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

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 lymophopoiesis.

- 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.

- Primary: To assess safety of Lupron after 2nd HSCT 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 HSCT will be enrolled at 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.

Design:

- This is a prospective pilot study, the primary aims of which are: 1) to assess whether
Lupron enhances lymphocyte recovery after HSCT and 2) whether FLT imaging can be used to
predict engraftment/immune reconstitution, and 3) whether Lupron 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 Lupron (30 mg) or placebo two weeks before
the preparative regimen for first BMT. Women and all individuals undergoing 2nd BMT will
receive Lupron at these doses per age and be evaluated in the treated cohort. At
Children s National Medical Center, the patients will not receive Lupron outside of the
context of clinical care, and will receive myeloablative HSCT 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 of these 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 Lupron (30 mg) two weeks before the
preparative regimen. All patients will undergo FLT imaging to evaluate whether this may
predict HSCT 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 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 NCI
patients will undergo a single 1 year FLT for evaluation of thymus reconstitution. 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.

-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.

- ELIGIBILITY CRITERIA:

INCLUSION CRITERIA: TRANSPLANT RECIPIENT

1. At 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

Adult: (greater than or equal to 22 years) greater than or equal to CR2 OR 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 CML are also eligible

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

- High 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 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% endconsolidation)

- 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)

- Extreme hypodiploidy (< 44 chromosomes or 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 karytoype (>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 MDS, MPN, or cytotoxic
chemotherapy

- Hyperleukocytosis (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 karyoptype, 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 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 HSCT 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 m2. 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 2D echocardiogram or MUGA.

11. 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. Pediatric
patients unable to complete PFTs may be enrolled as per enrolling institution 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 11-c-0136.

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 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

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 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. 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 NIH/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, HTLV negative, 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 DTM physician
precludes donation of marrow.

2. Anemia (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 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 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.