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

Phase 2

Completed

Conditions: Recurrent Childhood Hodgkin Lymphoma
Refractory Small Lymphocytic Lymphoma
Waldenstrom Macroglobulinemia
Plasma Cell Leukemia
Progression of Multiple Myeloma or Plasma Cell Leukemia
Recurrent Adult Non-Hodgkin Lymphoma
Recurrent Childhood Non-Hodgkin Lymphoma
Recurrent Small Lymphocytic Lymphoma
Refractory Childhood Hodgkin Lymphoma
t(14;16)

Interventions: Procedure: Allogeneic Bone Marrow Transplantation
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Procedure: Autologous Hematopoietic Stem Cell Transplantation
Procedure: Autologous-Allogeneic Tandem Hematopoietic Stem Cell Transplantation
Drug: Carmustine
Drug: Cyclophosphamide
Drug: Cytarabine
Drug: Etoposide
Drug: Fludarabine Phosphate
Other: Laboratory Biomarker Analysis
Drug: Melphalan
Drug: Mycophenolate Mofetil
Procedure: Peripheral Blood Stem Cell Transplantation
Drug: Tacrolimus
Radiation: Total-Body Irradiation

Registration Number: NCT01008462

Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary: This phase II trial studies 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. Autologous stem cell transplantation uses the patient's stem cells and does not cause graft versus host disease (GVHD) and has a very low risk of death, while minimizing the number of cancer cells. Peripheral blood stem cell (PBSC) transplant uses stem cells from the patient or a donor and may be able to replace immune cells that were destroyed by chemotherapy. These donated stem cells may help destroy cancer cells. Bone marrow transplant known as a nonmyeloablative transplant uses stem cells from a haploidentical family donor. Autologous peripheral blood stem cell transplant followed by donor bone marrow transplant may work better in treating patients with high-risk Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 16

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (autologous HCT, donor HCT)	Total-Body Irradiation	See Detailed Description
Treatment (autologous HCT, donor HCT)	Autologous-Allogeneic Tandem Hematopoietic Stem Cell Transplantation	See Detailed Description
Treatment (autologous HCT, donor HCT)	Allogeneic Bone Marrow Transplantation	See Detailed Description
Treatment (autologous HCT, donor HCT)	Peripheral Blood Stem Cell Transplantation	See Detailed Description
Treatment (autologous HCT, donor HCT)	Allogeneic Hematopoietic Stem Cell Transplantation	See Detailed Description
Treatment (autologous HCT, donor HCT)	Autologous Hematopoietic Stem Cell Transplantation	See Detailed Description
Treatment (autologous HCT, donor HCT)	Laboratory Biomarker Analysis	See Detailed Description
Treatment (autologous HCT, donor HCT)	Cytarabine	See Detailed Description
Treatment (autologous HCT, donor HCT)	Carmustine	See Detailed Description
Treatment (autologous HCT, donor HCT)	Cyclophosphamide	See Detailed Description
Treatment (autologous HCT, donor HCT)	Etoposide	See Detailed Description
Treatment (autologous HCT, donor HCT)	Fludarabine Phosphate	See Detailed Description
Treatment (autologous HCT, donor HCT)	Melphalan	See Detailed Description
Treatment (autologous HCT, donor HCT)	Mycophenolate Mofetil	See Detailed Description
Treatment (autologous HCT, donor HCT)	Tacrolimus	See Detailed Description

Primary Outcome Measures

Name	Time	Method
Event-Free Survival (EFS)	1 Year post-autograft	Number of patients surviving without relapsed/progressive disease

Secondary Outcome Measures

Name	Time	Method
Number of Patients With Relapsed/Progressive Disease	1 year post-autograft	Relapse/Progression defined as: Nodes, liver, and/or spleen ≥50% increased or new by physical exam / imaging studies. Circulating lymphocytes ≥50% increased by morphology and/or flow cytometry. Richter's transformation by lymph node biopsy .
Number of Patients With Grade II-IV Acute Graft-versus-Host-Disease and/or Chronic Extensive Graft-versus-Host-Disease	1 year post-allograft,	aGVHD The diagnosis of aGVHD is identified through various stages and grading of the disease related to Skin (Rash), Gut (Diarrhea, Nausea/vomiting and/or anorexia) and the liver (Bilirubin) assessed by severity and grading scale outlined in the section Grafts vs Hosts by Sullivan (1999). GVHD Grades Grade I: 1-2 Skin Rash; No gut or liver involvement Grade II: Stage 1-3 Skin rash; Stage 1 gut and/or stage 1 liver involvement Grade III: Stage 2-4 gut involvement and/or stage 2-4 liver involvement with or without rash Grade IV: Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death CGVHD The diagnosis of cGVHD requires at least one manifestation that is distinctive for chronic GVHD as opposed to acute GVHD. In all cases, infection and others causes must be ruled out in the differential diagnosis of chronic GVHD.
Non-relapse Mortality (NRM)	200 days and 1 Year post-allograft	Number of patients with non-relapse mortalities.
Number of Patients Who Engrafted	Day 84 post-allograft	Number of patients with donor engraftment.
Number of Patients Who Had Infections	1 Year post-autograft	Number of patients who had infections.
Overall Survival	1 year post-autograft	Number of patients surviving one year post-autograft

Trial Locations

Locations (2): Fred Hutch/University of Washington Cancer Consortium
🇺🇸
Seattle, Washington, United States
Froedtert and the Medical College of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States