NMA Allogeneic Hematopoietic Cell Transplant in Hematologic Cancer/Disorders
Study Details
Study Description
Brief Summary
RATIONALE: Giving low doses of chemotherapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving immunosuppressive therapy before or after the transplant may stop this from happening.
PURPOSE: This phase II trial is studying how well chemotherapy followed by donor peripheral stem cell transplant works in treating patients with hematologic cancer or aplastic anemia.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Detailed Description
OBJECTIVES:
-
Determine the safety and toxic effects of nonmyeloablative allogeneic peripheral blood stem cell transplantation in patients with a hematologic malignancy or aplastic anemia.
-
Determine clinical response and overall outcome of patients treated with this regimen.
-
Determine the incidence of graft-vs-tumor effect, graft-vs-host disease, and chimerism in patients treated with this regimen.
OUTLINE:
-
Preparative regimen:
-
Matched related and unrelated donor transplantation:
-
Patients receive cyclophosphamide IV over 2 hours on days -5 and -4 and fludarabine IV over 30 minutes on days -5 to -1.
-
Cord blood transplantation:
-
Patients receive the same regimen as above plus anti-thymocyte globulin IV over 4 hours on days -3 to -1.
-
Graft-vs-host disease (GVHD) prophylaxis:
-
Matched related and unrelated donor transplantation:
-
Patients receive oral tacrolimus (or IV) once daily and oral mycophenolate mofetil (MMF) (or IV) twice daily on days -1 to 60 followed by tapering* of this regimen. Patients then receive methotrexate IV on days 1, 3, and 6.
-
Cord blood transplantation:
-
Patients receive tacrolimus and MMF in the same regimen as above plus methylprednisolone twice daily on days 1-19 or until blood counts recover.
-
Allogeneic stem cell reinfusion: Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously daily beginning on day 7 and continuing until blood counts recover.
-
Donor lymphocyte infusion (DLI): Patients not converting to 100% donor T-cell chimerism by day 120 and showing signs of progresson of disease after tacrolimus and MMF withdrawal may receive DLI every 8 weeks for up to 3 infusions. Cord blood recipients do not receive DLI.
Patients are followed at day 100-120, every 3 months for 2 years, and then every 6 months for 5 years.
PROJECTED ACCRUAL: A total of 30-60 patients will be accrued for this study within 6-7 years.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: All patients All patients enrolled on study |
Biological: anti-thymocyte globulin
iv
Biological: graft-versus-tumor induction therapy
iv
Biological: sargramostim
iv
Biological: therapeutic allogeneic lymphocytes
iv
Drug: cyclophosphamide
injection
Drug: fludarabine phosphate
iv
Other Names:
Drug: methylprednisolone
oral
Drug: mycophenolate mofetil
oral
Drug: tacrolimus
oral
Procedure: allogeneic bone marrow transplantation
iv
Procedure: peripheral blood stem cell transplantation
iv
Procedure: umbilical cord blood transplantation
iv
|
Outcome Measures
Primary Outcome Measures
- Day 100 TRM [from start or conditioning (day -6 or -5) through day +100 after HSC infusion]
treatment related mortality within 100 days from hematopoietic stem cell (HSC) infusion on day 0
- Day 100 Best Response [from start of conditioning on day -6 or -5 through day +100 after HSC infusion]
Best disease response measured within 100 days from hematopoietic stem cell (HSC) infusion on day 0 using disease specific response criteria defined in the protocol
Secondary Outcome Measures
- PFS [1 year]
Progression free survival defined as time from HSC infusion (day 0) until progression of disease or death due to any cause. Patients are censored if alive without disease progression through 1 year after HSC infusion
- OS [1 year]
Overall survival with events defined as death due to any cause and censored patients are alive as of 1 year post HSC infusion
- Acute GvHD [Day +100]
overall grade II-IV acute GvHD
Eligibility Criteria
Criteria
DISEASE CHARACTERISTICS:
-
Diagnosis of aplastic anemia
-
Severe disease
-
Failed at least 1 course of standard immunosuppressive regimen with cyclosporine and anti-thymocyte globulin OR
-
Histologically confirmed hematologic malignancy including the following:
-
Acute leukemia
-
Any of the following types:
-
Acute myeloid leukemia (AML) with antecedent myelodysplastic syndromes
-
Secondary AML
-
AML with high-risk cytogenetic abnormalities
-
Acute lymphoblastic leukemia with high-risk cytogenetic abnormalities
-
Resistant or recurrent disease after combination chemotherapy with at least 1 standard regimen OR
-
In first remission at high risk of relapse
-
Chronic myelogenous leukemia
-
Chronic phase meeting at least 1 of the following criteria:
-
Failed imatinib mesylate
-
Failed interferon after at least 6 months of treatment with minimum of 21 million units of interferon per week
-
Unable to tolerate interferon
-
Accelerated phase (blasts less than 20%)
-
Myeloproliferative and myelodysplastic syndromes
-
Myelofibrosis (after splenectomy)
-
Refractory anemia
-
Refractory anemia with excess blasts
-
Chronic myelomonocytic leukemia
-
Lymphoproliferative disease
-
Chronic lymphocytic leukemia
-
Symptomatic disease after first-line chemotherapy
-
Low-grade non-Hodgkin's lymphoma (recurrent or persistent)
-
Symptomatic disease after first-line chemotherapy
-
Multiple myeloma
-
Progressive disease after autologous stem cell transplantation
-
Waldenstrom's macroglobulinemia
-
Failed 1 standard regimen
-
Non-Hodgkin's lymphoma meeting the following criteria:
-
Intermediate or high grade
-
Controlled and chemosensitive disease
-
First remission lymphoblastic or small non-cleaved cell lymphoma at high risk of relapse
-
Hodgkin's lymphoma
-
Relapsed and chemosensitive disease
-
Not eligible for standard myeloablative allogeneic stem cell transplantation
-
Availability of any of the following donor types:
-
Related donor matched at 5 or 6 HLA antigens (A, B, DR)
-
Unrelated donor fully matched by molecular analysis at A, B, DRB1, and DQB1 loci
-
Single antigen mismatch at C allowed
-
Cord blood that is 4, 5, or 6 match with recipient HLA antigens (A, B, DR) NOTE: No syngeneic donors permitted
-
No uncontrolled CNS disease (for hematologic malignancies) NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.
PATIENT CHARACTERISTICS:
Age
-
4 to 75 (if related or unrelated donor peripheral blood or marrow transplantation)
-
4 to 60 (if unrelated cord blood transplantation)
Performance status
- Karnofsky > 50%
Life expectancy
- Not specified
Hematopoietic
- Not specified
Hepatic
-
Bilirubin less than 3 times normal
-
Alkaline phosphatase less than 3 times normal
-
AST/ALT less than 3 times normal
-
No Child's class B or C liver failure
Renal
- Creatinine clearance greater than 40 mL/min
Cardiovascular
-
Cardiac ventricular ejection fraction at least 35% by MUGA
-
No cardiovascular disease
Pulmonary
- DLCO at least 40% of predicted, corrected for hemoglobin and/or alveolar ventilation
Other
-
Not pregnant or nursing
-
Negative pregnancy test
-
Fertile patients must use effective contraception
-
HIV antibody negative
-
No uncontrolled diabetes mellitus
-
No active serious infection
-
No other disease that would preclude study therapy
-
No other concurrent malignancy except non-melanoma skin cancer
-
No concurrent serious psychiatric illness
PRIOR CONCURRENT THERAPY:
Biologic therapy
-
See Disease Characteristics
-
patients may have received a prior autologous blood or marrow transplantation (BMT)
-
At least 6 months since prior allogeneic BMT
Chemotherapy
-
See Disease Characteristics
-
At least 2 weeks since prior chemotherapy, radiation or surgery
Endocrine therapy
- Not specified
Radiotherapy
- At least 2 weeks since prior radiotherapy
Surgery
- At least 2 weeks since prior surgery
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Roswell Park Cancer Institute | Buffalo | New York | United States | 14263-0001 |
Sponsors and Collaborators
- Roswell Park Cancer Institute
Investigators
- Principal Investigator: Philip L. McCarthy, MD, Roswell Park Cancer Institute
Study Documents (Full-Text)
More Information
Publications
None provided.- CDR0000269673
- RP01-05
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | All Patients |
---|---|
Arm/Group Description | All patients enrolled on study Patients received cyclophosphamide 50 mg/kg on days -5 and -4, and fludarabine 25 mg/m2 on days -5, -4, -3, -2, -1. Hematopoietic cells from peripheral blood or marrow were infused on day 0. Patients who received hematopoietic cells from cord blood additionally received ATG 30 mg/kg on days -3, -2, -1. Fanconi anemia patients received cyclophosphamide 7.5 mg/kg on days -6, -5, -4, -3, fludarabine 25 mg/m2 on days -6, -5, -4, -3, -2 and ATG 30 mg/kg on days -3, -2, -1 and hematopoietic cells infused on day 0. |
Period Title: Overall Study | |
STARTED | 41 |
COMPLETED | 41 |
NOT COMPLETED | 0 |
Baseline Characteristics
Arm/Group Title | All Patients |
---|---|
Arm/Group Description | All patients enrolled on study Patients received cyclophosphamide 50 mg/kg on days -5 and -4, and fludarabine 25 mg/m2 on days -5, -4, -3, -2, -1. Hematopoietic cells from peripheral blood or marrow were infused on day 0. Patients who received hematopoietic cells from cord blood additionally received ATG 30 mg/kg on days -3, -2, -1. Fanconi anemia patients received cyclophosphamide 7.5 mg/kg on days -6, -5, -4, -3, fludarabine 25 mg/m2 on days -6, -5, -4, -3, -2 and ATG 30 mg/kg on days -3, -2, -1 and hematopoietic cells infused on day 0. |
Overall Participants | 41 |
Age (Count of Participants) | |
<=18 years |
1
2.4%
|
Between 18 and 65 years |
37
90.2%
|
>=65 years |
3
7.3%
|
Age (years) [Median (Full Range) ] | |
Median (Full Range) [years] |
52
|
Sex: Female, Male (Count of Participants) | |
Female |
17
41.5%
|
Male |
24
58.5%
|
Race (NIH/OMB) (Count of Participants) | |
American Indian or Alaska Native |
0
0%
|
Asian |
1
2.4%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
Black or African American |
0
0%
|
White |
40
97.6%
|
More than one race |
0
0%
|
Unknown or Not Reported |
0
0%
|
Region of Enrollment (participants) [Number] | |
United States |
41
100%
|
Diagnosis (Count of Participants) | |
Acute lymphoblastic or myeloid leukemia |
12
29.3%
|
Hodgkin/non-Hodgkin lymphoma/prolymphocytic leukem |
21
51.2%
|
Multiple Myeloma |
2
4.9%
|
Myelodysplastic syndrome |
5
12.2%
|
Fanconi anemia |
1
2.4%
|
Outcome Measures
Title | Day 100 TRM |
---|---|
Description | treatment related mortality within 100 days from hematopoietic stem cell (HSC) infusion on day 0 |
Time Frame | from start or conditioning (day -6 or -5) through day +100 after HSC infusion |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | All Patients |
---|---|
Arm/Group Description | All patients enrolled on study |
Measure Participants | 41 |
Count of Participants [Participants] |
4
9.8%
|
Title | Day 100 Best Response |
---|---|
Description | Best disease response measured within 100 days from hematopoietic stem cell (HSC) infusion on day 0 using disease specific response criteria defined in the protocol |
Time Frame | from start of conditioning on day -6 or -5 through day +100 after HSC infusion |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | All Patients |
---|---|
Arm/Group Description | All patients enrolled on study |
Measure Participants | 41 |
Complete Response |
22
53.7%
|
Partial Response |
5
12.2%
|
Early Death/NE |
4
9.8%
|
No Response/Stable Disease |
2
4.9%
|
Progressed |
8
19.5%
|
Title | PFS |
---|---|
Description | Progression free survival defined as time from HSC infusion (day 0) until progression of disease or death due to any cause. Patients are censored if alive without disease progression through 1 year after HSC infusion |
Time Frame | 1 year |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | All Patients |
---|---|
Arm/Group Description | All patients enrolled on study |
Measure Participants | 41 |
Number (95% Confidence Interval) [percentage of participants] |
27
65.9%
|
Title | OS |
---|---|
Description | Overall survival with events defined as death due to any cause and censored patients are alive as of 1 year post HSC infusion |
Time Frame | 1 year |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | All Patients |
---|---|
Arm/Group Description | All patients enrolled on study |
Measure Participants | 41 |
Number (95% Confidence Interval) [percentage of participants] |
44
107.3%
|
Title | Acute GvHD |
---|---|
Description | overall grade II-IV acute GvHD |
Time Frame | Day +100 |
Outcome Measure Data
Analysis Population Description |
---|
2 participants died before they were eligible for this outcome |
Arm/Group Title | All Patients |
---|---|
Arm/Group Description | All patients enrolled on study |
Measure Participants | 39 |
Count of Participants [Participants] |
16
39%
|
Adverse Events
Time Frame | 100 days | |
---|---|---|
Adverse Event Reporting Description | SAE=died before absolute neutrophil count recovery (DBE) or survived to day +28 without absolute neutrophil count recovery (FTE) AE=overall grade III-IV acute GVHD | |
Arm/Group Title | All Patients | |
Arm/Group Description | All patients enrolled on study | |
All Cause Mortality |
||
All Patients | ||
Affected / at Risk (%) | # Events | |
Total | 8/41 (19.5%) | |
Serious Adverse Events |
||
All Patients | ||
Affected / at Risk (%) | # Events | |
Total | 3/41 (7.3%) | |
Blood and lymphatic system disorders | ||
DBE/FTE | 3/41 (7.3%) | 3 |
Other (Not Including Serious) Adverse Events |
||
All Patients | ||
Affected / at Risk (%) | # Events | |
Total | 6/41 (14.6%) | |
Immune system disorders | ||
acute GVHD grade III-IV | 6/41 (14.6%) | 6 |
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 | Theresa Hahn, PhD |
---|---|
Organization | Roswell Park Comprehensive Cancer Center |
Phone | 716084505819 |
theresa.hahn@roswellpark.org |
- CDR0000269673
- RP01-05