Donor Stem Cell Transplant in Treating Patients With High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

OBJECTIVES:

Primary

- To determine if this treatment can improve 2-year current progression-free survival
(PFS) in the early disease cohort compared to historical controls. Specifically, we plan
to study whether we can achieve 2-year PFS ≥ 70% and to exclude 2 year PFS ≤ 50%

Secondary

- To determine whether in the advanced disease cohort we can achieve 2-year current PFS ≥
50% and to exclude 2-year PFS ≤ 30%

- To assess objective response rate.

- To assess the incidence of grade 2-4 and 3-4 acute graft-vs-host disease (GVHD).

- To assess the incidence of extensive chronic GVHD.

- To assess the incidence of treatment-related mortality at 100 days and 1 year

- To assess overall survival

- To assess donor chimerism for CD3+ cells at 1 and 2 years after transplantation

- To investigate the presence of donor antigen-specific T-cell clones before and after
withdrawal of immune suppression.

- To compare the relapse profiles of patients with T-cell responses against CLL to those
whose CLL cells are not reactive

- To prospectively examine the impact of high-risk genomic features and immune-based
single nucleotide polymorphisms on response, toxicity, and 2-year PFS to reduced
intensity allogeneic stem cell transplant

OUTLINE: This is a multicenter study.

- Preparative regimen: Patients receive 1 of 2 preparative regimens at the discretion of
the participating institution.

- Preparative regimen 1: Patients receive rituximab IV on days -7, -1, 7, and 14 and
fludarabine phosphate IV over 30 minutes and busulfan IV over 3 hours on days -5 to
-2. .

- Preparative regimen 2: Patients receive rituximab IV on days -7, -1, 7, and 14,
fludarabine phosphate IV over 30 minutes on days -5 to -2, and cyclophosphamide IV
over 1-2 hours on days -5 to -3. Patients with matched unrelated donors also
receive anti-thymocyte globulin IV over 4-6 hours on days -6 to -4.

- Graft-vs-host disease (GVHD) prophylaxis: Patients who receive preparative regimen 1 may
receive either GVHD prophylaxis regimen 1 or 2; patients who receive preparative regimen
2 may only receive GVHD prophylaxis regimen 2.

- GVHD prophylaxis regimen 1: Patients receive tacrolimus either orally or IV and
oral sirolimus beginning on day -2 and continuing until day 60, followed by a taper
until day 180. Patients also receive methotrexate IV on days 1, 3, and 6.

- GVHD prophylaxis regimen 2: Patients receive tacrolimus either orally or IV
beginning on day -2 and continuing until day 60, followed by a taper until day 180.
Patients also receive methotrexate IV on days 1, 3, 6, and 11.

- Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation
on day 0.

- Maintenance therapy: Patients receive rituximab IV at 3, 6, 9, and 12 months after
transplantation.

Peripheral blood and bone marrow aspirate samples may be collected periodically for
correlative laboratory studies.

Patients are followed up periodically for a maximum of 5 years from study entry.

Patient Eligibility:

1. Diagnosis of B-cell chronic lymphocytic leukemia or B-cell small lymphocytic lymphoma.

Diagnosis should be according to International Workshop on Chronic Lymphocytic
Leukemia (IWCLL) 2008 Criteria

1. Early Disease Cohort - Patients in the early disease cohort must include one or
more of the following:

- FISH showing deletion 17p in ≥ 20% of cells (either at diagnosis or any time
prior to study entry) either alone or in combination with other cytogenetic
abnormalities

- FISH showing del 11q in ≥ 20% of cells (either at diagnosis or any time
prior to study entry) either alone or in combination with other cytogenetic
abnormalities, unless the patient has achieved a complete remission by IWCLL
2008 which includes CT scan, bone marrow morphology and flow cytometry

- Failure to achieve a partial response with initial chemotherapy, but with
lack of progression. These patients may receive a second therapy to improve
their response prior to transplant.

- Patients who, at the time of first progression, have a 17p deletion by FISH
in ≥ 20% of cells, either alone or in combination with other cytogenetic
abnormalities.

The duration of the first progression is not specified.

- In addition, patients in the early disease cohort must have all of the
following:

- Received at least 2 cycles of induction therapy. It is expected that
most patients will receive at least 4 months of therapy prior to
enrollment, but this is not required. Suggested regimens include but
are not limited to the following: fludarabine plus rituximab,
fludarabine, cyclophosphamide plus rituximab, pentostatin,
cyclophosphamide plus rituximab, bendumustine plus rituximab, or
alemtuzumab alone or in combination with other agents. Patients may
receive no more than 2 different regimens prior to proceeding to
transplantation.

- Nodes ≤ 5 cm

2. Advanced Disease Cohort - Patients in the advanced disease cohort must include
one or more of the following:

- FISH showing deletion 17p in ≥ 20% of cells (regardless of interval from
initial therapy) either alone or in combination with other cytogenetic
abnormalities

- First progression < 24 months after completing therapy. This includes
progression on initial therapy.

- Second or subsequent progression

- In addition, patients in the advanced disease cohort must have all of the
following:

- Stable disease or better by the Revised IWCLL 2008 NCI Criteria to
their most recent chemotherapy

- Nodes ≤ 5 cm

2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

3. Age Requirement - Patients must be between ≥ 18 and < 70 years of age

4. Cytotoxic Chemotherapy or Alemtuzamab - There must be at least 4 weeks after day 1 of
the last cycle of cytotoxic chemotherapy, or alemtuzamab.

5. Human Immunodeficiency Virus (HIV) Status - Patients must have no HIV infection.

Allogeneic transplantation in the HIV patient population is not well-defined and there
are likely to be requirements for concomitant anti-HIV therapy and anti-GVHD therapy
that would create potentially dangerous pharmacokinetic interactions among the
different agents that could constrain therapeutic options for controlling both HIV and
GVHD.

6. Hepatitis B and C - Patients must have no Hepatitis B sAg, anti-HBc or HCV.

7. Diffusion capacity of carbon monoxide DLCO must be ≥ 40% predicted

8. Left ventricular ejection fraction (LVEF) by Echocardiogram (ECHO) or Multiple gated
acquisition (MUGA) must be ≥ 30%

9. Diabetes or Serious Infection - Patients must have no uncontrolled diabetes mellitus
or active uncontrolled serious infections

10. Pregnancy and Nursing Status - Patients must be non-pregnant and non-nursing.
Treatment under this protocol would expose a fetus to significant risks. Women of
childbearing potential should have a negative pregnancy test prior to study entry.

Women and men of reproductive potential should agree to use an appropriate method of
birth control throughout their participation in this study due to the teratogenic
potential of the therapy utilized in this trial. Appropriate methods of birth control
include oral contraceptives, implantable hormonal contraceptives (Norplant®), or
double barrier method (diaphragm plus condom).

11. Richter's Transformation - Patients must have no history of Richter's transformation.

12. Initial Required Laboratory Values:

- Serum Creatinine < 2 mg/dL

- Calculated Creatinine Clearance ≥ 40 mL/min

- AST < 3 x ULN

- Total Bilirubin < 2 mg/dL (except for Gilbert's syndrome)

Donor Eligibility:

1. Donors may be either a 6/6 HLA-matched related donor by low-resolution typing at HLA
A, B, DR.

2. Donors may be an 8/8 HLA-matched unrelated donor at HLA A, B, C, DR. Unrelated donors
will be analyzed by molecular typing at both HLA Class I and Class II (A, B, C, DR
loci).

3. Syngeneic donors are not eligible

4. Donors must be healthy and must be an acceptable donor as per institutional standards
for stem cell donation.

5. There will be no donor age restriction.