Chronic Myeloproliferative Disorders, Graft Versus Host Disease, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms
Conditions
Keywords
graft versus host disease, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult Hodgkin lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent adult T-cell leukemia/lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent mycosis fungoides/Sezary syndrome, recurrent small lymphocytic lymphoma, splenic marginal zone lymphoma, Waldenström macroglobulinemia, recurrent adult acute lymphoblastic leukemia, refractory chronic lymphocytic leukemia, recurrent adult acute myeloid leukemia, 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), accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, previously treated myelodysplastic syndromes, primary myelofibrosis, atypical chronic myeloid leukemia, BCR-ABL1 negative, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, de novo myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasm, unclassifiable, refractory hairy cell leukemia, refractory multiple myeloma, secondary acute myeloid leukemia, secondary myelodysplastic syndromes
Brief summary
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.
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.
Interventions
DRUGbusulfan
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
DRUGcyclophosphamide
Cyclophosphamide as standard of care for myeloablative conditioning at the investigator's discretion
DRUGcyclosporin-A
Cyclosporin-A as standard of care for GVHD prophylaxis at the investigator's discretion
DRUGetoposide
Etoposide as standard of care for myeloablative conditioning at the investigator's discretion
DRUGmethotrexate
Methotrexate 1.5 mg/kg/day on days -3, -2, and -1 as standard of care for GVHD prophylaxis at the investigator's discretion
DRUGrasburicase
Rasburicase 0.20 mg/kg intravenous infusion over 30 minutes for 5 to 7 days
DRUGsirolimus
Sirolimus as standard of care for GVHD prophylaxis at the investigator's discretion
DRUGtacrolimus
Tacrolimus as standard of care for GVHD prophylaxis at the investigator's discretion
PROCEDUREallogeneic hematopoietic stem cell transplantation
PROCEDUREperipheral blood stem cell transplantation
RADIATIONtotal-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
DRUGfludarabine
Fludarabine 40 mg/m\^2/day from day -6 to day -3 as myeloablative conditioning at the investigator's discretion
DRUGallopurinol
Allopurinol per institutional guidelines
Sponsors
Massachusetts General Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Grades II to IV Acute Graft-Versus-Host Disease (aGVHD) | Up to 71 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Uric Acid Levels | Pre-transplant Day -7 to Day -1 and Post-transplant Day 0 to Day 6 | 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. |
| Number of Participant With Adverse Events (AE) | Up to 71 months | 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. |
| Graft-versus-host and Host-versus-graft Immune Responses | Days -2, 0, and Days 14, 21 and 35 days post-transplant | Laboratory tests such as limited dilution assay (LDA) were to be performed to assess graft-versus-host and host-versus-graft immune responses. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 21 |
| 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. | 21 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 6 | 9 |
| Overall Study | Participant Withdrew Consent | 1 | 0 |
Baseline characteristics
| Characteristic | Rasburicase Group | Control Group | Total |
|---|---|---|---|
| Age, Continuous | 42.9 years | 45 years | 44 years |
| Conditioning Protocol Interventions Busulfan + Cyclophosphamide | 12 Participants | 16 Participants | 28 Participants |
| Conditioning Protocol Interventions Busulfan + Fludarabine | 2 Participants | 0 Participants | 2 Participants |
| Conditioning Protocol Interventions Total Body Irradiation + Cyclophosphamide | 7 Participants | 5 Participants | 12 Participants |
| Graft-Versus-Host Disease (GVHD) Prophylaxis Intervention MRD: Cyclsporine + Methotrexate | 14 Participants | 11 Participants | 25 Participants |
| Graft-Versus-Host Disease (GVHD) Prophylaxis Intervention MRD: Tacrolimus + Methotrexate | 2 Participants | 2 Participants | 4 Participants |
| Graft-Versus-Host Disease (GVHD) Prophylaxis Intervention MUD: Tacrolimus + Methotrexate | 1 Participants | 2 Participants | 3 Participants |
| Graft-Versus-Host Disease (GVHD) Prophylaxis Intervention MUD: Tacrolimus + Methotrexate + ATG | 4 Participants | 8 Participants | 12 Participants |
| Sex: Female, Male Female | 7 Participants | 12 Participants | 19 Participants |
| Sex: Female, Male Male | 14 Participants | 9 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 21 | 21 / 21 |
| serious Total, serious adverse events | 10 / 21 | 9 / 21 |
Outcome results
Primary
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.
Time frame: Up to 71 months
Population: Intent-to-treat participants included in the analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rasburicase Group | Percentage of Participants With Grades II to IV Acute Graft-Versus-Host Disease (aGVHD) | 24 percentage of participants |
| Control Group | Percentage of Participants With Grades II to IV Acute Graft-Versus-Host Disease (aGVHD) | 57 percentage of participants |
p-value: 0.036Gray's test for competing risks
Secondary
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.
Time frame: Days -2, 0, and Days 14, 21 and 35 days post-transplant
Population: Due to laboratory and budgetary issues the planned laboratory testing and assays were not performed and no data were collected.
Secondary
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.
Time frame: Up to 71 months
Population: Safety population included all participants who received at least one dose of protocol specified treatment and were in remission at the time of transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rasburicase Group | Number of Participant With Adverse Events (AE) | 21 Participants |
| Control Group | Number of Participant With Adverse Events (AE) | 21 Participants |
Secondary
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.
Time frame: Pre-transplant Day -7 to Day -1 and Post-transplant Day 0 to Day 6
Population: Intent-to-treat population with data available for analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rasburicase Group | Uric Acid Levels | Day 0 | 0.938 mg/dL | Standard Deviation 0.887 |
| Rasburicase Group | Uric Acid Levels | Day -4 | 0.1 mg/dL | Standard Deviation 0.324 |
| Rasburicase Group | Uric Acid Levels | Day 1 | 1.624 mg/dL | Standard Deviation 1.205 |
| Rasburicase Group | Uric Acid Levels | Day -7 | 0.1 mg/dL | Standard Deviation 0.209 |
| Rasburicase Group | Uric Acid Levels | Day 2 | 2.076 mg/dL | Standard Deviation 1.37 |
| Rasburicase Group | Uric Acid Levels | Day -6 | 0.075 mg/dL | Standard Deviation 0.199 |
| Rasburicase Group | Uric Acid Levels | Day 3 | 2.271 mg/dL | Standard Deviation 1.303 |
| Rasburicase Group | Uric Acid Levels | Day -2 | 0.081 mg/dL | Standard Deviation 0.15 |
| Rasburicase Group | Uric Acid Levels | Day 4 | 2.548 mg/dL | Standard Deviation 1.454 |
| Rasburicase Group | Uric Acid Levels | Day -5 | 0.086 mg/dL | Standard Deviation 0.24 |
| Rasburicase Group | Uric Acid Levels | Day 5 | 2.595 mg/dL | Standard Deviation 1.729 |
| Rasburicase Group | Uric Acid Levels | Day -1 | 0.438 mg/dL | Standard Deviation 0.611 |
| Rasburicase Group | Uric Acid Levels | Day 6 | 2.705 mg/dL | Standard Deviation 1.665 |
| Rasburicase Group | Uric Acid Levels | Day -3 | 0.067 mg/dL | Standard Deviation 0.2 |
| Control Group | Uric Acid Levels | Day 6 | 2.653 mg/dL | Standard Deviation 1.33 |
| Control Group | Uric Acid Levels | Day -3 | 2.358 mg/dL | Standard Deviation 1.21 |
| Control Group | Uric Acid Levels | Day -5 | 2.967 mg/dL | Standard Deviation 1.437 |
| Control Group | Uric Acid Levels | Day -4 | 2.579 mg/dL | Standard Deviation 1.249 |
| Control Group | Uric Acid Levels | Day -6 | 3.419 mg/dL | Standard Deviation 1.752 |
| Control Group | Uric Acid Levels | Day -2 | 1.867 mg/dL | Standard Deviation 1.097 |
| Control Group | Uric Acid Levels | Day -1 | 1.71 mg/dL | Standard Deviation 0.931 |
| Control Group | Uric Acid Levels | Day 0 | 2.163 mg/dL | Standard Deviation 1.012 |
| Control Group | Uric Acid Levels | Day 1 | 2.671 mg/dL | Standard Deviation 1.056 |
| Control Group | Uric Acid Levels | Day 2 | 2.778 mg/dL | Standard Deviation 0.985 |
| Control Group | Uric Acid Levels | Day 3 | 2.805 mg/dL | Standard Deviation 1.028 |
| Control Group | Uric Acid Levels | Day 4 | 2.758 mg/dL | Standard Deviation 1.161 |
| Control Group | Uric Acid Levels | Day 5 | 2.579 mg/dL | Standard Deviation 1.318 |
| Control Group | Uric Acid Levels | Day -7 | 4.157 mg/dL | Standard Deviation 1.886 |