Fludarabine and Cyclophosphamide in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Chronic Lymphocytic Leukemia or Waldenstrom's Macroglobulinemia

NCT00281983 | Completed Phase 1

• 3 other identifiers: CLL3XEU-20554MEDAC-FLUD.10/CLL
• Study Type: interventional
• Target: 100
• Locations: 2 countries
• Sites: 13

Brief Summary

RATIONALE: Giving chemotherapy before a donor bone marrow transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. Also, monoclonal antibodies, such as alemtuzumab, can find cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving methotrexate, cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them (called graft-versus-tumor effect). Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) may boost this effect. PURPOSE: This phase I/II trial is studying the side effects of giving fludarabine together with cyclophosphamide and to see how well they work in treating patients who are undergoing donor stem cell transplant for B-cell chronic lymphocytic leukemia or Waldenström's macroglobulinemia.

Conditions

Chronic Lymphocytic Leukemia

Keywords

B-cell chronic lymphocytic leukemia; refractory chronic lymphocytic leukemia; stage III chronic lymphocytic leukemia; stage IV chronic lymphocytic leukemia; Waldenström macroglobulinemia

Outcome Measures

Primary Outcomes (2)

• Feasibility as measured by the proportion of eligible patients completing the transplant procedure successfully

• Safety as measured by a treatment-related mortality of < 25% at 2 years following transplant

Secondary Outcomes (4)

• Clinical remission rate by NIH criteria at 12 months following transplant

• Minimal residual disease negativity rate as measured by high-resolution flow or CDR PCR at 12 months following transplant

• Chimerism as measured by STR-PCR at 12 months following transplant

• Event-free and overall survival at 5 years following transplant

Study Arms (1)

Allogeneic stem cell transplantation

EXPERIMENTAL

1. Cytoreductive therapy for inducing a state of partial remission: FC or FC-R or alternative salvage regimens (e.g. Alemtuzumab) 2. Conditioning regimen: FC +/- ATG (Arm A) or FC/Busulfan +/- ATG (Arm C: refractory patients only) 3. allogeneic-PBSCT (from HLA-identical donor) 4. GVHD prophylaxis: CSA + MTX or MMF 5. +/- DLI (Donor lymphocyte infusions)

Biological: alemtuzumab; Biological: anti-thymocyte globulin; Biological: filgrastim; Biological: rituximab; Biological: therapeutic allogeneic lymphocytes; Drug: busulfan; Drug: cyclophosphamide; Drug: cyclosporine; Drug: fludarabine phosphate; Drug: methotrexate; Drug: mycophenolate mofetil; Procedure: peripheral blood stem cell transplantation; Radiation: radiation therapy

Interventions

alemtuzumab BIOLOGICAL

Allogeneic stem cell transplantation

anti-thymocyte globulin BIOLOGICAL

Allogeneic stem cell transplantation

filgrastim BIOLOGICAL

Allogeneic stem cell transplantation

rituximab BIOLOGICAL

Allogeneic stem cell transplantation

therapeutic allogeneic lymphocytes BIOLOGICAL

Allogeneic stem cell transplantation

busulfan DRUG

Allogeneic stem cell transplantation

cyclophosphamide DRUG

Allogeneic stem cell transplantation

cyclosporine DRUG

Allogeneic stem cell transplantation

fludarabine phosphate DRUG

Allogeneic stem cell transplantation

methotrexate DRUG

Allogeneic stem cell transplantation

mycophenolate mofetil DRUG

Allogeneic stem cell transplantation

peripheral blood stem cell transplantation PROCEDURE

Allogeneic stem cell transplantation

radiation therapy RADIATION

Allogeneic stem cell transplantation

Eligibility Criteria

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

DISEASE CHARACTERISTICS: * Diagnosis of B-cell chronic lymphocytic leukemia or lymphoplasmocytic lymphoma (Waldenstrom's macroglobulinemia) * Must have poor prognostic features and low probability of successful autografting, defined by one of the following criteria: * Progressive disease with unfavorable cytogenetics (deletion or mutation of critical regions on chromosomes 11q and/or 17p \[p53\]; and/or unmutated status of the immunoglobulin V\_H gene region; and/or usage of the V\_H 3-21 gene), defined as 1 of the following: * Doubling of lymphocyte count or nodal involvement within 3 months or less * Progressive decline of platelet count and/or hemoglobin values defining Binet stage C disease (or to 50% or less of baseline values within 3 months) not due to immune mechanisms * Symptomatic splenomegaly * Discomfort or imminent complications due to large tumor masses * B symptoms * Refractory disease or early relapse (within 12 months) after treatment with a fludarabine-containing regimen * Relapsed after autologous stem cell transplant (SCT) * Insufficient stem cell harvest for intended autologous SCT * Presence of a clonal CDR III rearrangement detected by polymerase chain reaction * No Richter's syndrome * HLA-identical sibling or unrelated donor available PATIENT CHARACTERISTICS: * ECOG performance status ≤ 1 * Creatinine clearance \> 60 mL/min * SGOT, SGPT, and bilirubin \< 2 times normal * Normal cardiac function determined by ECG and echocardiographic examination * Inspiratory vital capacity, FEV\_1, and DLCO \> 50% of predicted * No serious localized or systemic infections * No other concurrent malignant disease * No impaired organ function * No uncontrolled diabetes * No uncontrolled hypertension * Not pregnant or nursing * Fertile patients must use effective contraception * No HIV infection * No hepatitis B or C infection * No concurrent alcohol or drug abuse * No dementia or altered mental status that would preclude giving informed consent PRIOR CONCURRENT THERAPY: * Not specified

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• German CLL Study Group: lead

Study Sites (13)

Maisonneuve-Rosemont Hospital

Montreal, Quebec, H1T 2M4, Canada

Location

Charite - Universitaetsmedizin Berlin - Campus Benjamin Franklin

Berlin, 12200, Germany

Location

Universitaetsklinikum Essen

Essen, 45122, Germany

Location

Universitaetsklinikum Goettingen

Göttingen, 37075, Germany

Location

Asklepios Klinik St. Georg

Hamburg, D-20099, Germany

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

Universitaets-Kinderklinik Heidelberg

Heidelberg, D-69120, Germany

Location

Universitaetsklinikum des Saarlandes

Homburg, 66421, Germany

Location

Clinic for Bone Marrow Transplantation and Hematology and Oncology

Idar-Oberstein, D-55743, Germany

Location

University Hospital Schleswig-Holstein - Kiel Campus

Kiel, 24116, Germany

Location

University Hospital of Leipzig

Leipzig, 04103, Germany

Location

Klinikum der Universitaet Regensburg

Regensburg, 93053, Germany

Location

Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm

Ulm, 89081, Germany

Location

Related Publications (5)

• Dreger P, Dohner H, Ritgen M, Bottcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. doi: 10.1182/blood-2010-03-275420. Epub 2010 Jul 1.

  PMID: 20595516 RESULT

• Ritgen M, Bottcher S, Stilgenbauer S, Bunjes D, Schubert J, Cohen S, Humpe A, Hallek M, Kneba M, Schmitz N, Dohner H, Dreger P; German CLL Study Group. Quantitative MRD monitoring identifies distinct GVL response patterns after allogeneic stem cell transplantation for chronic lymphocytic leukemia: results from the GCLLSG CLL3X trial. Leukemia. 2008 Jul;22(7):1377-86. doi: 10.1038/leu.2008.96. Epub 2008 Apr 17.

  PMID: 18418404 RESULT

• Dreger P, Schnaiter A, Zenz T, Bottcher S, Rossi M, Paschka P, Buhler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Dohner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. doi: 10.1182/blood-2012-11-469627. Epub 2013 Feb 22.

  PMID: 23435461 RESULT

• Scheffold A, Jebaraj BMC, Jaramillo S, Tausch E, Steinbrecher D, Hahn M, Bottcher S, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Dohner H, Dreger P, Stilgenbauer S. Impact of telomere length on the outcome of allogeneic stem cell transplantation for poor-risk chronic lymphocytic leukaemia: results from the GCLLSG CLL3X trial. Br J Haematol. 2017 Oct;179(2):342-346. doi: 10.1111/bjh.14219. Epub 2016 Jul 8. No abstract available.

  PMID: 27391907 RESULT

• Kramer I, Stilgenbauer S, Dietrich S, Bottcher S, Zeis M, Stadler M, Bittenbring J, Uharek L, Scheid C, Hegenbart U, Ho A, Hallek M, Kneba M, Schmitz N, Dohner H, Dreger P. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 Sep 21;130(12):1477-1480. doi: 10.1182/blood-2017-04-775841. Epub 2017 Jul 17. No abstract available.

  PMID: 28716861 RESULT

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Waldenstrom Macroglobulinemia

Interventions

Alemtuzumab; Antilymphocyte Serum; Filgrastim; Rituximab; Busulfan; Cyclophosphamide; Cyclosporine; fludarabine phosphate; Methotrexate; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Radiotherapy

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; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immune Sera; Biological Products; Complex Mixtures; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors; Antibodies, Monoclonal, Murine-Derived; Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative

Study Officials

• Peter Dreger

  Universitaets-Kinderklinik Heidelberg

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: January 24, 2006
• First Posted: January 25, 2006
• Study Start: June 1, 2000
• Study Completion: July 1, 2010
• Last Updated: July 24, 2017

Record last verified: 2007-04

Data Sharing

• IPD Sharing: Will not share

Locations

DE (12); CA (1)