Non-Neoplastic Hematologic and Lymphocytic Disorder
Conditions
Keywords
nonmalignant diseases, nonmalignant inherited disorders, primary immunodeficiency diseases, primary immune deficiency disorders, chronic granulomatous, disease, IPEX syndrome, hemophagocytic lymphohistiocytosis, Wiskott Aldrich Syndrome, bone marrow failure syndromes, Shwachman Diamond Syndrome, Dyskeratosis Congenita, Diamond Blackfan Anemia, inborn errors of metabolism, metabolic diseases, hemoglobinopathies, sickle cell disease, thalassemia, reduced intensity transplantation, hematopoietic cell transplantation, bone marrow transplantation, umbilical cord blood transplantation
Brief summary
This phase II clinical trial studies how well treosulfan and fludarabine phosphate with or without low dose radiation before donor stem cell transplantation works in treating patients with nonmalignant (noncancerous) diseases. Hematopoietic cell transplantation has been shown to be curative for many patients with nonmalignant (noncancerous) diseases such as primary immunodeficiency disorders, bone marrow failure syndromes, hemoglobinopathies, and inborn errors of metabolism (metabolic disorders). Powerful chemotherapy drugs and/or radiation are often used to condition the patient before infusion of the new healthy donor cells. The purpose of the conditioning therapy is to destroy the patient's abnormal bone marrow which doesn't work properly in order to make way for the new healthy donor cells which functions normally. Although effective in curing the patient's disease, many hematopoietic cell transplantation regimens use intensive chemotherapy and/or radiation which can be quite toxic, have significant side effects, and can potentially be life-threatening. Investigators are investigating whether a new conditioning regimen that uses less intensive drugs (treosulfan and fludarabine phosphate) with or without low dose radiation results in new blood-forming cells (engraftment) of the new donor cells without increased toxicities in patients with nonmalignant (noncancerous) diseases.
Detailed description
OUTLINE: CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine phosphate IV over 1 hour on days -6 to -2. Patients receive anti-thymocyte globulin IV over 4-6 hours on days -4 to -2. Patients undergoing umbilical cord blood transplantation will also receive low dose total-body irradiation on day -1. TRANSPLANTATION: Patients receive either bone marrow, peripheral blood stem cells (PBSC), or umbilical cord blood (UCB) from the donor on day 0. The use of either bone marrow, PBSC, or umbilical cord blood will depend on the donor status. IMMUNOSUPPRESSION: Patients receive a combination of immunosuppressive medications to try and prevent graft-versus-host disease. There are 2 regimens depending on the donor. Regimen A: Patients undergoing bone marrow or PBSC transplantation receive tacrolimus daily from day -1 to 50 followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11. Regimen B: Patients undergoing UCB transplantation receive cyclosporine on days -3 to 100 followed by a taper until day 180 in the absence of GVHD. Patients also receive mycophenolate mofetil on days 0 to 40 followed by a taper until day 96 in the absence of GVHD. After completion of study treatment, patients are followed up periodically for 5 years.
Interventions
PROCEDUREAllogeneic Bone Marrow Transplantation
Infused IV
BIOLOGICALAnti-Thymocyte Globulin
Given IV
DRUGCyclosporine
Given IV or PO
DRUGFludarabine Phosphate
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGMethotrexate
Given IV
DRUGMycophenolate Mofetil
Given IV or PO
PROCEDUREPeripheral Blood Stem Cell Transplantation
Infused IV
DRUGTacrolimus
Given IV or PO
RADIATIONTotal-Body Irradiation
Undergo total body irradiation
DRUGTreosulfan
Given IV
PROCEDUREUmbilical Cord Blood Transplantation
Single or double unit umbilical cord blood transplant, infused IV
Sponsors
medac GmbH
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Fred Hutchinson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 49 Years
Healthy volunteers
No
Inclusion criteria
* Patients with a nonmalignant disease treatable by allogeneic HCT * Patients with a known nonmalignant disease that is not clearly defined will need to be discussed with the protocol principal investigator (PI) (Dr. Lauri Burroughs) and potentially the nonmalignant board to determine if they are eligible for HCT on this study * DONOR: Human leukocyte antigens (HLA)-identical related donors or unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 or mismatched for a single allele at HLA-A, B, C, DRB1 or a single DQB1 antigen or allele mismatch by high resolution deoxyribonucleic acid (DNA) typing * DONOR: PBSC is the preferred cell source (when feasible) for fully matched donors; PBSC may also be used for a mismatched donor following discussion with the PI; bone marrow is allowed when PBSC is not feasible or as determined by the PI * DONOR: HLA-matched sibling bone marrow in combination with HLA-matched sibling umbilical cord blood if the HLA-matched sibling umbilical cord blood was collected and stored; the HLA-matched sibling bone marrow and cord blood would be matched for HLA-A, B, C, DRB1, and DQB1 * DONOR: Unrelated Umbilical Cord Blood: Unit selection is based on the cryopreserved total nucleated cell (TNC) dose and matching at HLA-A, B antigen level and DRB1 allele level typing; while HLA-C antigen/allele level typing is not considered in the matching criteria, if available, may be used to optimize unit selection * DONOR: Unrelated Umbilical Cord Blood: The patient and the cord blood unit(s) must be matched for at least 4 of 6 loci as defined above * DONOR: Unrelated Umbilical Cord Blood: Selection of two umbilical cord blood (UCB) units is allowed to provide sufficient cell dose * DONOR: Unrelated Umbilical Cord Blood: The UCB unit with the least HLA disparity (with the patient) will be selected first (i.e., selection priority is 6/6 match \> 5/6 match\> 4/6 match); additional UCB units then may be selected to achieve the required cell dose; if a second unit is required, this unit will be the unit that most closely HLA matches the patient and meets minimum size criteria outlined below of at least 1.5 x 10\^7 TNC/kg (i.e. a smaller more closely matched unit will be selected over a larger less well matched unit as long as minimum criteria are met) * DONOR: Unrelated Umbilical Cord Blood: Each UCB unit MUST contain at least 1.5 x 10\^7 TNC per kilogram recipient weight * DONOR: Unrelated Umbilical Cord Blood: The total cell dose of the combined units must be at least 3.0 x 10\^7 TNC per kilogram recipient weight
Exclusion criteria
* Patients with idiopathic aplastic anemia and Fanconi anemia; (patients with aplastic anemia associated with paroxysmal nocturnal hemoglobinuria \[PNH\] or inherited marrow failure syndromes, except Fanconi anemia, will be allowed) * Patients with impaired cardiac function as evidenced by ejection fraction \< 35% (or, if unable to obtain ejection fraction, shortening fraction of \< 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease; patients with a shortening fraction \< 26% may be enrolled if approved by a cardiologist * Patients with impaired pulmonary function as evidenced by diffusion capacity of the lung for carbon monoxide (DLCO) \< 50% of predicted (or, if unable to perform pulmonary function tests, then oxygen \[O2\] saturation \< 92% on room air) * Patients with impaired renal function as evidenced by creatinine-clearance \< 50% for age, weight, height or serum creatinine \> 2 x upper normal limit or dialysis-dependent * Patients with evidence of synthetic dysfunction or severe cirrhosis requiring deferral of conditioning as recommended by a gastroenterology specialist * Patients with an active infectious disease requiring deferral of conditioning; as recommended by an infectious disease specialist * Patients who are positive for human immunodeficiency virus (HIV) * Females who are pregnant or breast-feeding * Patients with a known hypersensitivity to treosulfan and/or fludarabine * Receiving another experimental drug within 4 weeks of initiation of conditioning (day -6) unless approved by the PI * DONOR: Deemed unable to undergo marrow harvesting or PBSC mobilization and leukapheresis * DONOR: HIV-positive * DONOR: With active infectious hepatitis * DONOR: Females with a positive pregnancy test * DONOR: HLA-matched sibling cord blood exclusions: Any cord blood units that have not passed donor screening for infectious disease markers as recommended by the National Marrow Donor Project (NMDP) will not be used unless a waiver is signed by the clinical attending allowing use of cord blood unit; cord blood units are presumed to be cytomegalovirus (CMV) negative regardless of serologic testing due to passive transmission of maternal CMV antibodies * DONOR: Unrelated Umbilical Cord Blood: Any cord blood units with \< 1.5 x 10\^7 total nucleated cells per kilogram recipient weight * DONOR: Unrelated Umbilical Cord Blood: Any cord blood units that have not passed donor screening for infectious disease markers as recommended by NMDP will not be used unless a waiver is signed by the clinical attending allowing use of cord blood unit; cord blood units are presumed to be CMV negative regardless of serologic testing due to passive transmission of maternal CMV antibodies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Preliminary Efficacy | 1 year following transplant | Number of patients engrafted (\>5% donor CD3+ peripheral blood chimerisms) at 1 year following transplant |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Grade II-IV Acute Graft-versus-host Disease | Day 100 post transplant | Number of patients diagnosed with overall grade II-IV acute GVHD by Day 100 post transplant |
| Number of Patients With of Chronic Graft-versus-host Disease | 1 year following transplant | Number of patients diagnosed with chronic GVHD and requiring systemic immunosuppression within 1 year following transplant |
| Donor Chimerism CD3 at 100 Days Post Transplant | Day 100 post transplant | Number of patients with peripheral blood donor chimerism for CD3 less than 5%, 5-49%, 50-94% and greater than or equal to 95% at 100 days post transplant. |
| Disease Response at One Year Following Hematopoietic Cell Transplantation | 1 year following transplant | Number of patients with no evidence of disease at one year following transplant |
| Non-relapse Mortality | 1 year following transplant | Number of patients who experienced non-relapse mortality by 1 year following transplant |
| Number of Participants With Infections | 100 days post transplant | Number of participants with clinically significant infections (bacterial, fungal, viral) requiring treatment within 100 days following transplant |
| Overall Survival | 1 year following transplant | Number of patients alive at 1 year following transplant |
| Donor Chimerism CD33 at Day 100 Post Transplant | 100 days post transplant | Number of patients with peripheral blood donor chimerism for CD33 less than 5%, 5-49%, 50-94% and greater than or equal to 95% at 100 days post transplant. |
| Immune Reconstitution Following Hematopoietic Cell Transplantation | 1 year following transplant | Number of patients with immune reconstitution (defined by a normal range CD3) at 1 year post transplant |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regimen A (PBSCT and BMT) CONDITIONING REGIMEN A : Patients receive treosulfan IV on days -6 to -4 and fludarabine phosphate IV on days -6 to -2. Patients receive anti-thymocyte globulin IV on days -4 to -2. Patients undergoing umbilical cord blood transplantation will also receive low dose total-body irradiation on day -1.
TRANSPLANTATION: Patients receive either bone marrow, peripheral blood stem cells (PBSC), or umbilical cord blood from the donor on day 0. The use of either bone marrow, PBSC, or umbilical cord blood will depend on the donor status.
Patients undergoing bone marrow or PBSC transplantation receive tacrolimus IV continuously or PO twice daily on days -1 to 50 followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
Allogeneic Bone Marrow Transplantation: Infused IV
Anti-Thymocyte Globulin: Given IV
Fludarabine Phosphate: Given IV
Laboratory Biomarker Analysis: Correlative studies
Methotrexate: Given IV
Peripheral Blood Stem Cell Transplantation: Infused IV
Tacrolimus: Given IV or PO
Treosulfan: Given IV | 84 |
| Regimen B (UBCT) CONDITIONING REGIMEN B: Patients receive treosulfan IV on days -6 to -4 and fludarabine phosphate IV on days -6 to -2. Patients receive anti-thymocyte globulin IV on days -4 to -2. Patients undergoing umbilical cord blood transplantation will also receive low dose total-body irradiation on day -1 .
TRANSPLANTATION: Patients receive either bone marrow, peripheral blood stem cells (PBSC), or umbilical cord blood from the donor on day 0. The use of either bone marrow, PBSC, or umbilical cord blood will depend on the donor status.
Patients undergoing UCB transplantation receive cyclosporine IV over 1 hour every 8-12 hours on days -3 to 100 followed by a taper until day 180 in the absence of GVHD. Patients also receive mycophenolate mofetil IV or PO every 8 hours on days 0 to 40 followed by a taper until day 96 in the absence of GVHD.
Anti-Thymocyte Globulin: Given IV
Cyclosporine: Given IV or PO
Fludarabine Phosphate: Given IV
Laboratory Biomarker Analysis: Correlative studies
Mycophenolate Mofetil: Given IV or PO
Total-Body Irradiation: Undergo total body irradiation
Treosulfan: Given IV
Umbilical Cord Blood Transplantation: Single or double unit umbilical cord blood transplant, infused IV | 14 |
| Total | 98 |
Baseline characteristics
| Characteristic | Total | Regimen A (PBSCT and BMT) | Regimen B (UBCT) |
|---|---|---|---|
| Age, Categorical <=18 years | 83 Participants | 70 Participants | 13 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 14 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 87 Participants | 77 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 8 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 76 Participants | 67 Participants | 9 Participants |
| Region of Enrollment United States | 98 participants | 84 participants | 14 participants |
| Sex: Female, Male Female | 31 Participants | 28 Participants | 3 Participants |
| Sex: Female, Male Male | 67 Participants | 56 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 84 | 6 / 14 |
| other Total, other adverse events | 53 / 84 | 10 / 14 |
| serious Total, serious adverse events | 17 / 84 | 5 / 14 |
Outcome results
Primary
Preliminary Efficacy
Number of patients engrafted (\>5% donor CD3+ peripheral blood chimerisms) at 1 year following transplant
Time frame: 1 year following transplant
Population: Regimen B: Three patients expired without CD3+ chimerisms being performed, therefore could not be analyzed for primary efficacy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A (PBSCT and BMT) | Preliminary Efficacy | 83 Participants |
| Regimen B (UBCT) | Preliminary Efficacy | 10 Participants |
Secondary
Disease Response at One Year Following Hematopoietic Cell Transplantation
Number of patients with no evidence of disease at one year following transplant
Time frame: 1 year following transplant
Population: Regimen B: 3 patients expired prior to disease response being evaluated and could not be evaluated for this outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A (PBSCT and BMT) | Disease Response at One Year Following Hematopoietic Cell Transplantation | 78 Participants |
| Regimen B (UBCT) | Disease Response at One Year Following Hematopoietic Cell Transplantation | 8 Participants |
Secondary
Donor Chimerism CD33 at Day 100 Post Transplant
Number of patients with peripheral blood donor chimerism for CD33 less than 5%, 5-49%, 50-94% and greater than or equal to 95% at 100 days post transplant.
Time frame: 100 days post transplant
Population: Regimen B: 2 patients expired without CD33+ chimerisms being performed and could not be evaluated for this outcome
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Regimen A (PBSCT and BMT) | Donor Chimerism CD33 at Day 100 Post Transplant | Greater than equal to 95% | 72 Participants |
| Regimen A (PBSCT and BMT) | Donor Chimerism CD33 at Day 100 Post Transplant | 5-49% | 4 Participants |
| Regimen A (PBSCT and BMT) | Donor Chimerism CD33 at Day 100 Post Transplant | 50-94% | 8 Participants |
| Regimen A (PBSCT and BMT) | Donor Chimerism CD33 at Day 100 Post Transplant | Less than 5% | 0 Participants |
| Regimen B (UBCT) | Donor Chimerism CD33 at Day 100 Post Transplant | Less than 5% | 1 Participants |
| Regimen B (UBCT) | Donor Chimerism CD33 at Day 100 Post Transplant | Greater than equal to 95% | 7 Participants |
| Regimen B (UBCT) | Donor Chimerism CD33 at Day 100 Post Transplant | 50-94% | 2 Participants |
| Regimen B (UBCT) | Donor Chimerism CD33 at Day 100 Post Transplant | 5-49% | 2 Participants |
Secondary
Donor Chimerism CD3 at 100 Days Post Transplant
Number of patients with peripheral blood donor chimerism for CD3 less than 5%, 5-49%, 50-94% and greater than or equal to 95% at 100 days post transplant.
Time frame: Day 100 post transplant
Population: Regimen B: 3 patients expired without CD3+ chimerisms being performed and could not be evaluated for this outcome
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Regimen A (PBSCT and BMT) | Donor Chimerism CD3 at 100 Days Post Transplant | 5-49% | 6 Participants |
| Regimen A (PBSCT and BMT) | Donor Chimerism CD3 at 100 Days Post Transplant | 50 - 94% | 29 Participants |
| Regimen A (PBSCT and BMT) | Donor Chimerism CD3 at 100 Days Post Transplant | Less than 5% | 0 Participants |
| Regimen A (PBSCT and BMT) | Donor Chimerism CD3 at 100 Days Post Transplant | Greater than equal to 95% | 49 Participants |
| Regimen B (UBCT) | Donor Chimerism CD3 at 100 Days Post Transplant | Less than 5% | 1 Participants |
| Regimen B (UBCT) | Donor Chimerism CD3 at 100 Days Post Transplant | 50 - 94% | 2 Participants |
| Regimen B (UBCT) | Donor Chimerism CD3 at 100 Days Post Transplant | 5-49% | 1 Participants |
| Regimen B (UBCT) | Donor Chimerism CD3 at 100 Days Post Transplant | Greater than equal to 95% | 7 Participants |
Secondary
Immune Reconstitution Following Hematopoietic Cell Transplantation
Number of patients with immune reconstitution (defined by a normal range CD3) at 1 year post transplant
Time frame: 1 year following transplant
Population: Regimen A: 11 patients did not have lymphocyte subsets drawn post-transplant and could not be evaluated for outcome; Regimen B: 3 patients expired prior to lymphocyte subsets being evaluated and 2 patients did not have lymphocyte subsets drawn post-transplant and could not be evaluated for outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A (PBSCT and BMT) | Immune Reconstitution Following Hematopoietic Cell Transplantation | 39 Participants |
| Regimen B (UBCT) | Immune Reconstitution Following Hematopoietic Cell Transplantation | 4 Participants |
Secondary
Non-relapse Mortality
Number of patients who experienced non-relapse mortality by 1 year following transplant
Time frame: 1 year following transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A (PBSCT and BMT) | Non-relapse Mortality | 2 Participants |
| Regimen B (UBCT) | Non-relapse Mortality | 5 Participants |
Secondary
Number of Participants With Infections
Number of participants with clinically significant infections (bacterial, fungal, viral) requiring treatment within 100 days following transplant
Time frame: 100 days post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A (PBSCT and BMT) | Number of Participants With Infections | 57 Participants |
| Regimen B (UBCT) | Number of Participants With Infections | 9 Participants |
Secondary
Number of Patients With Grade II-IV Acute Graft-versus-host Disease
Number of patients diagnosed with overall grade II-IV acute GVHD by Day 100 post transplant
Time frame: Day 100 post transplant
Population: Regimen B: 2 patients expired too early for evaluation for acute GVHD and could not be evaluated for this outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A (PBSCT and BMT) | Number of Patients With Grade II-IV Acute Graft-versus-host Disease | 44 Participants |
| Regimen B (UBCT) | Number of Patients With Grade II-IV Acute Graft-versus-host Disease | 8 Participants |
Secondary
Number of Patients With of Chronic Graft-versus-host Disease
Number of patients diagnosed with chronic GVHD and requiring systemic immunosuppression within 1 year following transplant
Time frame: 1 year following transplant
Population: Regimen B: 3 patients expired too early for evaluation for chronic GVHD and could not be evaluated for this outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A (PBSCT and BMT) | Number of Patients With of Chronic Graft-versus-host Disease | 29 Participants |
| Regimen B (UBCT) | Number of Patients With of Chronic Graft-versus-host Disease | 5 Participants |
Secondary
Overall Survival
Number of patients alive at 1 year following transplant
Time frame: 1 year following transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A (PBSCT and BMT) | Overall Survival | 80 Participants |
| Regimen B (UBCT) | Overall Survival | 9 Participants |