Autologous Stem Cell Transplant Followed by Donor Stem Cell Transplant in Treating Patients With Relapsed or Refractory Lymphoma

PRIMARY OBJECTIVES:

I. To evaluate engraftment of human leukocyte antibody (HLA) identical peripheral blood stem
cell (PBSC) allografts given after conditioning with total-body irradiation (TBI) (200cGy)
+/- fludarabine (fludarabine phosphate), 90 mg/m^2 and post-grafting immunosuppression with
cyclosporine (CSP)/mycophenolate mofetil (MMF) in refractory or relapsed lymphoma patients
following an initial autologous peripheral blood stem cell transplant (PBSCT) for disease
cytoreduction.

II. To determine the non-relapse mortality at day 100 post-non-myeloablative allografting
following mobilization and high-dose chemotherapy with autografting.

SECONDARY OBJECTIVES:

I. To determine the disease free survival and overall survival of non-myeloablative
allografting following autologous PBSCT.

OUTLINE:

CONDITIONING REGIMEN: Patients with matched, related stem cell donors receive
cyclophosphamide intravenously (IV) on days -6 and -5 and undergo TBI twice daily (BID) on
days -3 to -1. Patients with matched, unrelated stem cell donors receive carmustine IV over 3
hours on day -7, etoposide IV over 2 hours BID on days -6 to -3, and cytarabine IV over 3
hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2.

TRANSPLANTATION: All patients undergo autologous PBSCT on day 0.

NON-MYELOABLATIVE CONDITIONING: Beginning 40-120 days following PBSC transplant, patients
with related donors undergo TBI on day 0. Patients with unrelated donors receive fludarabine
phosphate IV over 30 minutes on days -4 to -2 and undergo TBI on day 0.

TRANSPLANTATION: Patients undergo non-myeloablative allogeneic PBSCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) BID on days -3 to 56 (patients
with related donors) or 100 (patients with unrelated donors) followed by taper to day 180.
Patients also receive mycophenolate mofetil PO BID on days 0-27 (patients with related
donors) or thrice daily (TID) on days 0-27, then BID on days 28-40 followed by taper to day
96 (patients with unrelated donors).

Some patients may undergo donor lymphocyte infusion if there is evidence of disease
progression and no evidence of graft-vs-host disease (GVHD).

After completion of study treatment, patients are followed up at day 180, 1 year, 1.5 years,
2 years, 3 years, and then annually thereafter.

Inclusion Criteria:

- Patients with lymphoma (non-Hodgkin lymphoma [NHL], chronic lymphocytic leukemia/small
lymphocytic lymphoma [CLL/SLL] or Hodgkin's lymphoma) with primary refractory or
relapsed disease after standard chemotherapy at high risk of relapse with conventional
autografting; patients with a diagnosis of CLL (or small lymphocytic lymphoma) or
diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or
PLL

- Must have an HLA genotypically or phenotypically identical related donor or, at a
minimum, a high likelihood of identifying an HLA-matched unrelated donor; the
determination of availability of a suitable unrelated donor may be based on a
World-Book search

- Cross-over to other tandem autologous-allogeneic research protocol (#2241) will be
allowed if the patient loses the suitable HLA-matched related or unrelated donor but
has an available HLA-haploidentical donor before receiving the allogeneic
transplantation and if the patient meets the eligibility criteria of the subsequent
study

- Cross-over from other tandem autologous-allogeneic research protocol (#2241) will be
allowed if a suitable HLA-matched related or unrelated donor is identified before
receiving the allogeneic transplantation and if the patient meets the eligibility
criteria of the subsequent study

- Signed informed consent

- Detectable tumor on radiographic studies or bone marrow biopsy prior to mobilization
regimen

- Expected survival >= 3 months from study entry

- DONOR: HLA genotypically or phenotypically identical related donor

- DONOR: Must consent to granulocyte-colony stimulating factor (G-CSF) (filgrastim)
administration and leukapheresis for both PBSC allograft and subsequent donor
lymphocyte infusion (DLI)

- DONOR: Must have adequate veins for leukapheresis or agree to placement of central
venous catheter (femoral or subclavian)

- DONOR: Age < 75 years (yrs), older donors may be considered after review at Patient
Care Conference

- DONOR: Fred Hutchinson Cancer Research Center (FHCRC) matching allowed will be grades
1.0 to 2.1; unrelated donors who are prospectively: matched for HLA-A, B, C, DRB1 and
DQB1 by high resolution typing; only a single allele disparity will be allowed for
HLA-A, B, or C as defined by high resolution typing

- DONOR: Donors are excluded when preexisting immunoreactivity is identified that would
jeopardize donor hematopoietic cell engraftment; this determination is based on the
standard practice of the individual institution; the recommended procedure for
patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel
reactive antibody (PRA) screens to class I and class II antigens for all patients
before HCT; if the PRA shows > 10% activity, then flow cytometric or B and T cell
cytotoxic cross matches should be obtained; the donor should be excluded if any of the
cytotoxic cross match assays are positive; for those patients with an HLA class I
allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be
obtained regardless of the PRA results; a positive anti-donor cytotoxic crossmatch is
an absolute donor exclusion

- DONOR: Patient and donor pairs homozygous at a mismatched allele in the graft
rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and
the donor is A*0102, and this type of mismatch is not allowed

- DONOR: Only G-CSF mobilized peripheral blood mononuclear cells (PBMC) only will be
permitted as a hematopoietic stem cell (HSC) source on this protocol

Exclusion Criteria:

- Life expectancy severely limited by disease other than lymphoma

- Prior autologous hematopoietic stem cell transplant

- Patients at high risk of veno-occlusive disease of the liver (criteria not yet
rigorously defined but includes bilirubin > 2.0 mg and serum glutamic oxaloacetic
transaminase [SGOT] or serum glutamate pyruvate transaminase [SGPT] > 2 x normal);
patients may be accepted outside of this range if cleared by gastrointestinal (GI)
consult

- Cardiac ejection fraction (EF) < 40% on multi-gated acquisition (MUGA) scan or cardiac
echocardiogram (echo) (or if unable to obtain ejection fraction, shortening fraction
of < 26%); patients with active or a history of cardiac disease should be evaluated
with appropriate cardiac studies and/or consult; ejection fraction is required if age
> 50 years or there is a history of anthracyclines or history of cardiac disease;
patients with a shortening fraction < 26% may be enrolled if approved by a
cardiologist

- Baseline serum-creatinine > 2.0 mg/dl and a calculated or measured creatinine
clearance of < 50 ml/minute

- Seropositive for the human immunodeficiency virus (HIV)

- Pulmonary dysfunction as measured by a corrected diffusing capacity of the lung for
carbon monoxide (DLCO) < 50% of predicted total lung capacity (TLC) < 30%, forced
expiratory volume in 1 second (FEV1) < 30% and/or receiving supplementary continuous
oxygen; the FHCRC principal investigator (PI) of the study must approve enrollment of
all patients with pulmonary nodules

- Pregnancy or breast-feeding

- Patients with poorly controlled hypertension despite hypertensive medication

- Karnofsky score less than 60; pediatric criteria: Lansky Play-Performance Score < 40

- Patients with cluster of differentiation (CD)34 selected auto grafts

- Patients with active non-hematologic malignancies (except non-melanoma skin cancers);
this exclusion does not apply to patients with non-hematologic malignancies that do
not require therapy

- Patients with a history of non-hematologic malignancies (except non-melanoma skin
cancers) currently in a complete remission, who are less than 5 years from the time of
complete remission, and have a > 20% risk of disease recurrence; this exclusion does
not apply to patients with non-hematologic malignancies that do not require therapy

- DONOR: Identical twin

- DONOR: Age less than 12 years

- DONOR: Pregnancy

- DONOR: Human immunodeficiency virus (HIV) seropositivity

- DONOR: Inability to achieve adequate venous access

- DONOR: Known allergy to G-CSF

- DONOR: Current serious systemic illness

- DONOR: Failure to meet FHCRC criteria for stem cell donation

- DONOR: Donor (or centers) who will exclusively donate marrow