Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

NCT00104858 | Completed Phase 2 Results DMC

• 4 other identifiers: 1840.00NCI-2009-01594P01CA018029P30CA015704
• Study Type: interventional
• Target: 66
• Locations: 3 countries
• Sites: 5

Brief Summary

This phase II trial studies how well fludarabine phosphate with radiation therapy and rituximab followed by donor stem cell infusions work in treating patients with high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with low side effects. Nonmyeloablative stem cell transplants use low doses of chemotherapy (fludarabine phosphate) and radiation to suppress the patient's immune system enough to prevent rejection of the donor's stem cells. Following infusion of donor stem cells, a mixture of the patient's and the donor's stem cells will exist and is called "mixed chimerism". Donor cells will attack the patient's leukemia. This is called the "graft-versus-leukemia" effect. Rituximab will be given 3 days before and three times after infusing stem cells to help in controlling CLL early after transplant till the "graft-versus-leukemia" takes control. Further, rituximab could augment the "graft-versus-leukemia" effect by activating donor immune cells and hence improve disease control. Sometimes the transplanted cells from a donor can also attack the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

Conditions

Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma; T-Cell Large Granular Lymphocyte Leukemia

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  Number of participants surviving post-transplant

  At 18 months

Secondary Outcomes (9)

• Comparison of Survival, Serious Adverse Events, and B-cell and T-cell Immune Reconstitution With Historical Data

  At 18 months

• Number of Participants With Relapse/Progression

  Day 84

• Graft-versus-leukemia Analysis by Mechanism of Disease Resistance in Relapsed or Non-responding Patients and Isolation of Donor Cytotoxic T Lymphocytes Specific for Host Minor Histocompatibility Antigens

  Day 84

• Number of Participants With Grade II-III and III-IV Acute GVHD and Chronic GVHD

  Up to 1 year

• Number of Participants With Regimen-related Toxicity and Infections

  Within the first 100 days

Study Arms (1)

Treatment

EXPERIMENTAL

Patients receive a conditioning regimen comprising fludarabine IV on days -4 to -2 and rituximab IV on days -3, 10, 24, and 38. Patients undergo single fraction low-dose TBI on day 0. After completion of TBI, patients undergo allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive rituximab IV on days 10, 24, and 38. Patients receive an immunosuppressive regimen comprising cyclosporine PO BID on days -3 to 56 followed by a taper to day 180 (related recipients) or on days -3 to 100 followed by a taper to day 180 (unrelated recipients). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related recipients) or TID on days 0-40 followed by a taper to day 96 (unrelated recipients).

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cyclosporine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Pharmacological Study; Biological: Rituximab; Radiation: Total-Body Irradiation

Interventions

Allogeneic Hematopoietic Stem Cell Transplantation PROCEDURE

Undergo HSCT

Also known as: allogeneic stem cell transplantation, HSC, HSCT

Treatment

Cyclosporine DRUG

Given PO

Also known as: 27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCya

Treatment

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Oforta, SH T 586

Treatment

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment

Mycophenolate Mofetil DRUG

Given PO

Also known as: Cellcept, MMF

Treatment

Peripheral Blood Stem Cell Transplantation PROCEDURE

Undergo HSCT

Also known as: PBPC transplantation, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplantation

Treatment

Pharmacological Study OTHER

Correlative studies

Treatment

Rituximab BIOLOGICAL

Given IV

Also known as: BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar BI 695500, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, RTXM83

Treatment

Total-Body Irradiation RADIATION

Undergo TBI

Also known as: TOTAL BODY IRRADIATION, Whole-Body Irradiation

Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with a diagnosis of CLL (or SLL) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL)
• Patients with B-Cell CLL or PLL who:
• Failed to meet National Cancer Institute (NCI) Working Group criteria 2 for complete or partial response after 2 cycles of therapy with regimen containing fludarabine (or another nucleoside analog, e.g. cladribine \[2-CDA\], pentostatin) or with disease relapse within 12 months after completing therapy with a fludarabine (or another nucleoside analog) containing regimen
• Failed FCR or pentostatin/cyclophosphamide/rituximab (PCR) combination chemotherapy at any time point
• Patients with novo or acquired "17p deletion" cytogenetic abnormality; patients should have received induction treatment but could be transplanted in 1st CR
• Patients who have suitable human leukocyte antigen (HLA)-matched related or unrelated donors willing to receive filgrastim (G-CSF), undergo leukapheresis to collect peripheral blood mononuclear cell (PBMC), and to donate stem cells
• RELATED DONORS: When more than one potential donor exists, priority should be given to donors based on HLA identity \> cytomegalovirus (CMV) seronegativity \> ABO compatibility \> sex matching
• Donor who is HLA phenotypically or genotypically identical at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1
• Must consent to G-CSF administration and leukapheresis;
• Must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian);
• Only G-CSF mobilized PBMC only will be permitted as a hematopoietic stem cell (HSC) source on this protocol
• UNRELATED DONORS:
• 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

You may not qualify if:

• Infection with human immunodeficiency virus (HIV)
• Active diagnosis of central nervous system (CNS) involvement with CLL
• Patients unwilling to use contraceptive techniques before and for 12 months after HCT
• Pregnant women or females who are breastfeeding
• The addition of cytotoxic agents for 'cytoreduction' with the exception of tyrosine kinase inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the initiation of conditioning
• Active bacterial or fungal infections unresponsive to medical therapy
• Performance status: Karnofsky score \< 60 for adult patients
• Cardiac ejection fraction \< 40%; ejection fraction is required if age \> 50 years or there is a history of prior transplant, anthracycline exposure or history of cardiac disease; and poorly controlled hypertension despite multiple antihypertensives
• Diffusing capacity of the lung for carbon monoxide (DLCO) \< 40%, total lung capacity (TLC) \< 40%, forced expiratory volume in 1 second (FEV1) \< 40% and/or requiring continuous supplementary oxygen, or severe deficits in pulmonary function testing as defined by pulmonary consultant service; and the FHCRC principal investigator (PI) of the study must approve of enrollment of all patients with pulmonary nodules
• Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, hepatic damage with bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices or hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evidenced 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, or symptomatic biliary disease
• DONOR: Age \< 12 years
• DONOR: Identical twin
• DONOR: Pregnancy
• DONOR: Infection with HIV
• DONOR: Inability to achieve adequate venous access

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (5)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

VA Puget Sound Health Care System

Seattle, Washington, 98101, United States

Location

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Rigshospitalet University Hospital

Copenhagen, 2100, Denmark

Location

University of Torino

Torino, 10126, Italy

Location

Related Publications (1)

• Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, Shizuru J, Franke GN, Maris MB, Boyer M, Bruno B, Sahebi F, Langston AA, Hari P, Agura ED, Lykke Petersen S, Maziarz RT, Bethge W, Asch J, Gutman JA, Olesen G, Yeager AM, Hubel K, Hogan WJ, Maloney DG, Mielcarek M, Martin PJ, Flowers MED, Georges GE, Woolfrey AE, Deeg JH, Scott BL, McDonald GB, Storb R, Sandmaier BM. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2021 Jun 1;106(6):1599-1607. doi: 10.3324/haematol.2020.248187.

  PMID: 32499241 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic; Leukemia, Large Granular Lymphocytic

Interventions

Cyclosporine; Cyclosporins; fludarabine phosphate; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Rituximab; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, T-Cell

Intervention Hierarchy (Ancestors)

Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Radiotherapy; Investigative Techniques

Results Point of Contact

• Title: Dr. Mohamed Sorror
• Organization: Fred Hutchinson Cancer Research Center

msorror@fredhutch.org

206-667-6298

Study Officials

• Mohamed Sorror

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 3, 2005
• First Posted: March 4, 2005
• Study Start: December 1, 2004
• Primary Completion: March 30, 2018
• Study Completion: March 30, 2018
• Last Updated: July 11, 2019
• Results First Posted: July 11, 2019

Record last verified: 2019-06

Locations

DK (1); US (3); IT (1)