Busulfan, Cyclophosphamide, & Antithymocyte Globulin Followed by Stem Cell Transplant in Treating Hematologic Cancer

Phase 2

Completed

• Conditions: Leukemia; Graft Versus Host Disease; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Secondary Myelofibrosis
• Interventions: Biological: anti-thymocyte globulin; Drug: busulfan; Drug: cyclophosphamide; Drug: mycophenolate mofetil; Drug: tacrolimus; Genetic: polymerase chain reaction; Genetic: polymorphism analysis; Other: flow cytometry; Other: laboratory biomarker analysis; Other: pharmacogenomic studies; Other: pharmacological study; Procedure: allogeneic bone marrow transplantation; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation

• Registration Number: NCT00611351
• Lead Sponsor: University of Nebraska

Brief Summary

RATIONALE: Giving chemotherapy before a donor bone marrow transplant or peripheral stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When certain 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 tacrolimus and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving busulfan together with cyclophosphamide and antithymocyte globulin followed by donor stem cell transplant works in treating patients with hematologic cancer.

Detailed Description

OBJECTIVES:

Primary

* To determine the incidence of grade II-IV acute graft-versus-host disease in patients with hematologic cancer or other diseases treated with a myeloablative conditioning regimen comprising targeted (steady-state concentration of 800-1,000 ng/mL) busulfan, cyclophosphamide, and anti-thymocyte globulin followed by matched unrelated donor allogeneic hematopoietic stem cell transplantation.

* To determine the day +100 transplantation-related mortality in these patients.

Secondary

* To determine the effect of cyclophosphamide pharmacokinetic parameters on day +100 transplantation-related mortality in these patients.

* To determine the ability of low-dose anti-thymocyte globulin administered on day +5 to induce activation-induced cell death of activated donor lymphocytes.

* To determine the incidence of chronic graft-versus-host disease in patients treated with this regimen.

* To determine event-free and overall survival of patients treated with this regimen.

* To evaluate pharmacogenomic associations between genetic polymorphisms in drug disposition enzymes with the pharmacokinetics of busulfan and cyclophosphamide.

OUTLINE:

* Myeloablative conditioning regimen: Patients receive busulfan IV over 2 hours on days -8 to -5; cyclophosphamide IV over 4 hours on days -3 to -2; and anti-thymocyte globulin IV over 6 hours on day -3 and then over 4 hours on days -2, -1, and 5.

* Allogeneic hematopoietic stem cell transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell infusion on day 0.

* Graft-versus-host-disease prophylaxis: Patients receive tacrolimus IV continuously or orally on days 6 to150, followed by an even taper to day 180 in the absence of graft-versus-host-disease. Patients also receive mycophenolate mofetil IV or orally beginning on day 6 and continuing to day 28.

Patients undergo blood collection periodically during study for pharmacokinetic, pharmacogenomic, and other translational studies. Genomic DNA extracted from blood samples is analyzed by polymerase chain reaction for genetic polymorphisms in cyclophosphamide/busulfan disposition enzymes. Activated donor lymphocytes are assessed using flow cytometry to measure activation-induced cell death, as reflected by apoptosis in activated T cells. Chimerism on or around day 100 is also assessed using fluorescence in situ hybridization analysis and DNA fingerprinting.

After completion of study treatment, patients are followed periodically.

Study Timeline

• Study Start: 2005-06-07
• Primary Completion: 2008-02-01
• Study First Submitted: 2008-02-07
• Study First Submitted QC: 2008-02-07
• Study First Posted: 2008-02-08
• Study Completion: 2008-09-17
• Results First Submitted: 2018-03-05
• Results First Submitted QC: 2018-03-05
• Results First Posted: 2018-04-03
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-05
• Last Update Posted: 2023-10-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 5

Inclusion Criteria

• Pathologically confirmed diagnosis of 1 of the following:

  • Acute myeloid leukemia
  • Acute lymphocytic leukemia
  • Chronic myelogenous leukemia beyond first chronic phase (i.e., 2nd chronic phase, accelerated phase, or blast crisis)
  • Multiple myeloma
  • Myelodysplastic syndromes
  • Malignant lymphoma
  • Myelofibrosis

• Requirement for myeloablative conditioning regimen confirmed by attending physician

• Available donor must meet the following criteria:

  • HLA phenotypically identical unrelated donor by low, intermediate, or high resolution for HLA class I antigens, and by high resolution for HLA class II antigens
  • Matched at the A, B, and DRβ1 loci
  • Single HLA-A or HLA-B antigen mismatch allowed
  • Meets all National Marrow Donor Program or foreign registry criteria for allogeneic bone marrow/stem cell donors
  • Peripheral blood stem cells are the preferred product on this study but bone marrow is allowed

• Karnofsky performance status 70-100%

• DLCO ≥ 50% predicted

• LVEF ≥ 45%

• Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 65 mL/min

• Serum total bilirubin ≤ 2.0 mg/dL

• Fertile patients must use effective contraception

Exclusion Criteria

• No active uncontrolled infection
• Not pregnant or nursing/negative pregnancy test
• No HIV infection
• No chronic active hepatitis B or C or evidence of cirrhosis on liver biopsy

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Unrelated Donor Allogeneic	anti-thymocyte globulin	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	polymerase chain reaction	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	polymorphism analysis	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	flow cytometry	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	laboratory biomarker analysis	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	pharmacogenomic studies	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	pharmacological study	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	allogeneic bone marrow transplantation	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	allogeneic hematopoietic stem cell transplantation	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	peripheral blood stem cell transplantation	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	busulfan	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	cyclophosphamide	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	mycophenolate mofetil	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Unrelated Donor Allogeneic	tacrolimus	Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.

Primary Outcome Measures

Name	Time	Method
Transplantation-related Mortality at 100 Days Post-transplantation	at the 100 days post-transplant

Secondary Outcome Measures

Name	Time	Method
Overall Survival	2 years post transplant
Event-free Survival	2 years post transplant
Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD)	at day 100 post transplantation

Trial Locations

Locations (1)

Unversity of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States