Safety and Efficacy of Pentostatin and Low Dose TBI With Allogenic Peripheral Blood Stem Cell Transplant

This is a pilot study which began with a plan to enroll 50 patients (20 related and 30
unrelated donor transplants) with hematological malignancy assessing the safety and efficacy
of a minimally myelosuppressive regimen with Pentostatin and low-dose total body irradiation
(TBI) followed by allogeneic peripheral blood stem cell transplantation (alloPSCT). Patients
with persistent or progressive malignancy after transplantation will be treated with GM-CSF
(cytokine therapy) to assess its toxicity and potential therapeutic efficacy. Patients with
persistent or progressive disease who fail or do not qualify for the cytokine therapy portion
of the study will become candidates for donor leukocyte infusions.

The purpose of this protocol remains a pilot study which is now regarded as a phase II trial
with a plan to enroll 40 ADDITIONAL patients (20 related and 20 unrelated donor transplants)
with hematological malignancy assessing the safety and efficacy of a modified version of the
original preparative regimen of Pentostatin and low-dose total body irradiation (TBI)
followed by allogeneic peripheral blood stem cell transplantation (alloPSCT). Patients who
fail will become candidates for donor-leukocyte infusion (DLI).

Primary Objectives

1. To determine the safety of treating hematological malignancies by establishing donor
hematopoietic chimerism using pentostatin and low-dose total body irradiation followed
by allogeneic peripheral blood stem cell transplantation.

2. To determine the immunomodulatory effects of pentostatin as part of the conditioning
regimen for allogeneic peripheral blood stem cell transplantation.

Secondary Objectives

1. To determine the incidence of infections after using a minimally myelosuppressive
conditioning regimen.

2. To determine the kinetics of hematological and immunological reconstitution after
allotransplantation with a minimally myelosuppressive conditioning regimen.

3. To determine the incidence of chronic GVHD after using allogeneic peripheral blood stem
cell transplantation with a minimally myelosuppressive preparative regimen.

4. To evaluate the role of the preparative regimen and donor source (related versus
unrelated) on inflammatory cytokine profiles.

5. To evaluate blood and where possible, biopsy specimens for a recently identified nuclear
protein (molecular weight 44/46) in mononuclear cells obtained from study subjects.

Interventions, evaluation, and follow up will include:

Pentostatin 4 mg/m^2/d intravenously once a day x 3 days will be administered with 1000 cc NS
hydration before and after pentostatin ten days prior to stem cell infusion (days -10, -9,
and -8). Total-body irradiation (TBI): TBI 2.0 Gy will be given on day -1. Antiemetics will
be given as needed. Patients will receive one liter normal saline over 2 hours pre TBI. A
bone marrow biopsy and aspiration with cytogenetics and flow cytometry will be performed on
Day +28, Day +70 and 6, 12, 18 and 24 months following the transplant to monitor hematologic
recovery. DNA fingerprinting will also be conducted at the same time at 3, 4, 5, 6, 12, 18,
and 24 months to determine chimerism.

Inclusion Criteria:

Age 19-75 years

1. Patients who relapse after autologous stem cell transplantation.

2. Patients who are candidates for an autologous or conventional allogeneic stem cell
transplantation from a disease standpoint but who do not qualify functionally (from
the point of view of organ function, or performance status) for a myeloablative
protocol.

3. Any patient, where in the opinion of the primary treating oncologist, nonmyleoablative
therapy would be the treatment option in the best patients interest providing the
patient fits all other eligibility criteria for this protocol.

Identification of a matched related or unrelated stem cell donor

Diseases:

Acute myelogenous leukemia first complete remission with high-risk cytogenetics>second
complete remission minimal residual disease (<10% blasts*). Acute lymphocytic leukemia
first complete remission with high-risk cytogenetics >second complete remission minimal
residual disease (<10% blasts*). Chronic myelogenous leukemia first chronic phase,
accelerated phase (<10% blasts*)blast phase with minimal residual disease (<10%
blasts*)second chronic phase. Chronic lymphocytic leukemia recurrence after the front line
regimen (related donor transplant), chemorefractory disease (unrelated donor
transplant),T-CLL in partial remission or any minimal residual disease. Myelodysplastic
syndromes refractory anemia with or without ringed sideroblasts,RAEB, RAEB-T, and CMML (<
than 10% blasts*). *both in peripheral blood and bone marrow

Multiple myeloma - after receiving at least one regimen of prior chemotherapy

Non-Hodgkin's Lymphomas:

Small Lympho(plasma)cytic Lymphoma (B-SLL, B-LPL): recurrence after a front line regimen
(related donor transplant), or chemorefractory disease (related or unrelated donor
transplant). Follicular Low-Grade Lymphoma, Marginal Zone Lymphomas (splenic, nodal, or
extranodal/MALT type): chemorefractory disease or > 2 prior regimens. Mantle Cell Lymphoma:
first complete or partial remission, refractory disease, or failed prior ASCT. Diffuse
Large B-cell Lymphoma, Follicular Large cell Lymphoma, Peripheral T-cell Lymphoma,
Anaplastic Large Cell Lymphoma: refractory disease, or failed prior ASCT. Burkitt or Acute
Lymphoblastic Lymphomas: high-risk disease in remission, chemosensitive persistent or
recurrent disease. Cutaneous T-cell Lymphomas: (Mycosis Fungoides, Sezary Syndrome):
chemorefractory disease of > 2 prior regimens

Hodgkins Disease: refractory or persistent disease and not candidate for ASCT, or failed
prior ASCT.

Peripheral T-cell Lymphoma

Exclusion Criteria:

- Age > 75 years and < 19 years

- progressive disease within 8 weeks of prior therapy or within 12 weeks after prior
autologous stem cell transplantation

- Active CNS malignancy (patients with known positive CSF cytology or parenchymal
lesions visible by CT or MRI)

- Fertile men or women unwilling to use appropriate contraceptive techniques during and
for 12 months following treatment

- Females who are pregnant

- Patients who are HIV seropositive

- Active uncontrolled infection or immediate life-threatening condition at the time of
enrollment

- Significant Organ dysfunction:

1. Calculated Creatinine Clearance <55ml/min

2. cardiac ejection fraction <40%, NYHA class II or greater cardiac disease.

3. DLCO < 40% , FEV1/FVC ratio <50% predicted, or receiving supplementary continuous
oxygen

4. total bilirubin > 2x upper limit of normal (unless due to Gilberts disease or
malignancy), ALT and AST 4x the upper limit of normal

- Karnofsky score <60%

- Patients with uncontrolled medical illnesses (e.g., uncontrolled systemic
hypertension, diabetes)

Donor Inclusion Criteria:

- HLA genotypically matched relative

- siblings or first-degree relatives matched at HLA-A, B, or DR loci (6 antigen match)
are acceptable donors

- HLA matched unrelated volunteer donor

- unrelated donor matched at HLA-A, B, or DR loci (6 antigen match) are acceptable
donors

- One antigen mismatch related or unrelated donor will also be acceptable, molecular
typing needs to be used at each H LA-A, B, or DR loci in case of mismatched unrelated
donor.

Donor Exclusion Criteria:

- Identical twin

- Pregnancy

- HIV positive

- Serious Allergy to G-CSF

- Current serious systemic illness

- Failure to meet the UNMC or NMDP criteria for donors