Safety Study of Bone Marrow Transplant Using Mismatched Tissue Followed by Chemotherapy
Study Details
Study Description
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
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: 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. |
Drug: Busulfan
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.
Drug: Cyclophosphamide
Patient will receive Cy by IV once a day for 2 days.
Other Names:
Radiation: Total body irradiation
Patients will receive TBI once a day for 4 days.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Engraftment as Measured by Donor Chimerism [Day 60]
Percentage of participants who achieved donor chimerism >=95%.
Secondary Outcome Measures
- 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)
Eligibility Criteria
Criteria
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)
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Sidney Kimmel Comprehensive Cancer Center | Baltimore | Maryland | United States | 21231 |
2 | The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore | Maryland | United States | 21231 |
Sponsors and Collaborators
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Otsuka Pharmaceutical Co., Ltd.
- National Center for Research Resources (NCRR)
Investigators
- Principal Investigator: Heather Symons, M.D., Johns Hopkins University
Study Documents (Full-Text)
None provided.More Information
Publications
- J0820
- NA_00015795
- KL2RR025006
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail | 11 participants were screen failures. |
Arm/Group Title | Myeloablative Haploidentical BMT |
---|---|
Arm/Group Description | 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. |
Period Title: Overall Study | |
STARTED | 96 |
COMPLETED | 47 |
NOT COMPLETED | 49 |
Baseline Characteristics
Arm/Group Title | Myeloablative Haploidentical BMT |
---|---|
Arm/Group Description | 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. |
Overall Participants | 96 |
Age (Count of Participants) | |
<=18 years |
15
15.6%
|
Between 18 and 65 years |
80
83.3%
|
>=65 years |
1
1%
|
Age (years) [Median (Full Range) ] | |
Median (Full Range) [years] |
42
|
Sex: Female, Male (Count of Participants) | |
Female |
40
41.7%
|
Male |
56
58.3%
|
Race and Ethnicity Not Collected (Count of Participants) | |
Region of Enrollment (Count of Participants) | |
United States |
96
100%
|
Outcome Measures
Title | Engraftment as Measured by Donor Chimerism |
---|---|
Description | Percentage of participants who achieved donor chimerism >=95%. |
Time Frame | Day 60 |
Outcome Measure Data
Analysis Population Description |
---|
8 participants were not evaluable for this outcome because they died prior to Day 60. |
Arm/Group Title | Myeloablative Haploidentical BMT |
---|---|
Arm/Group Description | 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. |
Measure Participants | 88 |
Number (95% Confidence Interval) [percentage of participants] |
91
94.8%
|
Title | Non-relapse Mortality |
---|---|
Description | Number of participants deceased for reasons other than disease relapse or progression. |
Time Frame | Day 100, 1 year |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Myeloablative Haploidentical BMT |
---|---|
Arm/Group Description | 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. |
Measure Participants | 96 |
100 days |
10
10.4%
|
1 year |
10
10.4%
|
Title | Acute GVHD |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Myeloablative Haploidentical BMT |
---|---|
Arm/Group Description | 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. |
Measure Participants | 96 |
Grade II-IV |
11
11.5%
|
Grade III-IV |
4
4.2%
|
Title | Chronic GVHD |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Myeloablative Haploidentical BMT |
---|---|
Arm/Group Description | 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. |
Measure Participants | 96 |
6 months |
4
4.2%
|
12 months |
15
15.6%
|
Title | Survival |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Myeloablative Haploidentical BMT |
---|---|
Arm/Group Description | 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. |
Measure Participants | 96 |
Overall survival, 1 year |
73
76%
|
Overall survival, 2 years |
57
59.4%
|
Overall survival, 3 years |
54
56.3%
|
Event-free survival, 1 year |
58
60.4%
|
Event-free survival, 2 years |
52
54.2%
|
Event-free survival, 3 years |
50
52.1%
|
Title | Relapse |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
The entire set of participants was analyzed as one group, and the analysis was planned this way from the beginning of the study. |
Arm/Group Title | Myeloablative Haploidentical BMT |
---|---|
Arm/Group Description | 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. |
Measure Participants | 96 |
1 year |
35
36.5%
|
3 years |
43
44.8%
|
Adverse Events
Time Frame | Up to 2 years | |
---|---|---|
Adverse Event Reporting Description | Only the following adverse events were collected per protocol: non-relapse mortality in the first 100 days after BMT; graft failure; and all unexpected events considered significant by the principal investigator. Adverse events were assessed weekly through Day 60 and at Days 180, 365, and 730. | |
Arm/Group Title | Myeloablative Haploidentical BMT | |
Arm/Group Description | 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. | |
All Cause Mortality |
||
Myeloablative Haploidentical BMT | ||
Affected / at Risk (%) | # Events | |
Total | 49/96 (51%) | |
Serious Adverse Events |
||
Myeloablative Haploidentical BMT | ||
Affected / at Risk (%) | # Events | |
Total | 22/96 (22.9%) | |
Blood and lymphatic system disorders | ||
Deep vein thrombosis | 1/96 (1%) | 1 |
Cardiac disorders | ||
Cardiac arrest | 1/96 (1%) | 1 |
Cardiomegaly | 1/96 (1%) | 1 |
Cardiomyopathy | 1/96 (1%) | 1 |
Hypotension | 1/96 (1%) | 1 |
Pericardial effusion | 1/96 (1%) | 1 |
Sinus tachycardia | 1/96 (1%) | 1 |
Superior vena cava syndrome | 1/96 (1%) | 1 |
General disorders | ||
Bleeding | 1/96 (1%) | 1 |
Hepatobiliary disorders | ||
Liver failure | 2/96 (2.1%) | 2 |
Veno-occlusive disease | 3/96 (3.1%) | 5 |
Immune system disorders | ||
Liver graft-versus-host-disease | 1/96 (1%) | 1 |
Hemolytic anemia | 1/96 (1%) | 1 |
Multisystem organ dysfunction syndrome | 3/96 (3.1%) | 3 |
Infections and infestations | ||
Aspergillosis | 1/96 (1%) | 1 |
BK virus | 2/96 (2.1%) | 2 |
Cytomegalovirus | 1/96 (1%) | 1 |
Coagulase-negative staphylococcus | 1/96 (1%) | 1 |
Coronavirus NL63 | 1/96 (1%) | 1 |
Multi-drug resistant Klebsiella bacteremia | 1/96 (1%) | 1 |
Fungal pneumonia | 3/96 (3.1%) | 3 |
Fungal sinusitis | 1/96 (1%) | 1 |
Human herpesvirus 6 | 1/96 (1%) | 1 |
Human metapneumovirus | 1/96 (1%) | 1 |
Febrile neutropenia | 1/96 (1%) | 1 |
Pneumonia | 1/96 (1%) | 1 |
Rhinovirus | 1/96 (1%) | 1 |
Sepsis | 3/96 (3.1%) | 3 |
Vancomycin-resistant Enterococcus | 1/96 (1%) | 1 |
Investigations | ||
Graft failure | 2/96 (2.1%) | 2 |
Metabolism and nutrition disorders | ||
Metabolic acidosis | 2/96 (2.1%) | 2 |
Respiratory and metabolic acidosis | 1/96 (1%) | 1 |
Musculoskeletal and connective tissue disorders | ||
Fracture | 1/96 (1%) | 1 |
Nervous system disorders | ||
Altered mental status | 1/96 (1%) | 1 |
Intracranial hemorrhage | 1/96 (1%) | 1 |
Posterior reversible encephalopathy syndrome | 1/96 (1%) | 1 |
Subarachnoid hemorrhage | 1/96 (1%) | 1 |
Renal and urinary disorders | ||
Renal failure | 9/96 (9.4%) | 10 |
Respiratory, thoracic and mediastinal disorders | ||
Pleural effusion | 2/96 (2.1%) | 2 |
Respiratory failure | 6/96 (6.3%) | 6 |
Other (Not Including Serious) Adverse Events |
||
Myeloablative Haploidentical BMT | ||
Affected / at Risk (%) | # Events | |
Total | 37/96 (38.5%) | |
Infections and infestations | ||
BK virus | 6/96 (6.3%) | 6 |
Clostridium difficile | 13/96 (13.5%) | 13 |
Cytomegalovirus | 14/96 (14.6%) | 19 |
Febrile neutropenia | 7/96 (7.3%) | 7 |
Renal and urinary disorders | ||
Acute kidney injury | 8/96 (8.3%) | 8 |
Skin and subcutaneous tissue disorders | ||
Mucositis | 10/96 (10.4%) | 10 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Heather Symons, MD |
---|---|
Organization | Johns Hopkins University |
Phone | 4105029961 |
hsymons2@jhmi.edu |
- J0820
- NA_00015795
- KL2RR025006