Chronic Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic/Myeloproliferative Neoplasms, Myelodysplastic Syndromes
Conditions
Keywords
stage III adult Burkitt lymphoma, stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage III adult Hodgkin lymphoma, stage III adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage III marginal zone lymphoma, stage III small lymphocytic lymphoma, stage IV adult Burkitt lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult Hodgkin lymphoma, stage IV adult immunoblastic large cell lymphoma, stage IV adult lymphoblastic lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage IV mantle cell lymphoma, stage IV marginal zone lymphoma, stage IV small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, accelerated phase chronic myelogenous leukemia, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, 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), chronic phase chronic myelogenous leukemia, recurrent adult acute lymphoblastic leukemia, recurrent adult acute myeloid leukemia, secondary acute myeloid leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, de novo myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasm, unclassifiable, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, primary myelofibrosis, atypical chronic myeloid leukemia, BCR-ABL negative, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia
Brief summary
RATIONALE: Giving low doses of chemotherapy, monoclonal antibodies, and radiation therapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop 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 tacrolimus, sirolimus, and antithymocyte globulin before and after transplant may stop this from happening. PURPOSE: This phase II trial is studying the side effects of giving sirolimus together with tacrolimus and antithymocyte globulin and to see how well it works in preventing graft-versus-host disease in patients with hematologic cancer who are undergoing donor stem cell transplant.
Detailed description
OBJECTIVES: Primary * To determine the incidence and severity of acute graft-versus-host disease (GVHD) after HLA-matched or -mismatched unrelated donor peripheral blood stem cell transplantation (PBSCT) in patients with hematologic malignancies treated with immunosuppressive therapy comprising sirolimus, tacrolimus, and anti-thymocyte globulin as GVHD prophylaxis. * To determine the safety of this regimen in these patients at 6 months after PBSCT. Secondary * To determine the time to engraftment (i.e., platelet and absolute neutrophil recovery) in patients treated with this regimen. * To determine the length of hospital stay of these patients within 100 days after PBSCT. * To determine the incidence of infections, including CMV and EBV reactivation and post-transplant lymphoproliferative disorders, in patients treated with this regimen. * To determine the incidence of thrombotic microangiopathy and veno-occlusive disease in patients treated with this regimen. * To determine the incidence of chronic GVHD in patients treated with this regimen. * To determine the overall and disease-free survival of these patients at 2 years after PBSCT. * To determine the Karnofsky performance status of these patients at baseline and at various time points after PBSCT. * To conduct immunocorrelative studies prior to and at various time points after PBSCT. OUTLINE: * Conditioning regimen: Patients receive 1 of 6 conditioning regimens (standard of care treatment) between days -9 and -3, based on diagnosis and the treating physician's preference regarding regimen intensity. * Regimen I: Patients receive fludarabine phosphate IV and busulfan IV. * Regimen II: Patients undergo total body irradiation (TBI) twice daily for 8 fractions and receive etoposide IV. * Regimen III: Patients undergo TBI once or twice daily for 11 fractions and receive cyclophosphamide IV. * Regimen IV: Patients undergo TBI and receive fludarabine phosphate IV and busulfan IV. * Regimen V: Patients receive carmustine IV, etoposide IV, cytarabine IV, and melphalan IV. Some patients also receive rituximab IV. * Regimen VI: Patients receive fludarabine phosphate IV and melphalan IV. Some patients also undergo TBI. * Allogeneic peripheral blood stem cell transplantation: Patients undergo filgrastim (G-CSF)-mobilized allogeneic peripheral blood stem cell transplantation on day 0. * Graft-versus-host disease prophylaxis (GVHD): Patients receive tacrolimus IV continuously over 24 hours or orally and sirolimus orally beginning on day -3 and continuing until day 30 or day 90, followed by a taper in the absence of GVHD. Patients also receive anti-thymocyte globulin IV over 4-8 hours on days -3 to -1. Blood samples are obtained at baseline and periodically during study for correlative biomarker studies. Samples are analyzed by T-cell immunophenotyping, absolute subset number quantification, and multi-parameter flow cytometry for evaluation of immune reconstitution, T-cell differentiation status, NK-cell recovery, allo-reactivity of donor T-cells after transplantation, and regulatory T-cell reconstitution. After completion of study therapy, patients are followed periodically for up to 2 years.
Interventions
BIOLOGICALrituximab
Given IV
DRUGbusulfan
Given IV
DRUGcarmustine
Given IV
DRUGcyclophosphamide
Given IV
DRUGcytarabine
Given IV
DRUGetoposide
Given IV
DRUGfludarabine phosphate
Given IV
DRUGmelphalan
Given IV
RADIATIONtotal body irradiation (TBI)
Given once or twice daily
DRUGanti-thymocyte globulin IV
Given IV
Sponsors
National Cancer Institute (NCI)
Barbara Ann Karmanos Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of a hematological malignancy, including any of the following: * Non-Hodgkin lymphoma in complete remission (CR) or partial remission (PR) * Hodgkin lymphoma in CR or PR * Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) meeting either of the following criteria: * In CR * Not in CR and meets the following criteria: * Bone marrow blast \< 20% within 4 weeks of transplantation * Peripheral blood absolute blast count \< 500 per microliter on the day of initiating conditioning therapy * Myelodysplastic syndromes, treated or untreated * Chronic myeloid leukemia in chronic phase or accelerated phase * Multiple myeloma in CR or PR * Chronic lymphocytic leukemia in second or greater CR or PR * Myelofibrosis or other myeloproliferative disorders meeting the following criteria: * Bone marrow blasts \< 20% within 4 weeks of transplantation * Peripheral blood absolute blast count \< 500 per microliter on the day of initiating conditioning therapy * Patients with ascites not allowed * No prior bone marrow or ex vivo engineered or processed graft (i.e., CD34+ enrichment, T-cell depletion, etc) * Scheduled to undergo peripheral blood stem cell transplantation from a suitable HLA-matched or -mismatched unrelated donor, as determined by treating physician * High resolution molecular HLA typing is required for HLA class I and II * No more than one antigen or allele mismatch * No documented uncontrolled CNS disease PATIENT CHARACTERISTICS: * ECOG performance status (PS) 0-2 * Karnofsky PS 60-100% * Creatinine clearance \> 50 mL/min * Bilirubin \< 3 times upper limit of normal (ULN) * ALT and AST \< 3 times ULN * LVEF \> 50% * FVC, FEV\_1, or DLCO \> 50% predicted * Patients on home oxygen not allowed * Able to cooperate with oral medication intake * HIV negative * No active hepatitis B or hepatitis C * No known contraindication to sirolimus, tacrolimus, or anti-thymocyte globulin PRIOR CONCURRENT THERAPY: * See Disease Characteristics
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of Acute Graft-versus-host Disease (GVHD) | Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria |
| Severity of Acute Graft-versus-host Disease (GVHD) | Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria |
| Safety, as Defined by Serious Adverse Events and Adverse Events Related to Study Treatment. | Within 6 months after PBSCT |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Infections, Including Bacterial, Fungal, and Viral Infections (i.e., CMV and EBV Reactivation, Including Post-transplant Lymphoproliferative Disorders) | Within 6 months after PBSCT | — |
| Incidence of Chronic GVHD. | Within 2 years after PBSCT | — |
| Karnofsky Performance Status Performance Status | At 90 days after PBSCT | 100 - Normal; no complaints; no evidence of disease. 90 - Able to carry on normal activity; minor signs or symptoms of disease. 80 - Normal activity with effort; some signs or symptoms of disease. 70 - Cares for self; unable to carry on normal activity or to do active work. 60 - Requires occasional assistance, but is able to care for most of their personal needs. 50 - Requires considerable assistance and frequent medical care. 40 - Disabled; requires special care and assistance. 30 - Severely disabled; hospital admission is indicated although death not imminent. 20 - Very sick; hospital admission necessary; active supportive treatment necessary. 10 - Moribund; fatal processes progressing rapidly. 0 - Dead |
| Time to Engraftment (i.e., Absolute Neutrophil Recovery [ANC > 500/mm³] ) | post transplant, up to 4 weeks | — |
| Overall Survival. | At 2 years after PBSCT | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants All regimens were analyzed together.
Standard of Care (SOC) Chemotherapy or Standard of Care (SOC) Chemotherapy + total body irradiation
SOC chemotherapy or SOC chemotherapy + total body irradiation (TBI) of one of the following regimens:
Regimen I: Patients receive fludarabine phosphate IV and busulfan IV.
Regimen II: Patients undergo total body irradiation (TBI) twice daily for 8 fractions and receive etoposide IV.
Regimen III: Patients undergo TBI once or twice daily for 11 fractions and receive cyclophosphamide IV.
Regimen IV: Patients undergo TBI and receive fludarabine phosphate IV and busulfan IV.
Regimen V: Patients receive carmustine IV, etoposide IV, cytarabine IV, and melphalan IV. Some patients also receive rituximab IV.
Regimen VI: Patients receive fludarabine phosphate IV and melphalan IV. Some patients also undergo TBI. | 47 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Refused further treatment | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 53 years |
| Region of Enrollment United States | 47 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 47 |
| serious Total, serious adverse events | 44 / 47 |
Outcome results
Primary
Incidence of Acute Graft-versus-host Disease (GVHD)
Time frame: Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Incidence of Acute Graft-versus-host Disease (GVHD) | 44.7 percentage of participants |
Primary
Safety, as Defined by Serious Adverse Events and Adverse Events Related to Study Treatment.
Time frame: Within 6 months after PBSCT
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Safety, as Defined by Serious Adverse Events and Adverse Events Related to Study Treatment. | 93.62 % of participants with a reported SAE |
Primary
Severity of Acute Graft-versus-host Disease (GVHD)
Time frame: Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria
Population: The patients that contracted sever acute graph versus host disease (aGVHD) from those who developed aGVHD
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Severity of Acute Graft-versus-host Disease (GVHD) | 33.3 % of participants with severe aGVHD |
Secondary
Incidence of Chronic GVHD.
Time frame: Within 2 years after PBSCT
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Incidence of Chronic GVHD. | 44.68 percentage of participants |
Secondary
Incidence of Infections, Including Bacterial, Fungal, and Viral Infections (i.e., CMV and EBV Reactivation, Including Post-transplant Lymphoproliferative Disorders)
Time frame: Within 6 months after PBSCT
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Incidence of Infections, Including Bacterial, Fungal, and Viral Infections (i.e., CMV and EBV Reactivation, Including Post-transplant Lymphoproliferative Disorders) | 80.85 percentage of participants |
Secondary
Karnofsky Performance Status Performance Status
100 - Normal; no complaints; no evidence of disease. 90 - Able to carry on normal activity; minor signs or symptoms of disease. 80 - Normal activity with effort; some signs or symptoms of disease. 70 - Cares for self; unable to carry on normal activity or to do active work. 60 - Requires occasional assistance, but is able to care for most of their personal needs. 50 - Requires considerable assistance and frequent medical care. 40 - Disabled; requires special care and assistance. 30 - Severely disabled; hospital admission is indicated although death not imminent. 20 - Very sick; hospital admission necessary; active supportive treatment necessary. 10 - Moribund; fatal processes progressing rapidly. 0 - Dead
Time frame: At 90 days after PBSCT
Population: All participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Karnofsky Performance Status Performance Status | 80 units on a scale |
Secondary
Overall Survival.
Time frame: At 2 years after PBSCT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Overall Survival. | 57.4 percentage of participants |
Secondary
Time to Engraftment (i.e., Absolute Neutrophil Recovery [ANC > 500/mm³] )
Time frame: post transplant, up to 4 weeks
Population: All participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Time to Engraftment (i.e., Absolute Neutrophil Recovery [ANC > 500/mm³] ) | 11 Days |