Haploidentical Donor Bone Marrow Transplant in Treating Patients With High-Risk Hematologic Cancer
Study Details
Study Description
Brief Summary
This phase II trial studies how well giving fludarabine phosphate, cyclophosphamide, tacrolimus, mycophenolate mofetil and total-body irradiation together with a donor bone marrow transplant works in treating patients with high-risk hematologic cancer. Giving low doses of chemotherapy, such as fludarabine phosphate and cyclophosphamide, and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer cells by stopping them from dividing or killing them. Giving cyclophosphamide after transplant may also stop the patient's immune system from rejecting the donor's bone marrow stem cells. The donated stem cells may replace the patient's immune system 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 and mycophenolate mofetil after the transplant may stop this from happening
Detailed Description
OBJECTIVES:
- To determine if engraftment can be achieved safely in patients with high-risk hematologic malignancies who undergo non-myeloablative bone marrow transplantation (BMT) from human leukocyte antigen (HLA)-haploidentical donors.
OUTLINE:
NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2 and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total body irradiation on day -1.
TRANSPLANTATION: Patients undergo BMT, from an HLA-haploidentical donor, on day 0.
POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on day 3.
GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus IV over 1-2 hours and then tacrolimus orally (PO), once tolerated, on days 4-180, with taper on day 86 in the absence of graft-versus-host disease. Patients also receive mycophenolate mofetil PO three times daily on days 4-35.
Treatment continues in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 6 months and then annually thereafter.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (nonmyeloablative HSCT) NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total body irradiation on day -1. TRANSPLANTATION: Patients undergo BMT, from an HLA-haploidentical donor, on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on day 3. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus IV over 1-2 hours and then tacrolimus PO, once tolerated, on days 4-180, with taper on day 86 in the absence of graft-versus-host disease. Patients also receive mycophenolate mofetil PO three times daily on days 4-35. |
Drug: cyclophosphamide
Given IV
Other Names:
Drug: fludarabine phosphate
Given IV
Other Names:
Drug: tacrolimus
Given IV or orally
Other Names:
Drug: mycophenolate mofetil
Given orally
Other Names:
Genetic: polymerase chain reaction
Correlative studies
Other Names:
Genetic: fluorescence in situ hybridization
Correlative studies
Other Names:
Genetic: polymorphism analysis
Correlative studies
Genetic: gene expression analysis
Correlative studies
Radiation: total-body irradiation
Undergo total-body irradiation
Other Names:
Procedure: allogeneic bone marrow transplantation
Undergo haploidentical hematopoietic bone marrow transplantation
Other Names:
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo haploidentical hematopoietic bone marrow transplantation
|
Outcome Measures
Primary Outcome Measures
- Donor Engraftment (Chimerism) [At day +84 after transplantation]
Defined by the detection of at least 50% donor derived T-cells (CD3+), as a proportion of the total T-cell population
- Incidence of Grades III-IV Acute GVHD [At any time within 200 days after transplantation]
Grade III GVHD represents moderate severity. Grade IV GVHD represents extreme severity
- Non-relapse-related Mortality [Up to 200 days after transplantation]
Number of deaths without progression or recurrence of malignant disease
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Chronic myeloid leukemia (CML) in accelerated phase (AP)
-
Acute myeloid leukemia (AML) with high-risk cytogenetics [del(5q)/-5, del(7q)/-7, abnormal 3q, 9q, 11q, 20q, 21q, 17p, t(6:9), t(9;22), complex karyotypes (>= 3 abnormalities)] in complete remission (CR)1
-
AML >= CR2; patients should have < 5% marrow blasts at the time of transplant
-
High-risk ALL defined as: CR1 with high-risk cytogenetics; t(9;22), t(4;11), or hypodiploid (< 45 chromosomes) for pediatric patients; t(9;22), t(8;14), t(4;11), t(1;19) for adult patients; > 4 wk to achieve CR1; >= CR2 (patients should have < 5% marrow blasts at the time of transplant)
-
Myelodysplastic syndromes (MDS) (>int-1 per IPSS) after >= 1 prior cycle of induction chemotherapy; should have < 5% marrow blasts at the time of transplant
-
Multiple myeloma (MM) Stage II or III patients who have progressed after an initial response to chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) or MM patients with refractory disease who may benefit from tandem autologous-nonmyeloablative allogeneic transplant
-
Chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL) or Hodgkin's Disease (HD) who are ineligible for autologous HSCT or who have resistant/refractory disease and who may benefit from tandem autologous nonmyeloablative allogeneic transplant
-
Patients who have received a prior allogeneic HSCT and who have either rejected their grafts or who have become tolerant of their grafts with no active graft-versus-host disease (GvHD) requiring immunosuppressive therapy
-
DONOR: Related donors who are identical for one HLA haplotype and mismatched at the HLA-A, -B, -C or DRB1 loci of the unshared haplotype with the exception of single HLA-A, -B or -C allele mismatches
Exclusion Criteria:
-
Cross-match positive with donor
-
Patients with suitably matched related or unrelated donors
-
Patients with conventional transplant options (a conventional transplant should be the priority for eligible patients =< 50 yr of age who have a related donor mismatched for a single HLA-A, -B or DRB1 antigen)
-
Central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
-
Presence of active, serious infection (e.g., mucormycosis, uncontrolled aspergillosis, tuberculosis)
-
Karnofsky Performance Status < 60 for adult patients
-
Lansky-Play Performance Score < 60 for pediatric patients
-
Left ventricular ejection fraction < 35%
-
Diffusing capacity of the lung for carbon monoxide (DLCO) < 35% and/or receiving supplemental continuous oxygen
-
Liver abnormalities: fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction as evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL or symptomatic biliary disease
-
Human immunodeficiency virus (HIV)-positive patients
-
Women of childbearing potential who are pregnant (beta-HCG+) or breast feeding
-
Fertile men and women unwilling to use contraceptives during and for 12 months post-transplant
-
Life expectancy severely limited by diseases other than malignancy
-
DONOR: Donor-recipient pairs in which the HLA-mismatch is only in the HVG direction
-
DONOR: Cross-match positive with recipient
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium | Seattle | Washington | United States | 98109 |
Sponsors and Collaborators
- Fred Hutchinson Cancer Center
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Paul O'Donnell, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 1667.00
- NCI-2010-00166
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Treatment (Nonmyeloablative HSCT) |
|---|---|
| Arm/Group Description | NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total body irradiation on day -1. TRANSPLANTATION: Patients undergo BMT, from an HLA-haploidentical donor, on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on day 3. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus IV over 1-2 hours and then tacrolimus PO, once tolerated, on days 4-180, with taper on day 86 in the absence of graft-versus-host disease. Patients also receive mycophenolate mofetil PO three times daily on days 4-35. |
| Period Title: Overall Study | |
| STARTED | 55 |
| COMPLETED | 55 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Treatment (Nonmyeloablative HSCT) |
|---|---|
| Arm/Group Description | NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total body irradiation on day -1. TRANSPLANTATION: Patients undergo BMT, from an HLA-haploidentical donor, on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on day 3. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus IV over 1-2 hours and then tacrolimus PO, once tolerated, on days 4-180, with taper on day 86 in the absence of graft-versus-host disease. Patients also receive mycophenolate mofetil PO three times daily on days 4-35. |
| Overall Participants | 55 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
40
|
| Sex: Female, Male (Count of Participants) | |
| Female |
21
38.2%
|
| Male |
34
61.8%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
3
5.5%
|
| Not Hispanic or Latino |
49
89.1%
|
| Unknown or Not Reported |
3
5.5%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
3
5.5%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
5
9.1%
|
| White |
41
74.5%
|
| More than one race |
3
5.5%
|
| Unknown or Not Reported |
3
5.5%
|
| Region of Enrollment (participants) [Number] | |
| United States |
55
100%
|
Outcome Measures
| Title | Donor Engraftment (Chimerism) |
|---|---|
| Description | Defined by the detection of at least 50% donor derived T-cells (CD3+), as a proportion of the total T-cell population |
| Time Frame | At day +84 after transplantation |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients receiving haploidentical transplant who had T cell chimerism tested at day +84 |
| Arm/Group Title | Treatment (Nonmyeloablative HSCT) |
|---|---|
| Arm/Group Description | NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total body irradiation on day -1. TRANSPLANTATION: Patients undergo BMT, from an HLA-haploidentical donor, on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on day 3. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus IV over 1-2 hours and then tacrolimus PO, once tolerated, on days 4-180, with taper on day 86 in the absence of graft-versus-host disease. Patients also receive mycophenolate mofetil PO three times daily on days 4-35. |
| Measure Participants | 36 |
| Count of Participants [Participants] |
34
61.8%
|
| Title | Incidence of Grades III-IV Acute GVHD |
|---|---|
| Description | Grade III GVHD represents moderate severity. Grade IV GVHD represents extreme severity |
| Time Frame | At any time within 200 days after transplantation |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment (Nonmyeloablative HSCT) |
|---|---|
| Arm/Group Description | NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total body irradiation on day -1. TRANSPLANTATION: Patients undergo BMT, from an HLA-haploidentical donor, on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on day 3. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus IV over 1-2 hours and then tacrolimus PO, once tolerated, on days 4-180, with taper on day 86 in the absence of graft-versus-host disease. Patients also receive mycophenolate mofetil PO three times daily on days 4-35. |
| Measure Participants | 55 |
| Count of Participants [Participants] |
4
7.3%
|
| Title | Non-relapse-related Mortality |
|---|---|
| Description | Number of deaths without progression or recurrence of malignant disease |
| Time Frame | Up to 200 days after transplantation |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment (Nonmyeloablative HSCT) |
|---|---|
| Arm/Group Description | NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total body irradiation on day -1. TRANSPLANTATION: Patients undergo BMT, from an HLA-haploidentical donor, on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on day 3. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus IV over 1-2 hours and then tacrolimus PO, once tolerated, on days 4-180, with taper on day 86 in the absence of graft-versus-host disease. Patients also receive mycophenolate mofetil PO three times daily on days 4-35. |
| Measure Participants | 55 |
| Count of Participants [Participants] |
12
21.8%
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Treatment (Nonmyeloablative HSCT) | |
| Arm/Group Description | NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total body irradiation on day -1. TRANSPLANTATION: Patients undergo BMT, from an HLA-haploidentical donor, on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on day 3. GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus IV over 1-2 hours and then tacrolimus PO, once tolerated, on days 4-180, with taper on day 86 in the absence of graft-versus-host disease. Patients also receive mycophenolate mofetil PO three times daily on days 4-35. | |
All Cause Mortality |
||
| Treatment (Nonmyeloablative HSCT) | ||
| Affected / at Risk (%) | # Events | |
| Total | 30/55 (54.5%) | |
Serious Adverse Events |
||
| Treatment (Nonmyeloablative HSCT) | ||
| Affected / at Risk (%) | # Events | |
| Total | 11/55 (20%) | |
| Blood and lymphatic system disorders | ||
| Secondary myeloid malignancy | 1/55 (1.8%) | |
| Immune system disorders | ||
| Graft-versus-host disease | 2/55 (3.6%) | |
| Infections and infestations | ||
| Bacterial infection | 7/55 (12.7%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Diffuse alveolar hemorrhage | 1/55 (1.8%) | |
Other (Not Including Serious) Adverse Events |
||
| Treatment (Nonmyeloablative HSCT) | ||
| Affected / at Risk (%) | # Events | |
| Total | 55/55 (100%) | |
| Blood and lymphatic system disorders | ||
| Recurrent or progressive malignancy | 22/55 (40%) | |
| Infections and infestations | ||
| Invasive Fungal Infection | 6/55 (10.9%) | |
| CMV reactivation | 27/34 (79.4%) | |
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 | Rachel Salit |
|---|---|
| Organization | Fred Hutchinson Cancer Research Center |
| Phone | 206-667-1317 |
| rsalit@fredhutch.gov |
- 1667.00
- NCI-2010-00166