Fludarabine Phosphate and Total-Body Irradiation Before Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia

Allogeneic Hematopoietic Stem Cell Transplantation With Nonmyeloablative Conditioning for Patients With Chronic Lymphocytic Leukemia - A Multi-center Trial

This clinical trial studies how well giving fludarabine phosphate together with total-body irradiation (TBI) before donor peripheral blood stem cell transplant works in treating patients with chronic lymphocytic leukemia or small lymphocytic leukemia. Giving low doses of chemotherapy, such as fludarabine phosphate, and TBI before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. Giving chemotherapy before or after peripheral blood stem cell transplant also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil before and after the transplant may stop this from happening.

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Prolymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia; B-Cell Prolymphocytic Leukemia
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Radiation: Total-Body Irradiation; Drug: Fludarabine Phosphate; Drug: Cyclosporine; Procedure: Hematopoietic Cell Transplantation; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Detailed Description

PRIMARY OBJECTIVES:

I. To determine whether nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) from matched-related donors can improve the probability of survival 18 months after treatment for fludarabine (fludarabine phosphate)-refractory, fludarabine phosphate, cyclophosphamide, and rituximab (FCR)-failed, or del 17p chronic lymphocytic leukemia (CLL) beyond that observed in historical controls (30%).

SECONDARY OBJECTIVES:

I. To assess the rate of relapse with allogeneic HSCT using nonmyeloablative conditioning for patients with fludarabine-refractory, FCR-failed, or del 17p CLL compared with historical data on autologous HSCT.

II. To estimate the incidence of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD in patients with CLL treated with low-dose TBI, fludarabine, peripheral blood stem cell (PBSC) infusion and immunosuppression with cyclosporine and mycophenolate mofetil.

III. To characterize the rate and types of infections with this regimen.

IV. To estimate the rate of transplant-related mortality in the first 200 days.

OUTLINE:

NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and TBI on day 0.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant on day 0.

GVHD PROPHYLAXIS: Patients receive cyclosporine orally (PO) every 12 hours on days -3 to 180 with taper beginning on day 56 and mycophenolate mofetil PO every 12 hours on days 0-27.

After completion of study treatment, patients are followed up at 12 and 18 months and then annually for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Torino, Italy, 10126
    • University of Torino
• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
    • Seattle, Washington, United States, 98108
      • Veterans Administration Center-Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with CLL (or small lymphocytic lymphoma) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or PLL
• Patients with B-Cell CLL or PLL who have at least one of the following:
• 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. cladribine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing fludarabine (or another nucleoside analog)
• Failed FCR combination chemotherapy at any time point
• Had de novo of acquired "17p deletion" cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in first (1st) complete response (CR)
• Patient has a suitable human leukocyte antigen (HLA)-matched related donor who is willing to undergo leukapheresis initially for collection of PBSC and subsequently for collection of peripheral blood mononuclear cells (PBMC) with filgrastim (G-CSF) mobilization and willing to donate stem cells
• DONOR: Related donor who is HLA phenotypically or genotypically identical at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1
• DONOR: Donor must consent to G-CSF administration and leukapheresis
• DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian)

Exclusion Criteria:

• Infection with human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV)-1, or HTLV-2
• Active central nervous system (CNS) involvement with CLL
• Patients with active non-hematologic malignancies (except non-melanoma skin cancers)
• 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
• Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
• Pregnant or breastfeeding women
• Karnofsky score =< 70
• Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
• Cytotoxic agents for "cytoreduction" (with the exception of imatinib mesylate [Gleevec], cytokine therapy, hydroxyurea, chlorambucil or Rituxan) within three weeks of the initiation of conditioning
• Active bacterial or fungal infections unresponsive to medical therapy
• Cardiovascular: cardiac ejection fraction < 40%; patients with poorly controlled hypertension despite multiple antihypertensives
• Pulmonary: diffusing capacity of carbon monoxide (DLCO) < 40%, total lung capacity (TLC) < 40%, forced expiratory volume in one second (FEV1) < 40% and/or requiring continuous supplementary oxygen, or severe deficits in pulmonary function testing as defined by pulmonary consultant service
• Liver function abnormalities: 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, bridging fibrosis, 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, 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 > 3mg/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
• DONOR: Known allergy to filgrastim (G-CSF)
• DONOR: Current serious systemic illness

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Treatment (enzyme inhibitor, transplant, GVHD prophylaxis); NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and TBI on day 0. TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant on day 0. GVHD PROPHYLAXIS: Patients receive cyclosporine PO every 12 hours on days -3 to 180 with taper on day 56 and mycophenolate mofetil PO every 12 hours on days 0-27.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Mycophenolate Mofetil; Given PO; Other Names: Cellcept; MMF; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Whole-Body Irradiation; TOTAL BODY IRRADIATION; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; Oforta; SH T 586; Drug: Cyclosporine; Given PO; Other Names: 27-400; Sandimmune; Ciclosporin; CsA; Neoral; Sandimmun; Cyclosporin; Cyclosporin A; OL 27-400; SangCya; Procedure: Hematopoietic Cell Transplantation; Undergo allogeneic peripheral blood stem cell transplant; Other Names: HSCT; HCT; Hematopoietic Stem Cell Transplantation; stem cell transplantation; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic peripheral blood stem cell transplant; Other Names: NST; Non-myeloablative allogeneic transplant; Nonmyeloablative Stem Cell Transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Number of patients surviving 18 months post-transplant.	At 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Relapse	Number of patients with relapsed disease post-transplant. Relapse/progression is defined as 1) Physical exam/Imaging studies (nodes, liver, and/or spleen) ≥50% increase or new, 2) circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, or 3) lymph node Biopsy Richter's transformation.	18 months
Acute Grade II-IV GVHD and Chronic (Extensive) GVHD	Number of patients who developed acute/chronic GVHD post-transplant. aGVHD Stages Skin: a maculopapular eruption involving < 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma with bullous formation and often with desquamation Liver: bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL bilirubin > 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 3 skin and/or stage 1 gut involvement and/or stage 1 liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death	aGVHD: 100 days after transplant; cGVHD: 1 Year after transplant.
Rate and Types of Infections	Number of infections patients experienced, by infection type.	18 months
Transplant-related Mortality	Defined as death before day +200 not related to progression of disease.	At 200 days

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2003
• Primary Completion (ACTUAL): September 1, 2010
• Study Completion (ACTUAL): September 22, 2010

Study Registration Dates

• First Submitted: May 6, 2003
• First Submitted That Met QC Criteria: May 6, 2003
• First Posted (ESTIMATE): May 7, 2003

Study Record Updates

• Last Update Posted (ACTUAL): December 8, 2017
• Last Update Submitted That Met QC Criteria: December 5, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, B-Cell; Leukemia, T-Cell; Leukemia; Recurrence; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, T-Cell; Leukemia, Prolymphocytic, B-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Fludarabine; Fludarabine phosphate; Mycophenolic Acid; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 1711.00 (OTHER: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); NCI-2010-01276 (REGISTRY: CTRP (Clinical Trial Reporting Program)); NCI-2011-01116