Rasburicase in Preventing Graft-Versus-Host Disease in Patients With Hematologic Cancer or Other Disease Undergoing Donor Stem Cell Transplant

Rasburicase to Prevent Graft -Versus-Host Disease

RATIONALE: Rasburicase may be an effective treatment for graft-versus-host disease caused by a donor stem cell transplant.

PURPOSE: This clinical trial is studying how well rasburicase works in preventing graft-versus-host disease in patients with hematologic cancer or other disease undergoing donor stem cell transplant.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Myelodysplastic Syndromes; Leukemia; Chronic Myeloproliferative Disorders; Multiple Myeloma and Plasma Cell Neoplasm; Graft Versus Host Disease; Myelodysplastic/Myeloproliferative Neoplasms
• Intervention / Treatment: Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Drug: busulfan; Drug: cyclophosphamide; Drug: cyclosporin-A; Drug: etoposide; Drug: methotrexate; Drug: rasburicase; Drug: sirolimus; Drug: tacrolimus; Radiation: total-body irradiation; Drug: fludarabine; Drug: allopurinol

Detailed Description

OBJECTIVES:

Primary

• To evaluate the incidence and severity of acute graft-vs-host disease (GVHD) in rasburicase-treated patients who will undergo myeloablative human leukocyte antigen (HLA)-matched related or unrelated donor allogeneic peripheral blood hematopoietic stem cell transplantation (SCT) for hematologic malignancies and compare these outcomes with those of historical controls.

Secondary

• To evaluate the efficacy (in terms of reduction of uric acid levels) and safety of rasburicase in patients undergoing myeloablative allogeneic SCT.
• To evaluate the graft-versus-host and host-versus-graft immune responses in rasburicase-treated patients.

OUTLINE: This is a multicenter study.

Patients receive a conventional myeloablative conditioning regimen consisting of high doses of cyclophosphamide, busulfan, and etoposide, with or without total-body irradiation. Depending on the preparative regimen selected, the conditioning of recipients will take a total of 6 to 7 days. On day 0, patients will receive filgrastim (G-CSF)-mobilized HLA-matched, related, or unrelated donor allogeneic peripheral blood stem cells (unmanipulated). Patients will receive standard graft-vs-host disease prophylaxis consisting of cyclosporine or tacrolimus and methotrexate or sirolimus. Patients will receive rasburicase IV over 30 minutes, beginning on the first day of conditioning therapy, for 5 consecutive days. If after 5 days of rasburicase the patient's uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total.

Blood is obtained on day 0 and then at 14, 28, and 42 days post-transplant for immunologic studies, including quantitative analysis to follow the recovery of T cells, B cells, natural killer cells, dendritic cells (DC), and monocytes using flow cytometry (FCM); phenotypic analysis of T cells, DC and monocytes by FCM; lymphocyte activation analysis: CD3, CD4, CD8, CD25 2. CD3, CD8, CD71, CD69; DC analysis: CD45, CD14, DR, CD86, CD80 2. CD45, CD14, CD40, CD11c; and in vitro functional studies such as mixed lymphocyte reaction (MLR) and cell-mediated lysis (CML) to assess for the graft-versus-host and host-versus-graft responses. Peripheral blood is collected for chimerism studies on days 28 and 100 post-transplant.

After completion of study treatment, patients are followed periodically.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114-2617
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Patients with hematologic malignancies for whom conventional myeloablative allogeneic stem cell transplantation is deemed clinically appropriate and who are eligible for conventional myeloablative allogeneic stem cell transplantation on treatment plans/protocols, including any of the following:

  • Non-Hodgkin lymphoma or Hodgkin lymphoma (relapsed or refractory disease)
  • Chronic lymphocytic leukemia (received more than one previous treatment regimen)
  • Acute myelogenous or lymphoblastic leukemia (AML/ALL) (high-risk disease, in first complete remission [CR1] or subsequent remission, or primary refractory disease)
  • Chronic myelogenous leukemia in tyrosine-kinase resistant chronic phase, accelerated or blast phase, or primary refractory disease
  • Myelodysplastic syndromes in International Prognostic Scoring System (IPSS) high-intermediate or high-risk groups
  • Other hematologic disorders for which allogeneic stem cell transplantation is appropriate (e.g., myelofibrosis)
• Patients who have relapsed after standard autologous and/or allogeneic bone marrow transplant are eligible

• Must be receiving filgrastim (G-CSF)-mobilized related or unrelated donor allogeneic peripheral blood stem cells

  • Patients receiving hematopoietic stem cells of any other sources such as a marrow graft or umbilical cord blood will not be eligible for this study
• Donor must be HLA-genotypically or phenotypically 6 of 6 antigen matched (at the A, B, DR loci) related or unrelated

PATIENT CHARACTERISTICS:

Inclusion criteria:

• Patients with a "currently active" second malignancy other than non-melanoma skin cancers can only be registered if survival from the second malignancy is expected to be more than 1 year
• Ejection fraction ≥ 45% by either radioisotope Multiple Gated Acquisition Scan (MUGA) scan or Echocardiogram (ECHO)
• Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) ≥ 50% of predicted with no symptomatic pulmonary disease
• Mini Mental Status Exam Score ≥ 20
• Patients must have an expected life expectancy of at least 3 months

• Patients with symptomatic visceral, blood stream or nervous system opportunistic infection are eligible if the infection has been appropriately treated and controlled

  • Patients with a fungal infection must have had treatment for at least one month and must have proof of regression of the infection prior to enrollment
  • Patients may be on antibiotics at the time of transplant

Exclusion criteria:

• Human Immunodeficiency Virus (HIV) infection
• Uncontrolled diabetes mellitus

• Active congestive heart failure from any cause

  • Previous history of congestive heart failure allowed
• Active angina pectoris
• Oxygen-dependent obstructive pulmonary disease
• Failure to demonstrate adequate compliance with medical therapy and follow-up
• Known history of Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency or history of hemolysis indicative of G6PD deficiency

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rasburicase Group; Myeloablative (bone marrow depletion) conditioning protocol as per standard of care at the investigator's discretion followed by granulocyte colony-stimulating factor (GCSF)-mobilized human leukocyte antigen (HLA)-matched, related or unrelated donor allogeneic peripheral blood stem cells (unmanipulated), standard graft-versus-host disease (GVHD) prophylaxis as per standard of care at the investigator's discretion and rasburicase 0.20 mg/kg/day administered by intravenous infusion for 5 consecutive days. If after 5 days of rasburicase the participant's uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total.	Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Drug: busulfan; Busulfan 3.2 mg/kg/day from day -7 to day -4 as standard of care for myeloablative (bone marrow depletion) conditioning at the investigator's discretion; Drug: cyclophosphamide; Cyclophosphamide as standard of care for myeloablative conditioning at the investigator's discretion; Drug: cyclosporin-A; Cyclosporin-A as standard of care for GVHD prophylaxis at the investigator's discretion; Drug: etoposide; Etoposide as standard of care for myeloablative conditioning at the investigator's discretion; Drug: methotrexate; Methotrexate 1.5 mg/kg/day on days -3, -2, and -1 as standard of care for GVHD prophylaxis at the investigator's discretion; Drug: rasburicase; Rasburicase 0.20 mg/kg intravenous infusion over 30 minutes for 5 to 7 days; Drug: sirolimus; Sirolimus as standard of care for GVHD prophylaxis at the investigator's discretion; Drug: tacrolimus; Tacrolimus as standard of care for GVHD prophylaxis at the investigator's discretion; Radiation: total-body irradiation; Total body irradiation 13.2 Gy over 8 fractions from day -7 to day - 4 for myeloablative conditioning at the investigator's discretion; Drug: fludarabine; Fludarabine 40 mg/m^2/day from day -6 to day -3 as myeloablative conditioning at the investigator's discretion
Other: Control Group; Historical chart review of patients from the Blood and Marrow Transplant database who received myeloablative allogeneic stem cell/bone marrow transplantation followed by standard GVHD prophylaxis in the past 10 years. Participants received allopurinol per institutional guidelines.	Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Drug: busulfan; Busulfan 3.2 mg/kg/day from day -7 to day -4 as standard of care for myeloablative (bone marrow depletion) conditioning at the investigator's discretion; Drug: cyclophosphamide; Cyclophosphamide as standard of care for myeloablative conditioning at the investigator's discretion; Drug: cyclosporin-A; Cyclosporin-A as standard of care for GVHD prophylaxis at the investigator's discretion; Drug: etoposide; Etoposide as standard of care for myeloablative conditioning at the investigator's discretion; Drug: methotrexate; Methotrexate 1.5 mg/kg/day on days -3, -2, and -1 as standard of care for GVHD prophylaxis at the investigator's discretion; Drug: sirolimus; Sirolimus as standard of care for GVHD prophylaxis at the investigator's discretion; Drug: tacrolimus; Tacrolimus as standard of care for GVHD prophylaxis at the investigator's discretion; Radiation: total-body irradiation; Total body irradiation 13.2 Gy over 8 fractions from day -7 to day - 4 for myeloablative conditioning at the investigator's discretion; Drug: fludarabine; Fludarabine 40 mg/m^2/day from day -6 to day -3 as myeloablative conditioning at the investigator's discretion; Drug: allopurinol; Allopurinol per institutional guidelines

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Grades II to IV Acute Graft-Versus-Host Disease (aGVHD)	aGVHD severity was determined using International Bone Marrow Transplant Registry (IBMTR) scale stage and grade of the skin, liver and gut. Stage 1: Skin=maculopapular rash <25% of body surface; Liver=Bilirubin 2-3 mg/dL and Gut=500-999 mL diarrhea/day or peristent nausea with histologic evidence of GvHD. Stage 2: Skin=maculopapular rash 25-50% of body surface; Liver=Bilirubin 3.1-6 mg/dL and Gut=1000-1499 mL diarrhea/day. Stage 3: Skin=maculopapular rash >50% of body surface; Liver=Bilirubin 6.1-15 mg/dL and Gut=≥1500 mL diarrhea/day. Stage 4: Skin=generalized erythroderma with bulla formation; Liver=Bilirubin >15 mg/dL and Gut=severe abdominal pain. Grade 1: Stage 1-2 rash; no liver or gut involvement. Grade II: Stage 3 rash, or stage 1 liver involvement, or stage 1 gut involvement. Grade III: None to stage 3 skin rash with stage 2-3 liver, or stage 2-4 gut involvement. Grade IV: Stage 4 skin rash, or stage 4 liver involvement.	Up to 71 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Uric Acid Levels	Blood was collected and analyzed at a laboratory for serum uric acid levels reported in milligrams(mg)/deciliter(dL). Data is presented for those participants who experienced Grade II to IV aGVHD and those participants who did not experience Grade II to IV aGVHD at pre-transplant and post-transplant.	Pre-transplant Day -7 to Day -1 and Post-transplant Day 0 to Day 6
Number of Participant With Adverse Events (AE)	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.	Up to 71 months
Graft-versus-host and Host-versus-graft Immune Responses	Laboratory tests such as limited dilution assay (LDA) were to be performed to assess graft-versus-host and host-versus-graft immune responses.	Days -2, 0, and Days 14, 21 and 35 days post-transplant

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Investigators: Principal Investigator: Bimalangshu R. Dey, MD, PhD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Yeh AC, Brunner AM, Spitzer TR, Chen YB, Coughlin E, McAfee S, Ballen K, Attar E, Caron M, Preffer FI, Yeap BY, Dey BR. Phase I study of urate oxidase in the reduction of acute graft-versus-host disease after myeloablative allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014 May;20(5):730-4. doi: 10.1016/j.bbmt.2014.02.003. Epub 2014 Feb 12.

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): February 12, 2013
• Study Completion (Actual): February 12, 2013

Study Registration Dates

• First Submitted: August 6, 2007
• First Submitted That Met QC Criteria: August 6, 2007
• First Posted (Estimate): August 8, 2007

Study Record Updates

• Last Update Posted (Actual): May 25, 2017
• Last Update Submitted That Met QC Criteria: April 20, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: primary myelofibrosis; recurrent grade 3 follicular lymphoma; recurrent adult diffuse large cell lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult Burkitt lymphoma; chronic myelomonocytic leukemia; de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); secondary acute myeloid leukemia; chronic phase chronic myelogenous leukemia; recurrent adult acute myeloid leukemia; recurrent adult Hodgkin lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent adult diffuse mixed cell lymphoma; blastic phase chronic myelogenous leukemia; relapsing chronic myelogenous leukemia; recurrent grade 1 follicular lymphoma; recurrent grade 2 follicular lymphoma; recurrent marginal zone lymphoma; recurrent small lymphocytic lymphoma; extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue; nodal marginal zone B-cell lymphoma; splenic marginal zone lymphoma; recurrent adult lymphoblastic lymphoma; recurrent mantle cell lymphoma; refractory chronic lymphocytic leukemia; recurrent cutaneous T-cell non-Hodgkin lymphoma; recurrent adult T-cell leukemia/lymphoma; angioimmunoblastic T-cell lymphoma; anaplastic large cell lymphoma; recurrent mycosis fungoides/Sezary syndrome; refractory multiple myeloma; recurrent adult acute lymphoblastic leukemia; refractory hairy cell leukemia; Waldenström macroglobulinemia; accelerated phase chronic myelogenous leukemia; myelodysplastic/myeloproliferative neoplasm, unclassifiable; chronic eosinophilic leukemia; atypical chronic myeloid leukemia, BCR-ABL1 negative; graft versus host disease
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Precancerous Conditions; Neoplasms; Lymphoma; Syndrome; Myelodysplastic Syndromes; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia; Preleukemia; Plasmacytoma; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Reproductive Control Agents; Antioxidants; Free Radical Scavengers; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Gout Suppressants; Calcineurin Inhibitors; Cyclophosphamide; Etoposide; Fludarabine; Methotrexate; Tacrolimus; Sirolimus; Busulfan; Rasburicase; Allopurinol; Cyclosporine; Cyclosporins
• Other Study ID Numbers: CDR0000558480; MGH-07-071; DFCI-07-071