Leukemia, Lymphoma, Lymphoproliferative Disorder, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms
Conditions
Keywords
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), juvenile myelomonocytic leukemia, prolymphocytic leukemia, recurrent adult acute myeloid leukemia, recurrent adult T-cell leukemia/lymphoma, recurrent childhood acute myeloid leukemia, refractory chronic lymphocytic leukemia, recurrent adult Hodgkin 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 grade III lymphomatoid granulomatosis, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent childhood grade III lymphomatoid granulomatosis, recurrent childhood large cell lymphoma, recurrent childhood lymphoblastic lymphoma, recurrent childhood small noncleaved cell lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent mycosis fungoides/Sezary syndrome, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, recurrent/refractory childhood Hodgkin lymphoma, childhood diffuse large cell lymphoma, childhood grade III lymphomatoid granulomatosis, childhood immunoblastic large cell lymphoma, childhood nasal type extranodal NK/T-cell lymphoma, post-transplant lymphoproliferative disorder, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, refractory multiple myeloma, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, childhood myelodysplastic syndromes, recurrent childhood anaplastic large cell lymphoma, adult acute myelomonocytic leukemia (M4), childhood acute myelomonocytic leukemia (M4), adult acute minimally differentiated myeloid leukemia (M0), childhood acute minimally differentiated myeloid leukemia (M0), adult acute myeloblastic leukemia without maturation (M1), childhood acute myeloblastic leukemia without maturation (M1), adult acute myeloblastic leukemia with maturation (M2), childhood acute myeloblastic leukemia with maturation (M2), adult acute promyelocytic leukemia (M3), childhood acute promyelocytic leukemia (M3), adult acute monoblastic leukemia (M5a), adult acute monocytic leukemia (M5b), childhood acute monoblastic leukemia (M5a), childhood acute monocytic leukemia (M5b), adult erythroleukemia (M6a), adult pure erythroid leukemia (M6b), childhood acute erythroleukemia (M6), adult acute megakaryoblastic leukemia (M7), childhood acute megakaryocytic leukemia (M7), childhood Burkitt lymphoma, atypical chronic myeloid leukemia, BCR-ABL1 negative, chronic myelomonocytic leukemia, cutaneous B-cell non-Hodgkin lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, myelodysplastic/myeloproliferative neoplasm, unclassifiable
Brief summary
RATIONALE: Giving chemotherapy, such as busulfan and fludarabine phosphate, before a 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving methotrexate, tacrolimus, and antithymocyte globulin before and 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 II trial is studying how well donor stem cell transplant works in treating patients with relapsed hematologic malignancies or secondary myelodysplasia previously treated with high-dose chemotherapy and autologous stem cell transplant .
Detailed description
OBJECTIVES: Primary * To demonstrate the efficacy of performing reduced-intensity conditioning allogeneic hematopoietic cell transplantation in patients with relapsed hematologic malignancies or secondary myelodysplasia after completion of prior high-dose chemotherapy and autologous hematopoietic stem cell transplantation. * To compare the strategy of this regimen with the strategy used in CALGB-100002. Secondary * To describe the response rate at 6 and 12 months in patients treated with this regimen. * To describe the time-to-progression in patients treated with this regimen. * To determine the ability to use pharmacokinetic-directed busulfan to achieve AUC within 20% of target AUC in \> 80% of patients. * To determine percent of donor chimerism in T-cell, myeloid and B-cell populations achieved with this regimen compared with CALGB-100002. * To determine the risk of acute and chronic graft-versus-host disease and other toxicities of this regimen in these patients. * To describe the overall survival and disease-free survival of patients treated on this regimen. * To determine the rate of viral, bacterial, and fungal opportunistic infections occurring in the first year after transplantation compared with CALGB-100002. OUTLINE: This is a multicenter study. * Preparative Regimen: * Busulfan test dose: Patients receive busulfan IV over 45 minutes once during days -14 and -9. * Busulfan treatment dose: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV over 3 hours on days -6 to -3. * Graft-vs-Host Disease (GVHD) Prophylaxis: * HLA-identical donor: Patients receive antithymocyte globulin IV over 6-10 hours on days -6 to -5; oral tacrolimus twice daily on days -2 to 90 followed by a taper\* as tolerated until day 150 or 180; and methotrexate IV on days 1, 3, and 6. NOTE: \* Tacrolimus may be tapered on days 60-90 if donor chimerism of CD3+ cells is \< 50% at day 60 or patient has progressive disease. * Matched-unrelated donor: Patients receive antithymocyte globulin, tacrolimus, and methotrexate as in HLA-identical donor regimen. Patients also receive oral mycophenolate mofetil twice daily on days 0 to 60. * Allogeneic Stem Cell Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on days 0 and 1. Patients then receive filgrastim subcutaneously daily beginning on day 7 and continuing until blood counts recover. * Donor Lymphocyte Infusion (DLI): After day 180 (or day 210 for patients without an HLA-identical donor), patients with stable or progressive disease and no active GVHD may receive up to 3 DLIs every 8 weeks. Blood samples are collected at baseline and then periodically during study therapy for pharmacokinetic studies. After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for up to 5½ years.
Interventions
BIOLOGICALanti-thymocyte globulin
BIOLOGICALdonor lymphocytes
BIOLOGICALfilgrastim
BIOLOGICALtherapeutic allogeneic lymphocytes
DRUGbusulfan
DRUGfludarabine phosphate
DRUGmethotrexate
DRUGmycophenolate mofetil
DRUGtacrolimus
PROCEDUREallogeneic hematopoietic stem cell transplantation
PROCEDUREperipheral blood stem cell transplantation
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 69 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed hematologic malignancies: * Chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL) * Absolute lymphocytosis of \> 5,000/μL * Lymphocytes must appear morphologically mature with \< 55% prolymphocytes (CLL) * Patients with \> 55% prolymphocytes are considered as having PLL * Lymphocyte phenotype with expression of CD20, CD19, and CD5 (CLL) * Non-Hodgkin lymphoma * Any WHO classification of histologic subtype * Core biopsies acceptable for primary diagnosis and immunophenotyping * Bone marrow biopsies as sole means of diagnosis not allowed for follicular lymphoma * Hodgkin lymphoma * Any WHO classification of histologic subtype * Core biopsies acceptable for primary diagnosis and immunophenotyping * Bone marrow biopsy is required * Multiple myeloma * Patients must have active disease requiring treatment (Durie-Salmon stage I-III) * Acute myeloid leukemia * Must have \< 10% bone marrow blasts and no circulating blasts * Myelodysplastic syndrome (MDS) * MDS as define by WHO criteria * Must have \< 10% marrow blasts * Relapsed or progressive disease or myelodysplasia ≥ 6 months after prior high-dose chemotherapy with autologous hematopoietic cell support * Prior syngeneic transplantation allowed * Healthy donor meeting one of the following criteria: * HLA-identical sibling (6/6) * Serologic typing for class I (A, B) and molecular typing for class II (DRB1) required * 8/8 matched-unrelated donor * Molecular identity at HLA A, B, C, and DRB1 by high-resolution typing required * No syngeneic donors PATIENT CHARACTERISTICS: * Creatinine clearance ≥ 40 mL/min * Total bilirubin ≤ 2 mg/dL * AST ≤ 3 times upper limit of normal * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * DLCO ≥ 40% with no symptomatic pulmonary disease * LVEF ≥ 30% by MUGA or ECHO * No uncontrolled diabetes mellitus or active serious infection * No known hypersensitivity to E.coli-derived products * No HIV infection PRIOR CONCURRENT THERAPY: * See Disease Characteristics * At least 4 weeks should elapse between prior standard cytotoxic chemotherapy, radiation therapy, or surgery and the planned start of the preparative regimen on day -7
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) | Duration of study (up to 5.5 years) | EFS was defined as the date of transplant to date of progression or develop myelodysplasia after autologous transplant. EFS was estimated using the Kaplan Meier method. |
| Comparison of EFS Distribution to That of CALGB-100002 | 2 years | EFS distributions between CALGB-100002 and this study will be compared using the two-sample log-rank test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate | Up to 5.5 years | Complete response (CR) rate is reported as the percentage of participants who achieved a CR. |
| Overall Survival | Up to 5.5 years | Overall survival (OS) was defined as the transplant from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% confidence interval (CI) was estimated using the Kaplan Meier method. |
| Rate of Opportunistic Infections | 1 year post transplant | Percent of participants who have an opportunistic (viral, bacterial and fungal) infection in the first year following transplant. |
Countries
United States
Participant flow
Recruitment details
Between May 2010 and March 2012, 6 participants were recruited.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Participants will receive:
Busulfan test dose of 25 mg/m\^2 IV over 45 minutes between days -14 and -9; Fludarabine 30 mg/m\^2/day IV over 30 minutes on days -7 to -3; Busulfan IV x 4 days on days -6 through -3 (dosage based on AUC of 4000 mmol/min based on pharmacokinetics determined from test dose); Allopurinol was given at discretion of treating physician; Rabbit antithymocyte globulin 1.5 mg/kg/day IV on days -6 and -5; Peripheral Blood Stem Cell Transplant (PBST) on Day 0 and +1; and methotrexate 5 mg/m\^2/day IV on days +1, +3 and +6. G-CSF of 5mcg/kg/day SQ began daily on day +7 continuing until ANC \> 1000/mL for 3 consecutive days. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Treatment |
|---|---|
| Age, Continuous | 67 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 3 / 6 |
Outcome results
Primary
Comparison of EFS Distribution to That of CALGB-100002
EFS distributions between CALGB-100002 and this study will be compared using the two-sample log-rank test.
Time frame: 2 years
Population: Due to study termination, data were not collected and the outcome measure was not analyzed.
Primary
Event-free Survival (EFS)
EFS was defined as the date of transplant to date of progression or develop myelodysplasia after autologous transplant. EFS was estimated using the Kaplan Meier method.
Time frame: Duration of study (up to 5.5 years)
Population: Due to study termination, data were not collected and the outcome measure was not analyzed.
Secondary
Complete Response Rate
Complete response (CR) rate is reported as the percentage of participants who achieved a CR.
Time frame: Up to 5.5 years
Population: Due to study termination, data were not collected and the outcome measure was not analyzed.
Secondary
Overall Survival
Overall survival (OS) was defined as the transplant from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% confidence interval (CI) was estimated using the Kaplan Meier method.
Time frame: Up to 5.5 years
Population: Due to study termination, data were not collected and the outcome measure was not analyzed.
Secondary
Rate of Opportunistic Infections
Percent of participants who have an opportunistic (viral, bacterial and fungal) infection in the first year following transplant.
Time frame: 1 year post transplant
Population: Due to study termination, data were not collected and the outcome measure was not analyzed.