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

Chronic Lymphocytic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00060424
• Other study ID #: 1711.00
• Secondary ID: NCI-2010-01276NC
• Status: Completed
• Phase: Phase 2
• First received: May 6, 2003
• Last updated: December 5, 2017
• Start date: March 2003
• Est. completion date: September 22, 2010

Study information

• Verified date: December 2017
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: September 22, 2010
• Est. primary completion date: September 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

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

Related Conditions & MeSH terms

• B-Cell Prolymphocytic Leukemia
• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Leukemia, Prolymphocytic
• Leukemia, Prolymphocytic, B-Cell
• Leukemia, Prolymphocytic, T-Cell
• Prolymphocytic Leukemia
• Recurrent Chronic Lymphocytic Leukemia
• Recurrent Small Lymphocytic Lymphoma
• Refractory Chronic Lymphocytic Leukemia
• T-Cell Prolymphocytic Leukemia

Intervention

Drug:
• Cyclosporine
Given PO
• Fludarabine Phosphate
Given IV

Procedure:
• Hematopoietic Cell Transplantation
Undergo allogeneic peripheral blood stem cell transplant

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Mycophenolate Mofetil
Given PO

Procedure:
• Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic peripheral blood stem cell transplant

Radiation:
• Total-Body Irradiation
Undergo TBI

Locations

Country	Name	City	State
Italy	University of Torino	Torino
United States	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington
United States	Veterans Administration Center-Seattle	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Research Center	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	Number of patients surviving 18 months post-transplant.	At 18 months
Secondary	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
Secondary	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.
Secondary	Rate and Types of Infections	Number of infections patients experienced, by infection type.	18 months
Secondary	Transplant-related Mortality	Defined as death before day +200 not related to progression of disease.	At 200 days