Autologous Peripheral Blood Stem Cell Transplant Followed by Donor Bone Marrow Transplant in Treating Patients With High-Risk Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

PRIMARY OBJECTIVES:

I. Event-free survival (EFS) at 1-year after autograft.

SECONDARY OBJECTIVES:

I. Relapse rates at 1-year after autograft.

II. Overall survival (OS) at 1-year after autograft.

III. Incidence of grades II-IV acute GVHD and chronic extensive GVHD.

IV. Non-relapse mortality (NRM) at 200 days and 1 year after allograft.

V. Donor engraftment at day +84.

VI. Incidence of infections.

OUTLINE:

CONDITIONING REGIMEN 1 (lymphoma, Waldenstrom macroglobulinemia, or chronic lymphocytic
leukemia [CLL] with no dose limiting radiation or significant comorbidities: Patients receive
cyclophosphamide intravenously (IV) on days -6 and -5. Patients undergo high-dose total body
irradiation (TBI) twice daily (BID) on days -3 to -1.

CONDITIONING REGIMEN 2 (lymphoma, Waldenstrom Macroglobulinemia, CLL, with prior
dose-limiting radiation, or significant comorbidities): Patients receive carmustine IV on day
-7, etoposide IV BID on days -6 to -3, cytarabine IV BID on days -6 to -3, and melphalan IV
on day -2.

CONDITIONING REGIMEN 3 (multiple myeloma or plasma cell leukemia, with no significant renal
insufficiency or other significant comorbidities): Patients receive high-dose melphalan IV on
day -2.

CONDITIONING REGIMEN 4 (multiple myeloma or plasma cell leukemia, with significant renal
insufficiency or other significant comorbidities): Patients receive lessened dose of
melphalan IV on day -2.

PBSC TRANSPLANTATION: All patients undergo autologous PBSC transplantation on day 0.

WAITING INTERVAL: Between 40 and 120 days.

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV once daily
(QD) on days -6 to -2 and cyclophosphamide IV QD on days -6 to -5 and day 3. Patients infused
with donor's peripheral blood stem cells will additionally receive cyclophosphamide IV on day
4. Patients undergo low-dose TBI on day -1.

ALLOGENEIC BONE MARROW TRANSPLANTATION: Patients undergo donor bone marrow transplantation on
day 0.

GRAFT VERSUS HOST DISEASE PROPHYLAXIS: Beginning on day 4, patients receive tacrolimus orally
(PO) or IV and taper beginning on day 86 if no graft-versus-host disease. Patients also
receive mycophenolate mofetil PO thrice daily (TID) on days 4 - 35.

PERIPHERAL BLOOD COUNT SUPPORT: Patients receive filgrastim (G-CSF) IV or subcutaneously (SC)
beginning from day 4 and continue till blood counts recover.

ALLOGENEIC PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) TRANSPLANTATION: Patients undergo donor
PBMC transplantation on day 0.

GRAFT VERSUS HOST DISEASE PROPHYLAXIS: Beginning on day 5, patients receive tacrolimus orally
(PO) or IV and taper beginning on day 86 if no graft-versus-host disease. Patients also
receive mycophenolate mofetil PO thrice daily (TID) on days 5 - 35.

PERIPHERAL BLOOD COUNT SUPPORT: Patients receive filgrastim IV or SC beginning from day 5 and
continue till blood counts recover.

After completion of study treatment, patients are followed up annually for 5 years.

Inclusion Criteria:

- Must have the capacity to give informed consent

- Detectable tumor prior to mobilization regimen

- Patients with stored autologous stem cells will be allowed

- Stem cells from an identical donor could be used for autologous hematopoietic cell
transplant (HCT)

- Marrow is the preferred source of stem cells from the HLA-haploidentical donor,
however, peripheral blood mononuclear cells (PBMC) could be used as stem cell source,
after clearance with the Fred Hutchinson Cancer Research Center (FHCRC) principal
investigator, in the case of difficulties or contraindications to bone marrow harvest
from the donor

- Cross-over to other tandem autologous-allogeneic research protocol (#1409 or other
appropriate protocol) 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

- Cross-over from other tandem autologous-allogeneic research protocol (#1409 or other
appropriate protocol) 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

- Lymphoma: patients with

- Diagnosis of non-Hodgkin lymphoma (NHL) or Hodgkin's lymphoma (HL), of any
histological grade

- Refractory or relapsed disease after standard chemotherapy

- High risk of early relapse following autograft alone

- Waldenstrom's macroglobulinemia: must have failed 2 courses of therapy

- CLL:

- Patients with either a:

- Diagnosis of T-cell CLL or T-cell prolymphocytic leukemia (PLL) who have
failed initial chemotherapy, patients with T cell CLL or PLL or

- Diagnosis of B-cell CLL, B-cell small lymphocytic lymphoma, or B-cell CLL
that progressed to PLL who either:

1. Failed to meet National Cancer Institute (NCI) Working Group criteria
for complete or partial response after therapy with a regimen
containing fludarabine (or another nucleoside analog, e.g.
2-chlorodeoxyadenosine [CDA], pentostatin) or experience disease
relapse within 12 months after completing therapy with a regimen
containing fludarabine (or another nucleoside analog)

2. Failed any aggressive chemotherapy regimen, such as fludarabine,
cyclophosphamide and rituximab (FCR), at any time point

3. Have "17p deletion" cytogenetic abnormality and relapsed at any time
point after initial chemotherapy

- Harvesting criteria for autologous HCT:

- Previously collected PBMC may be used

- Circulating CLL cells < 5000

- Marrow involvement with CLL cells < 50%

- Multiple myeloma (MM): patients who

- Have received induction therapy for a minimum of 4 cycles

- In addition, patients must meet at least one of the following criteria I-IX
(I-VII at time of diagnosis or pre-autograft):

- Any abnormal karyotype by metaphase analysis except for isolated t(11,14),

- Fluorescent in situ hybridization (FISH) translocation 4:14,

- FISH translocation 14:16,

- FISH deletion 17p,

- Beta2 (B2)-microglobulin > 5.5 mg/ml,

- Cytogenetic hypodiploidy

- Plasmablastic morphology (>= 2%)

- Recurrent or non-responsive (less than partial remission [PR]) MM after at
least two different lines of conventional chemotherapy

- Progressive MM after a previous autograft (provided stored autologous
cluster of differentiation [CD]34 cells are available)

- Plasma cell leukemia: after induction chemotherapy

- DONOR: Related donors who are genotypically identical for one HLA haplotype and who
may be mismatched at the HLA-A, -B, -C or DRB1 loci of the unshared haplotype with the
exception of single HLA-A, -B or -C allele mismatches

- DONOR: Marrow is the preferred source of stem cells from the HLA-haploidentical donor,
however PBMC could be used as stem cell source, after clearance with the FHCRC
principal investigator, in the case of difficulties or contraindications to bone
marrow harvest from the donor

- DONOR: In the case that PBMC will be used as stem cell source, ability of donors < 18
years of age to undergo apheresis without use of a vascular access device; vein check
must be performed and verified by an apheresis nurse prior to arrival at the Seattle
Cancer Care Alliance (SCCA)

- DONOR: Age >= 12 years of age

Exclusion Criteria:

- Life expectancy severely limited by disease other than malignancy

- Seropositive for the human immunodeficiency virus

- Female patients who are pregnant or breastfeeding

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

- Central nervous system (CNS) involvement with disease refractory to intrathecal
chemotherapy

- Patients with active non-hematological malignancies (except non-melanoma skin cancers)
or those with non-hematological malignancies (except non-melanoma skin cancers) who
have been rendered with no evidence of disease, but have a greater than 20% chance of
having disease recurrence within 5 years

- This exclusion does not apply to patients with non-hematologic malignancies that
do not require therapy

- Patients with fungal infection and radiological progression after receipt of
amphotericin B or active triazole for greater than 1 month

- Symptomatic coronary artery disease or ejection fraction < 40% or other cardiac
failure requiring therapy (or, if unable to obtain ejection fraction, shortening
fraction of < 26%); ejection fraction is required if the patient has a history of
anthracyclines or history of cardiac disease; patients with a shortening fraction <
26% may be enrolled if approved by a cardiologist

- Corrected diffusion capacity of the lungs for carbon monoxide (DLCO) < 50% of
predicted, forced expiratory volume in one second (FEV1) < 50% of predicted, and/or
receiving supplementary continuous oxygen; the FHCRC principal investigator (PI) of
the study must approve of enrollment of all patients with pulmonary nodules

- Patient with clinical or laboratory evidence of liver disease will be evaluated for
the cause of liver disease, its clinical severity in terms of liver function, bridging
fibrosis, and the degree of portal hypertension; the patient will be excluded if
he/she is found to have fulminant liver failure, cirrhosis of the liver with evidence
of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding
esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic
dysfunction evinced by prolongation of the prothrombin time, ascites related to portal
hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral
hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease

- Karnofsky score < 50% for adult patients

- Lansky play-performance score < 40 for pediatric patients

- Patient with poorly controlled hypertension despite multiple antihypertensives

- DONOR: Donor-recipient pairs in which the HLA-mismatch is only in the
host-versus-graft (HVG) direction

- DONOR: Infection with human immunodeficiency virus (HIV)

- DONOR: Weight < 20 kg

- DONOR: A positive anti-donor cytotoxic crossmatch