Leukemias, Lymphomas, MDS
Conditions
Keywords
Leukemia, Lymphoma, Hematologic malignancies, ALL, AML, MDS, Transplantation, Mismatched, Haploidentical, Busulfan, Cyclophosphamide, Cellcept, Tacrolimus, TBI, CMMOL, CML, JMML
Brief summary
The purpose of this study is to see if giving high dose chemotherapy and total body irradiation before and repeating high dose chemotherapy after a bone marrow transplant could reduce the incidence of graft rejection and disease for patients with blood cancers
Detailed description
Allogeneic blood or marrow transplantation (alloBMT), following either marrow-ablative or nonmyeloablative conditioning, is a potentially curative treatment for a variety of hematologic malignancies and non-malignant hematologic disorders. Of all the potential sources of allografts, transplantation of stem cells from a human leukocyte antigen (HLA)-matched sibling has generally produced the best overall outcomes, i.e. overall and progression-free survival. Unfortunately, only about a third of candidates for alloBMT have HLA-matched siblings. For patients who lack HLA-matched siblings, there are three alternative sources of stem cells for alloBMT: 1) volunteer unrelated donors; 2) umbilical cord blood; and 3) partially HLA-mismatched, or haploidentical, related donors. Since any patient shares exactly one HLA haplotype with each biological parent or child and half of siblings, an eligible haploidentical donor can be identified rapidly in nearly all cases. However, haploidentical BMT has been associated with significant risks of graft rejection and severe GVHD, which are manifestations of excessive alloreactivity by host and donor T cells, respectively. The risk of severe GVHD may be reduced in intensively conditioned recipients of grafts that have been rigorously depleted of mature T cells or selectively depleted of alloreactive T cells, but the risks of serious infection and death from prolonged immune compromise in these patients remains high. Cyclophosphamide(Cy) is a highly immunosuppressive antineoplastic agent that has an established role in conditioning for alloBMT. Typically, the drug is administered prior to transplantation to prevent graft rejection by suppressing the host immune system. However, pre-transplantation conditioning with Cy increases the risk of GVHD following allogeneic T cell infusion in mouse models. In contrast, administration of a properly timed, high dose of Cy after BMT inhibits both graft rejection and GVHD.
Interventions
DRUGBusulfan
Participant will receive Busulfan injections, 4 times a day for 4 days with dilantin prophylaxis (in patients 10 years of age or older). Busulfan levels in the blood will be measured and dose adjusted, if needed.
DRUGCyclophosphamide
Patient will receive Cy by IV once a day for 2 days.
RADIATIONTotal body irradiation
Patients will receive TBI once a day for 4 days.
Sponsors
Otsuka Pharmaceutical Co., Ltd.
National Center for Research Resources (NCRR)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 65 Years
Healthy volunteers
No
Inclusion criteria
* Acute lymphocytic leukemia in high risk CR1 * Acute myeloid leukemia in CR1 * Therapy-related AML * RAEB with \>5% and \<20% bone marrow blasts * Chronic myelogenous leukemia beyond 1st chronic phase; Patients cannot be in blast crisis * CMMoL * JMML * Chemotherapy-resistant Hodgkins Lymphoma or intermediate or high grade Non-Hodgkins lymphoma (Less than a PR after standard or salvage chemotherapy) * Mantle cell lymphoma: chemotherapy refractory (Less than a PR after standard or salvage chemotherapy) or patients beyond CR1 with chemosensitive disease * Follicular Lymphoma, Grade 3 * Transformed indolent lymphomas
Exclusion criteria
* Poor cardiac function: left ventricular ejection fraction \<45% as determined by MUGA or ECHO. For pediatric patients LVEF \<45% or a shortening fraction below normal limits for age. * Poor pulmonary function: FEV1 and FVC \<50% predicted for patients who have not received thoracic or mantle irradiation. For patients who have received thoracic or mantle irradiation, FEV1 and FVC \<70% predicted or DLCO \< 50 of predicted. For children unable to perform PFTs because of developmental stage pulse oximetry \< 85% on RA * Poor liver function: bilirubin \>2 mg/dl (not due to hemolysis, Gilbert's or primary malignancy) * Poor renal function: Creatinine \>2.0mg/dl or creatinine clearance * HIV-positive * Positive leukocytotoxic crossmatch * Women of childbearing potential who currently are pregnant or who are not practicing adequate contraception * Uncontrolled viral, bacterial, or fungal infections Patients with symptoms consistent with RSV, influenza A, B, or parainfluenza at the time of enrollment will be assayed for the above viruses and if positive are not eligible for the trial until they are no longer symptomatic (patients may have continued assay positivity for a period of time post resolution of symptoms secondary to the nature of the assay. * Indolent lymphomas (Follicular Grade 1 and 2, marginal zone, chronic lymphocytic leukemia, small lymphocytic lymphoma, MALT)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Engraftment as Measured by Donor Chimerism | Day 60 | Percentage of participants who achieved donor chimerism \>=95%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Non-relapse Mortality | Day 100, 1 year | Number of participants deceased for reasons other than disease relapse or progression. |
| Acute GVHD | Day 100 | Percentage of participants who experience grade II-IV or III-IV acute graft-versus-host-disease (GVHD) by Przepiorka criteria. The stages are defined as follows: * Stage II: Rash on \>50% of skin, bilirubin 2-3 mg/dL, or diarrhea 500-1000 mL/day * Stage III: Bilirubin 3-15 mg/dL or diarrhea \>1000 mL/day * Stage IV: Generalized erythroderma with bullae or bilirubin \>15 mg/dL This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999) |
| Chronic GVHD | 6 months, 12 months | Percentage of participants who experience chronic GVHD. Chronic GVHD is graded using NIH consensus criteria and Seattle criteria. This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999) |
| Survival | 1 year, 2 years, 3 years | Percentage of participants alive (overall survival) and alive without disease relapse, progression, or diagnosis of myeloid malignancy (event-free survival). Estimated using Kaplan-Meier method. |
| Relapse | 1 year, 3 years | Percentage of participants who experienced disease progression or relapse. This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999) |
Countries
United States
Participant flow
Pre-assignment details
11 participants were screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Myeloablative Haploidentical BMT * All participants except those with acute lymphoblastic leukemia and lymphoblastic lymphoma: Busulfan will be administered 1 mg/kg oral (or 0.8 mg/kg IV) four times per day for four days, followed by cyclophosphamide 50 mg/kg once per day for two days.
* Participants with acute lymphocytic leukemia or lymphoblastic lymphoma: Cyclophosphamide will be administered 50 mg/kg once per day for two days, followed by total body irradiation at 300 cGy per day for four days. | 96 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 49 |
Baseline characteristics
| Characteristic | Myeloablative Haploidentical BMT | — |
|---|---|---|
| Age, Categorical <=18 years | 15 Participants | — |
| Age, Categorical >=65 years | 1 Participants | — |
| Age, Categorical Between 18 and 65 years | 80 Participants | — |
| Age, Continuous | 42 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 96 Participants | — |
| Sex: Female, Male Female | 40 Participants | — |
| Sex: Female, Male Male | 56 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 49 / 96 |
| other Total, other adverse events | 37 / 96 |
| serious Total, serious adverse events | 22 / 96 |
Outcome results
Primary
Engraftment as Measured by Donor Chimerism
Percentage of participants who achieved donor chimerism \>=95%.
Time frame: Day 60
Population: 8 participants were not evaluable for this outcome because they died prior to Day 60.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Myeloablative Haploidentical BMT | Engraftment as Measured by Donor Chimerism | 91 percentage of participants |
Secondary
Acute GVHD
Percentage of participants who experience grade II-IV or III-IV acute graft-versus-host-disease (GVHD) by Przepiorka criteria. The stages are defined as follows: * Stage II: Rash on \>50% of skin, bilirubin 2-3 mg/dL, or diarrhea 500-1000 mL/day * Stage III: Bilirubin 3-15 mg/dL or diarrhea \>1000 mL/day * Stage IV: Generalized erythroderma with bullae or bilirubin \>15 mg/dL This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999)
Time frame: Day 100
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Myeloablative Haploidentical BMT | Acute GVHD | Grade II-IV | 11 percentage of participants |
| Myeloablative Haploidentical BMT | Acute GVHD | Grade III-IV | 4 percentage of participants |
Secondary
Chronic GVHD
Percentage of participants who experience chronic GVHD. Chronic GVHD is graded using NIH consensus criteria and Seattle criteria. This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999)
Time frame: 6 months, 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Myeloablative Haploidentical BMT | Chronic GVHD | 6 months | 4 percentage of participants |
| Myeloablative Haploidentical BMT | Chronic GVHD | 12 months | 15 percentage of participants |
Secondary
Non-relapse Mortality
Number of participants deceased for reasons other than disease relapse or progression.
Time frame: Day 100, 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Myeloablative Haploidentical BMT | Non-relapse Mortality | 100 days | 10 Participants |
| Myeloablative Haploidentical BMT | Non-relapse Mortality | 1 year | 10 Participants |
Secondary
Relapse
Percentage of participants who experienced disease progression or relapse. This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999)
Time frame: 1 year, 3 years
Population: The entire set of participants was analyzed as one group, and the analysis was planned this way from the beginning of the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Myeloablative Haploidentical BMT | Relapse | 1 year | 35 percentage of participants |
| Myeloablative Haploidentical BMT | Relapse | 3 years | 43 percentage of participants |
Secondary
Survival
Percentage of participants alive (overall survival) and alive without disease relapse, progression, or diagnosis of myeloid malignancy (event-free survival). Estimated using Kaplan-Meier method.
Time frame: 1 year, 2 years, 3 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Myeloablative Haploidentical BMT | Survival | Overall survival, 1 year | 73 percentage of participants |
| Myeloablative Haploidentical BMT | Survival | Overall survival, 2 years | 57 percentage of participants |
| Myeloablative Haploidentical BMT | Survival | Overall survival, 3 years | 54 percentage of participants |
| Myeloablative Haploidentical BMT | Survival | Event-free survival, 1 year | 58 percentage of participants |
| Myeloablative Haploidentical BMT | Survival | Event-free survival, 2 years | 52 percentage of participants |
| Myeloablative Haploidentical BMT | Survival | Event-free survival, 3 years | 50 percentage of participants |