prior autologous stem cell transplants will be included.
However, patients with prior allogeneic stem cell transplants will not be
eligible.

14. 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

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 PI or 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. 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 Lupron intolerance. Note: patients ARE eligible if prior or
current lupron exposure.

INCLUSION CRITERIA: MATCHED RELATED TRANSPLANT DONOR

- Age greater than or equal to 8 and less than or equal to 60 years old and able
to give consent or assent. For donors less than 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 less than 10 gm/dl) or thrombocytopenia (less than 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 AI 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
(at 8/8 or 7/8 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 greater than 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.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

To determine if Lupron improves B lymphocyte reconstitution after HSCT.

Outcome Time Frame:

12 months post-transplant

Safety Issue:

No

Principal Investigator

Ronald E Gress, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110136

NCT ID:

NCT01338987

Start Date:

March 2011

Completion Date:

April 2016

Related Keywords:

  • Acute Lymphocytic Leukemia
  • Acute Myelogenous Leukemia
  • Myelodysplastic Syndrome RAEB 1
  • FLT
  • Lupron
  • Thymic Renewal
  • Stem Cell Transplant
  • Acute Lymphocytic Leukemia
  • Acute Myelogenous Leukemia
  • Myelodyplastic Syndrome
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
University of OklahomaOklahoma City, Oklahoma  73190