Stem Cell Transplantation for Patients With Cancers of the Blood

Peripheral blood stem cell transplant research carried out by the NHLBI BMT Unit focus on
approaches in transplant techniques designed to decrease graft versus host disease (GVHD),
increase the graft-versus-leukemia (GVL) effect, and/or reduce the risk for post-transplant
graft rejection or disease relapse.

Ex vivo selective depletion of alloreacting T cells, hereafter referred as selective
depletion (SD), represents a translational strategy aiming to reduce severe GVHD whilst
preserving GVL. We found that selectively depleted transplants are safe to administer and
associated with less severe acute GVHD. This protocol is designed to evaluate the safety and
efficacy of photodepletion (PD) as an improved selective depletion procedure in the
HLA-matched peripheral blood stem cell transplant setting and to determine whether
post-transplant immunosuppression with cyclosporine is necessary to prevent severe GVHD after
a photodepleted transplant.

The protocol will accrue subjects ages 18-75 who are diagnosed with a hematological
malignancy where allogeneic stem cell transplantation from an HLA-matched sibling would be
normally indicated. Diagnostic categories will include acute and chronic leukemias,
myelodysplastic syndromes, B-cell lymphomas, multiple myeloma, and myeloproliferative
syndromes.

Participants have a central intravenous (IV) line placed into a large vein. The tube is used
for giving the donated stem cells and antibiotics and other medicines, for transfusions of
red blood cells and platelets, and for collecting blood samples. Treatment starts with a
conditioning regimen of chemotherapy (fludarabine and cyclophosphamide) and total body
irradiation to suppress immunity and prevent rejection of the donated stem cells. The day
after chemotherapy ends, the stem cells are given through the central line. This is followed
by transfusion of the donor's immune cells, which have been treated to remove cells that
could cause severe GVHD. Also to minimize the risk of GVHD, patients are given cyclosporine.
Not all participants receive the same amount of this drug; in order to determine how much
immunosuppression is needed to protect against severe GVHD, the length of treatment with
cyclosporine varies among patients, depending on when they entered the study and how well
preceding patients did.

The average hospital stay for stem cell transplantation is 3 to 4 weeks. Patients return for
frequent follow-up visits for the first 2 to 4 months after transplantation. The patient's
referring physician is asked to send results of any laboratory testing to the NIH researchers
at least every 3 months for the first 3 years and annually thereafter. Patient follow-up
visits are scheduled at NIH at 1, 2, and 3 years after transplantation. After 3 years,
participants are offered the opportunity to enroll in NHLBI's long-term evaluation and
follow-up care protocol.

Subjects will receive a myeloablative conditioning regimen of cyclophosphamide, fludarabine
and total body irradiation, followed by an infusion of a stem cell product prepared using the
Miltenyi CliniMacs system for CD34 selection and a lymphocyte product that has been
selectively depleted using the photodepletion approach (Kiadis Pharma). Older subjects will
receive a lower dose of irradiation to reduce the regimen intensity.

To determine appropriate level of post transplant immunosuppression, we will utilize a three
sequential de-escalation stage design involving 17 subjects per cohort (minimum 17, maximum
51 total evaluable subjects in study). Stopping rules for non-relapse mortality in each
cohort will determine whether to continue to the next stage; to continue accumulating
subjects at the same level; or to stop the protocol.

Cohort 1: Low dose cyclosporine until day 90 then dose tapered to stop within 2 weeks.

Cohort 2: If no severe GVHD is encountered in Cohort 1, the cyclosporine withdrawal will
begin on day 45.

Cohort 3: If no severe GVHD is encountered in Cohort 2, cyclosporine will not be used in the
post-transplant period.

Primary endpoints will be the incidence of acute grade III/IV GVHD at day 90. Secondary
endpoints will be standard transplant outcome variables: toxicity, non relapse mortality and
survival.

INCLUSION CRITERIA:

Recipient Criteria:

- Diagnosed with one of the following hematological conditions:

- Chronic myelogenous leukemia (CML): chronic phase who have failed treatment with
imatinib, have intolerance to imatinib, or who did not receive imatinib at therapeutic
doses within the first 12 months from diagnosis; accelerated phase or blast
transformation.

- Acute B-lymphoblastic leukemia (B-ALL): any of these categories: B-ALL in first
remission with high-risk features (presenting leukocyte count greater than 100,000/cu
mm, Karyotypes t9; 22, t4, t19, t11, biphenotypic leukemia), all second or subsequent
remissions, primary induction failure, partially responding or untreated relapse.

- Acute myelogenous leukemia (AML): AML in first remission - except AML with good risk
karyotypes: AML M3 (t15; 17), AML M4Eo (inv 16), AML t (8; 21). All AML in second or
subsequent remission, primary induction failure and resistant relapse.

- Myelodysplastic syndromes (MDS): any of these categories - refractory anemia with
transfusion dependence, refractory anemia with excess of blasts, transformation to
acute leukemia, chronic myelomonocytic leukemia, atypical MDS/myeloproliferative
syndromes.

- Myeloproliferative disorders including atypical (Ph negative) chronic myeloid and
neutrophilic leukemias, progressing myelofibrosis, and polycythemia vera, essential
thrombocythemia in transformation to acute leukemia or with progressive transfusion
requirements or pancytopenia.

- Chronic lymphocytic leukemia refractory to fludarabine treatment and with bulky
progressive disease or with thrombocytopenia (less than or equal to 100,000 /microl)
or anemia (less than or equal to 10g/dl) not due to recent chemotherapy.

- Non-Hodgkin's lymphoma including Mantle cell lymphoma relapsing or refractory to
standard of care treatments.

- Multiple myeloma, Waldenstroms macroglobulinemia, unresponsive or relapsed following
standard of care treatments.

- Ages 18-75 years inclusive.

- HLA identical (6/6) related donor.

- Ability to comprehend the investigational nature of the study and provide informed
consent.

Donor Criteria:

- Related HLA identical (6/6) with recipient.

- Weight greater than or equal to 18 kg.

- Age greater than or equal to 2 or less than or equal to 80 years old.

- For adults: Ability to comprehend the investigational nature of the study and provide
informed consent. For minors: Written informed consent from one parent or guardian and
informed assent: The process will be explained to the minor on a level of complexity
appropriate for their age and ability to comprehend.

EXCLUSION CRITERIA:

Recipient Criteria (any of the following):

- Malignant cells expressing a T cell phenotype (in particular T-ALL and T cell NHL).

- DLCO less than 65 percent predicted.

- Left ventricular ejection fraction less than 40 percent (evaluated by ECHO) or less
than 30 percent (evaluated by MUGA).

- AST/SGOT greater than 10 times ULN (CTCAE grade IV v3.0).

- Bilirubin greater than 5 times ULN (CTCAE grade IV v3.0).

- Creatinine greater than 4.5 times ULN (CTCAE grade IV v 3.0).

- HIV positive (Recipients who are positive for hepatitis B (HBV), hepatitis C (HCV) or
human T-cell lymphotropic virus (HTLV-1/II) are not excluded from participation).

- Positive pregnancy test for women of childbearing age.

- Prior allogeneic stem cell transplantation.

- Estimated probability of surviving less than three months.

- Major anticipated illness or organ failure incompatible with survival from transplant.

- Severe psychiatric illness or mental deficiency sufficiently severe as to make
compliance with the transplant treatment unlikely and informed consent impossible.

Donor Criteria (any of the following):

- Pregnant or lactating.

- Unfit to receive filgrastim (G-CSF) and undergo apheresis (abnormal blood counts,
history of stroke, uncontrolled hypertension).

- Sickling hemoglobinopathies including HbSS, HbAS, HbSC.

- HIV positive Donors who are positive for hepatitis B (HBV), hepatitis C (HCV) or human
T-cell lymphotropic virus (HTLV-I/II) will be used at the discretion of the
investigator following counseling and approval from the recipient.

- Severe psychiatric illness or mental deficiency sufficiently severe as to make
compliance with the donation of stem cells unlikely and informed consent impossible.