Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts From HLA-Matched Related and Unrelated Donors in Preventing GVHD

PRIMARY OBJECTIVES:

I. To estimate the probability of developing chronic GHVD among patients who receive naive T
cell (TN)-depleted peripheral blood stem cell transplant (PBSCT) in each of the following
groups: a) Arm A: patients who receive TN-depleted peripheral blood stem cells (PBSC) from a
human leukocyte antigens (HLA) matched related donor (MRD) following high-intensity
myeloablative conditioning (total body irradiation [TBI] 1320 cGy, thiotepa, fludarabine
phosphate [fludarabine]) and pharmacological immunosuppression with tacrolimus and
methotrexate; b) Arm B: patients who receive TN-depleted PBSC from a MRD following
lower-intensity myeloablative conditioning (TBI 400 cGy, thiotepa, fludarabine and
cyclophosphamide) and pharmacological immunosuppression with tacrolimus and mycophenolate
mofetil (MMF); c) Arm C: patients who receive TN-depleted PBSC from a HLA-matched unrelated
donor (MUD) following high-intensity myeloablative conditioning (TBI 1320 cGy, thiotepa,
fludarabine) and pharmacological immunosuppression with tacrolimus and methotrexate; d) Arm
D: patients who receive TN-depleted PBSC from a MUD following lower-intensity myeloablative
conditioning (TBI 400 cGy, thiotepa, fludarabine and cyclophosphamide) and pharmacological
immunosuppression with tacrolimus and MMF.

II. To estimate the probability of acute (a)GVHD grade II-IV following TN-depleted (TND)
PBSCT with tacrolimus and methotrexate (Arm A) or MMF (Arm B) GVHD prophylaxis in MRD
recipients.

III. Estimate the rate of aGVHD grade II-IV following TND PBSCT with tacrolimus and
methotrexate (Arm C) or MMF (Arm D) prophylaxis in recipients of MUD hematopoietic cell
transplantation (HCT).

IV. Estimate the probability of graft failure in recipients of CD45RA+ TN-depleted PBSCT with
tacrolimus and methotrexate (MTX) or MMF GVHD prophylaxis.

SECONDARY OBJECTIVES:

I. Estimate the probability of transplant-related mortality by day 100.

II. Estimate the probability of relapse.

III. Evaluate immune reconstitution and pathogen-specific immune reconstitution.

OUTLINE: Patients are assigned to 1 of 4 treatment arms.

CONDITIONING:

ARMS A AND C (high-intensity myeloablative conditioning): Patients undergo total body
irradiation twice daily (BID) on days -10 to -7. Patients also receive thiotepa intravenously
(IV) over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6
to -2.

ARMS B AND D (lower-intensity myeloablative conditioning): Patients receive cyclophosphamide
IV over 1 hour on day -6, fludarabine phosphate IV over 30 minutes on days -6 to -2, and
thiotepa IV over 4 hours on days -5 and -4. Patients also undergo total body irradiation once
daily (QD) on days -2 and -1.

TRANSPLANT: In all arms, patients undergo allogeneic HSCT with granulocyte colony-stimulating
factor (GCSF)-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0.

GVHD PROPHYLAXIS:

ARMS A AND C: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or orally
(PO) (BID if given PO) for 50 days with taper in the absence of GVHD. Patients also receive
methotrexate IV on days 1, 3, 6, and 11.

ARMS B AND D: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if
given PO) for 50 days and mycophenolate mofetil IV and PO every 8 hours on days -3 to
approximately day 30, with or without taper at the discretion of the treating physician.
Mycophenolate mofetil should be continued or resumed after day 30 if donor chimerism is low,
after discussion with the principal investigator.

After completion of study treatment, patients are followed up at 80-100 days, 360 days, and
then yearly for up to 5 years.

Inclusion Criteria:

- Patients who are considered appropriate candidates for allogeneic hematopoietic stem
cell transplantation and have one of the following diagnoses:

- Acute lymphocytic leukemia in first or subsequent remission

- Acute myeloid leukemia in first or subsequent remission

- Acute lymphocytic leukemia in relapse or primary refractory disease with a
circulating blast count of no more than 10,000/mm^3 (Arms A or C only)

- Acute myeloid leukemia in relapse or primary refractory disease with a
circulating blast count of no more than 10,000/mm^3 (Arms A or C only)

- Refractory anemia with excess blasts (RAEB-1 and RAEB-2) (if the patient has
received previous induction chemotherapy within 60 days)

- Chronic myelogenous leukemia with a history of accelerated phase or blast crisis
(if the patient has received at least one course of induction chemotherapy)

- Other acute leukemia or related neoplasm (including but not limited to
'biphenotypic', 'undifferentiated' or 'ambiguous lineage' acute leukemia, blastic
plasmacytoid dendritic cell neoplasm or lymphoblastic lymphoma)

- Patients 0-49 years old will be enrolled in Arm A or C (high-intensity)

- Patients 50-60 years old will be enrolled in Arm B or D (lower intensity); patients
eligible for Arms B or D also include those who have received previous allogeneic HCT,
or who have co-morbid conditions rendering them unsuitable for high-dose conditioning,
determined in consultation with the principal investigator

- Patient with a HLA-matched (HLA-A, B, C, and DR beta 1 [DRB1] molecularly matched)
unrelated donor or related donor capable of donating PBSC

- DONOR INCLUSION:

- HLA-matched related donors >= 18 years and capable and willing to donate PBSC (Arms A
and B)

- HLA-matched unrelated donors (HLA-A, B, C, and DRB1 matched based on high-resolution
typing) capable and willing to donate PBSC (Arms C and D)

Exclusion Criteria:

- Patients with central nervous system (CNS) involvement refractory to intrathecal
chemotherapy and/or standard cranial-spinal radiation

- Patients on other experimental protocols for prevention of acute GVHD

- Patient weight >= 100 kg; patients >= 70 kg with MUDs must be discussed with the
principal investigator

- Patients who are human immunodeficiency virus positive (HIV+)

- Patients with uncontrolled infections for whom myeloablative HCT is considered
contraindicated by the consulting infectious disease physician (upper respiratory
tract viral infection does not constitute an uncontrolled infection in this context)

- Patients with organ dysfunction

- ARM A OR C EXCLUSION:

- Creatinine > 1.5 mg/dl at the present time; patients with a known history of
creatinine > 1.5 mg/dl must have a current estimated creatinine clearance of > 40
ml/min

- Cardiac ejection fraction < 45%

- Diffusing capacity of the lung for carbon monoxide (DLCO) corrected < 60%; patients
who are unable to perform pulmonary function tests (for example, due to young age
and/or developmental status) will be excluded if the oxygen (O2) saturation is < 92%
on room air

- Liver function abnormality; patients who have liver function tests (LFTs) (including
total bilirubin, aspartate aminotransferase [AST] and alanine aminotransferase [ALT])
>= twice the upper limit of normal should be evaluated by a gastrointestinal (GI)
physician; unless there is a clear precipitating factor (such as an azole,
methotrexate, Bactrim or another drug); if the GI physician considers that HCT on the
high-intensity arms of protocol is contraindicated for that patient the patient may be
considered for treatment on the lower intensity arm of the protocol or excluded from
the protocol; patients with Gilbert's syndrome and no other known liver function
abnormality and patients with reversible drug-related transaminitis do not necessarily
require GI consultation and may be included on the high-intensity arms of the protocol

- ARM B OR D EXCLUSION:

- Creatinine > 2.0 mg/dl at the present time; patients with a known history of
creatinine > 1.5 mg/dl must have a current estimated creatinine clearance > 40 ml/min

- Cardiac ejection fraction < 35%

- DLCO corrected < 50%; patients who are unable to perform pulmonary function tests (for
example, due to young age and/or developmental status) will be excluded if the O2
saturation is < 92% on room air; patients with a DLCO 50-60% must also have a partial
pressure of oxygen (pO2) of > 80 mmHg

- Liver function abnormality; patients who have LFTs >= twice the upper limit of normal
should be evaluated by a GI physician unless there is a clear precipitating factor
(such as an azole, methotrexate, Bactrim or another drug); patients with fulminant
liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis,
alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices,
hepatic encephalopathy, or correctable hepatic synthetic dysfunction evidenced by
prolongation of the prothrombin time, ascites related to portal hypertension,
bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total
serum bilirubin > 3 mg/dL, and symptomatic biliary disease will be excluded

- Patients will be excluded from Arms A and C if they have received a previous
myeloablative transplant; patients who have received a prior HCT at least 6 months
prior may be considered for inclusion on Arms B or D after discussion with the
principal investigator (PI)

- Patients with a life expectancy < 3 months from co-existing disease other than the
leukemia or RAEB

- Patients who are pregnant or breast-feeding

- Fertile patients of child bearing age unwilling to use contraception during and for 12
months post-transplant

- Patients with a significant other medical conditions that would make them unsuitable
for transplant

- Patients with a known hypersensitivity to tacrolimus, methotrexate (Arm A or C) or MMF
(Arm B or D)

- DONOR EXCLUSION:

- Donors who are HIV-1, HIV-2, human T-lymphotropic virus (HTLV)-1, HTLV-2 seropositive
or with active hepatitis B or hepatitis C virus infection

- Donors who fail eligibility requirements for donation of cells or tissue for donation
of a Human Cell and Tissue Products (HCT/P) will be excluded unless use of the cells
complies urgent medical need or allogeneic use in a first-degree or second-degree
relative

- Unrelated donors donating outside of the United States of America (USA)