Chronic Myeloproliferative Disorders, Graft Versus Host Disease, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic/Myeloproliferative Diseases, Myelodysplastic Syndromes, Precancerous/Nonmalignant Condition
Conditions
Keywords
graft versus host disease, recurrent adult acute lymphoblastic leukemia, recurrent childhood acute lymphoblastic leukemia, untreated adult acute lymphoblastic leukemia, untreated childhood acute lymphoblastic leukemia, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, refractory anemia with excess blasts in transformation, refractory anemia with excess blasts, atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, myelodysplastic/myeloproliferative disease, unclassifiable, recurrent adult acute myeloid leukemia, recurrent childhood acute myeloid leukemia, adult acute myeloid leukemia in remission, childhood acute myeloid leukemia in remission, secondary 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, childhood chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, chronic eosinophilic leukemia, chronic idiopathic myelofibrosis, chronic neutrophilic leukemia, essential thrombocythemia, polycythemia vera, Waldenstrom macroglobulinemia, 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 immunoblastic large cell lymphoma, recurrent adult lymphoblastic 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 small lymphocytic lymphoma, splenic marginal zone lymphoma, recurrent childhood grade III lymphomatoid granulomatosis, childhood nasal type extranodal NK/T-cell lymphoma, recurrent childhood large cell lymphoma, childhood diffuse large cell lymphoma, childhood immunoblastic large cell lymphoma, recurrent childhood lymphoblastic lymphoma, Burkitt lymphoma, recurrent childhood small noncleaved cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, recurrent adult T-cell leukemia/lymphoma, recurrent adult grade III lymphomatoid granulomatosis, adult nasal type extranodal NK/T-cell lymphoma, recurrent adult Hodgkin lymphoma, recurrent/refractory childhood Hodgkin lymphoma, refractory chronic lymphocytic leukemia, refractory multiple myeloma, stage III multiple myeloma, aplastic anemia, paroxysmal nocturnal hemoglobinuria, adult acute lymphoblastic leukemia in remission, childhood acute lymphoblastic leukemia in remission, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent mycosis fungoides/Sezary syndrome, stage II multiple myeloma
Brief summary
RATIONALE: Giving chemotherapy and total-body irradiation before a donor peripheral stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy 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, methotrexate, cyclosporine, mycophenolate mofetil, and sirolimus before and after transplant may stop this from happening. PURPOSE: This phase II trial is studying how well donor peripheral stem cell transplant works in treating patients with advanced hematologic cancer or other disorders.
Detailed description
OBJECTIVES: Primary * To evaluate hematopoietic recovery, using neutrophil and platelet engraftment as the primary criterion, in patients with advanced hematologic malignancies or other disorders undergoing allogeneic peripheral blood stem cell (PBSC) transplantation from matched unrelated donors. * To evaluate the incidence of acute and chronic graft-versus-host-disease (GVHD) in patients undergoing allogeneic PBSC transplantation from matched unrelated donors. Secondary * To evaluate the impact of HLA class I and class II allele-matching on the incidence of GVHD and on the survival outcome of these patients. * To evaluate overall survival, disease-free survival, and relapse in these patients. OUTLINE: Patients are stratified according to type of conditioning regimen (myeloablative vs reduced-intensity myeloablative). Patients are assigned to a conditioning regimen according to diagnosis, age, disease status, prior radiotherapy, and prior autologous stem cell transplantation. * Conditioning regimen: * Regimen I: Patients undergo total body irradiation (TBI) on days -7 to -4 and receive cyclophosphamide IV on days -3 and -2. Alternatively, patients may receive cyclophosphamide on days -7 and -6 and undergo TBI on days -4 to -1. * Regimen II: Patients receive busulfan IV over 2 hours once on day -8 and then every 6 hours on days -7 to -4. Patients also receive cyclophosphamide IV on days -3 and -2. * Regimen III: Patients undergo TBI on days -7 to -4 and receive etoposide IV on day -3. * Regimen IV: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and melphalan IV on day -2. * Regimen V: Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo TBI on day 0. * Regimen VI: Patients receive busulfan IV over 3 hours and fludarabine phosphate IV over 30 minutes on days -5 to -2. * Allogeneic peripheral blood stem cell (PBSC) transplantation: All patients undergo allogeneic PBSC transplantation on day 0. * Graft-versus-host disease (GVHD) prophylaxis: Patients receive one of the following GVHD prophylaxis regimens: * Regimen A: Patients receive tacrolimus IV or orally on days -1 to 180 and methotrexate IV on days 1, 3, 6, and 11. * Regimen B: Patients receive cyclosporine IV or orally twice daily on days -1 to 180, mycophenolate mofetil IV over 2 hours or orally twice daily on days 0-27, and methotrexate IV on days 1, 3, and 6. * Regimen C: Patients receive tacrolimus IV continuously or orally, and oral sirolimus beginning on day -3. Patients also receive methotrexate IV on days 1, 3, and 6. After completion of study therapy, patients are followed periodically.
Interventions
DRUGbusulfan
DRUGcyclophosphamide
DRUGcyclosporine
DRUGetoposide
DRUGfludarabine phosphate
DRUGmelphalan
DRUGmethotrexate
DRUGmycophenolate mofetil
DRUGsirolimus
DRUGtacrolimus
PROCEDUREallogeneic hematopoietic stem cell transplantation
PROCEDUREperipheral blood stem cell transplantation
RADIATIONtotal-body irradiation
Sponsors
City of Hope Medical Center
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of one of the following: * Acute lymphocytic leukemia (ALL), meeting one of the following criteria: * In first relapse or beyond * High-risk ALL, defined by any of the following: * Hypoploidy (≤ 44 chromosomes) * Pseudodiploidy with translocations or molecular evidence of t(9;22), 11q23, or t(8;14), excluding B-cell ALL * Elevated WBC at presentation (WBC \> 20,000/mm³ \[for patients \> 18 years of age\]; WBC \> 200,000/mm³ \[for patients 12-18 years of age\]) * Acute myeloid leukemia (AML), meeting one of the following criteria: * In first complete remission * Failed to achieve remission * In first relapse or beyond * Secondary AML (\> 30% blasts in marrow aspirate) * Should receive induction chemotherapy to obtain remission, if possible, before transplant * Chronic myelogenous leukemia, meeting one of the following criteria: * In first or second chronic phase or accelerated phase * In blast crisis, defined as \> 30% promyelocytes plus blasts in the bone marrow * Myelodysplastic syndromes, including any of the following: * Refractory anemia with excess blasts (RAEB) * Chronic myelomonocytic leukemia * RAEB in transformation * Refractory non-Hodgkin lymphoma, chronic lymphocytic leukemia, Hodgkin lymphoma, or multiple myeloma * Received and failed front-line therapy, high-dose therapy and autologous stem cell transplantation, or salvage therapy * Myeloproliferative disorders/myelofibrosis may be allowed on a case by case basis * Severe aplastic anemia, paroxysmal nocturnal hemoglobinuria, or any other hematologic disorder requiring transplantation * Patients \> 55 years of age with hematologic diseases treatable by allogeneic stem cell transplantation who are not eligible for IRB 99190 are eligible * No uncontrolled CNS involvement of disease * No matched (6/6) related donor available * HLA-identical unrelated donor available * HLA-phenotypically identical for HLA-A and HLA-B alleles and identical for DRB1 alleles by DNA typing for both class I and class II antigens * Allele mismatch for HLA class I (i.e., B 2701 vs B 2702) allowed if no alternative donors * Allele mismatch for class II (i.e., DRB1 0401 vs 0402) or minor mismatch for class I cross reactive group (CREG) (i.e., A 2 vs A 28) allowed in patients ≤ 35 years of age requiring urgent transplant PATIENT CHARACTERISTICS: * Karnofsky performance status 50-100% * Life expectancy \> 8 weeks * LVEF ≥ 45% at rest * AST ≤ 2 times normal (unless liver function abnormality is due to underlying disease) * Total bilirubin \< 1.5 times normal (unless liver function abnormality is due to underlying disease) * Creatinine ≤ 1.5 times normal OR creatinine clearance ≥ 60 mL/min * DLCO ≥ 40% of predicted (corrected for hemoglobin) * No coexisting medical problem that would significantly increase the risk of the transplant procedure * HIV negative * Not pregnant PRIOR CONCURRENT THERAPY: * See Disease Characteristics
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neutrophil Engraftment - The Days Till ANC Recovery | Up to 180 days post transplant | The primary engraftment endpoint, neutrophil engraftment, is defined as the first of three consecutive days on which the absolute neutrophil count is \> 500/µL. The duration and extent of neutrophil engraftment is the time from transplant to neutrophil engraftment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Two-year Overall Survival | Up to 2 years post transplant | Overall survival (OS) was measured from peripheral stem cell infusion to death from any cause. It was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula. Participants were followed up to 2 years after transplant and Kaplan-Meier survival analysis was used to generate the two-year Overall Survival estimate presented. |
Contacts
STUDY_CHAIRAuayporn P. Nademanee, MD
City of Hope Medical Center
Participant flow
Recruitment details
Among the 260 enrolled patients, who consented to the study, 5 patients were not eligible.
Participants by arm
| Arm | Count |
|---|---|
| Regimen I Patients undergo total body irradiation (TBI) on days -7 to -4 and receive cyclophosphamide IV on days -3 and -2. Alternatively, patients may receive cyclophosphamide on days -7 and -6 and undergo TBI on days -4 to -1.
cyclophosphamide
cyclosporine
methotrexate
mycophenolate mofetil
sirolimus
tacrolimus
allogeneic hematopoietic stem cell transplantation
peripheral blood stem cell transplantation
total-body irradiation | 62 |
| Regimen II Patients receive busulfan IV over 2 hours once on day -8 and then every 6 hours on days -7 to -4. Patients also receive cyclophosphamide IV on days -3 and -2.
busulfan
cyclophosphamide
cyclosporine
methotrexate
mycophenolate mofetil
sirolimus
tacrolimus
allogeneic hematopoietic stem cell transplantation
peripheral blood stem cell transplantation | 17 |
| Regimen III Patients undergo TBI on days -7 to -4 and receive etoposide IV on day -3.
cyclosporine
etoposide
methotrexate
mycophenolate mofetil
sirolimus
tacrolimus
allogeneic hematopoietic stem cell transplantation
peripheral blood stem cell transplantation
total-body irradiation | 130 |
| Regimen IV Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and melphalan IV on day -2.
cyclosporine
fludarabine phosphate
melphalan
methotrexate
mycophenolate mofetil
sirolimus
tacrolimus
allogeneic hematopoietic stem cell transplantation
peripheral blood stem cell transplantation | 4 |
| Regimen V Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo TBI on day 0.
cyclosporine
fludarabine phosphate
methotrexate
mycophenolate mofetil
sirolimus
tacrolimus
allogeneic hematopoietic stem cell transplantation
peripheral blood stem cell transplantation
total-body irradiation | 40 |
| Regimen VI Patients receive busulfan IV over 3 hours and fludarabine phosphate IV over 30 minutes on days -5 to -2.
busulfan
cyclosporine
fludarabine phosphate
methotrexate
mycophenolate mofetil
sirolimus
tacrolimus
allogeneic hematopoietic stem cell transplantation
peripheral blood stem cell transplantation | 2 |
| Total | 255 |
Baseline characteristics
| Characteristic | Regimen I | Total | Regimen VI | Regimen V | Regimen IV | Regimen III | Regimen II |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 38 years | 44 years | 44 years | 37 years | 22 years | 50 years | 52 years |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 13 Participants | 0 Participants | 2 Participants | 1 Participants | 8 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 55 Participants | 232 Participants | 2 Participants | 38 Participants | 2 Participants | 118 Participants | 17 Participants |
| Region of Enrollment United States | 62 participants | 255 participants | 2 participants | 40 participants | 4 participants | 130 participants | 17 participants |
| Sex: Female, Male Female | 24 Participants | 120 Participants | 1 Participants | 17 Participants | 2 Participants | 65 Participants | 11 Participants |
| Sex: Female, Male Male | 38 Participants | 135 Participants | 1 Participants | 23 Participants | 2 Participants | 65 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 45 / 62 | 14 / 17 | 103 / 130 | 2 / 4 | 32 / 40 | 1 / 2 |
| other Total, other adverse events | 14 / 62 | 4 / 17 | 38 / 130 | 0 / 4 | 10 / 40 | 1 / 2 |
| serious Total, serious adverse events | 4 / 62 | 1 / 17 | 7 / 130 | 0 / 4 | 3 / 40 | 1 / 2 |
Outcome results
Primary
Neutrophil Engraftment - The Days Till ANC Recovery
The primary engraftment endpoint, neutrophil engraftment, is defined as the first of three consecutive days on which the absolute neutrophil count is \> 500/µL. The duration and extent of neutrophil engraftment is the time from transplant to neutrophil engraftment.
Time frame: Up to 180 days post transplant
Population: Some patients had engraftment failure and some had missing data. Therefore, the overall number of participants analyzed in each regimen is less than the overall number in the Participant Flow module.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regimen I | Neutrophil Engraftment - The Days Till ANC Recovery | 17 days |
| Regimen II | Neutrophil Engraftment - The Days Till ANC Recovery | 16 days |
| Regimen III | Neutrophil Engraftment - The Days Till ANC Recovery | 15 days |
| Regimen IV | Neutrophil Engraftment - The Days Till ANC Recovery | 14 days |
| Regimen V | Neutrophil Engraftment - The Days Till ANC Recovery | 18 days |
| Regimen VI | Neutrophil Engraftment - The Days Till ANC Recovery | 16 days |
Secondary
Two-year Overall Survival
Overall survival (OS) was measured from peripheral stem cell infusion to death from any cause. It was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula. Participants were followed up to 2 years after transplant and Kaplan-Meier survival analysis was used to generate the two-year Overall Survival estimate presented.
Time frame: Up to 2 years post transplant
Population: 1 subject in Regimen II did not have transplant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen I | Two-year Overall Survival | 58 percentage of survival probability |
| Regimen II | Two-year Overall Survival | 50 percentage of survival probability |
| Regimen III | Two-year Overall Survival | 54 percentage of survival probability |
| Regimen IV | Two-year Overall Survival | 50 percentage of survival probability |
| Regimen V | Two-year Overall Survival | 38 percentage of survival probability |
| Regimen VI | Two-year Overall Survival | 50 percentage of survival probability |