Acute Lymphoblastic Leukemia, Acute Myelogenous Leukemia, Biphenotypic Leukemia, Burkitt Lymphoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Follicular Lymphoma, Hodgkin Lymphoma, Large-cell Lymphoma, Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Marginal Zone B-Cell Lymphoma, Multiple Myeloma, Myelodysplastic Syndromes, Natural Killer Cell Malignancies, Prolymphocytic Leukemia, Small Lymphocytic Lymphoma, Undifferentiated Leukemia
Conditions
Keywords
CML, MDS, CLL, ALL, AML
Brief summary
This is a single center pilot study of a non-myeloablative umbilical cord blood transplant for the treatment of a hematological malignancy with a single infusion of T regulatory (Treg) given shortly after UCB transplantation.
Interventions
BIOLOGICALInfusion of Treg
Allopurinol on day -7 to day 0 Cyclophosphamide 50 mg/kg IV over 2 hours on day -6 Fludarabine 30mg/m2 IV over 1 hour on day -6, -5, -4, -3, and -2 Total Body Irradiation 200 cGy as a single dose Sirolimus 8mg-12mg oral loading dose followed by single dose 4mg/day. Levels are to be monitored 3 times/week in the first week, weekly until day +60, and as clinically indicated until day +100 post-transplantation. Mycophenolate Mofetil (MMF) 3 gram/day IV/PO divided in 2 or 3 doses. Stop MMF at day +30 or 7 days after neutrophil recovery, whichever day is later, if no acute GVHD. DUCBT followed Tregs - double umbilical cord blood transplant (FIRST) followed by the Treg cell infusion (SECOND) no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Must be ≥18, but \< 70 years of age with no matched 7/8 or 8/8 sibling donor - patients ≥ 70 and ≤ 75 years of age may be eligible if they have a Co-Morbidity score ≤ 2 (http://www.qxmd.com/calculate-online/hematology/hct-ci) * UCB unit(s) composing the graft will be selected according to the current University of Minnesota umbilical cord blood graft selection algorithm and an additional cord blood unit to be used as the source to manufacture the Treg product. This UCB unit must be matched at 4-6/6 to the patient, considering HLA-A, B at the antigen level and DRB1 at the allele level * Acute Leukemias: Must be in remission by morphology. Also a small percentage of blasts that is equivocal between marrow regeneration versus early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse. Refer to Section 5.2 for complete definitions. * Burkitt's Lymphoma in CR2 or subsequent CR * Natural Killer Cell Malignancies * Chronic Myelogenous Leukemia: all types except refractory blast crisis. Chronic phase patients must have failed at least two different tyrosine-kinase inhibitors (TKIs), or been intolerant to all available TKIs or have T315I mutation. * Myelodysplastic Syndrome: IPSS INT-2 or High Risk; R-IPSS High or Very High; WHO classification: RAEB-1, RAEB-2; Severe Cytopenias: ANC \< 0.8, Anemia or thrombocytopenia requiring transfusion; Poor or very poor risk cytogenetics based on IPSS or R-IPSS definitions; therapy-related MDS. Blasts must be be \< 5%, preferably \< 20% blasts by morphology by bone marrow aspirate morphology.. If ≥ 5% blasts, chemotherapy for cytoreduction to \<5% blasts prior to transplantation may be considered. * Chronic myeloid neoplasms, including but not limited to CMML with blasts must around 5% blasts, preferably \< 20% blasts by morphology by bone marrow aspirate morphology. If ≥5% blasts, chemotherapy for cytoreduction to \<5% blasts prior to transplantation may be considered. * Large-Cell Lymphoma, Hodgkin Lymphoma and Multiple Myeloma with chemotherapy sensitive disease that has failed or patients who are ineligible for an autologous transplant. * Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Marginal Zone B-Cell Lymphoma, Follicular Lymphoma, which have progressed within 12 months of achieving a partial or complete remission. Patients who had remissions lasting \> 12 months are eligible after at least two prior therapies. Patients with bulky disease should be considered for debulking chemotherapy before transplant. Patients with refractory disease are eligible, unless has bulky disease and an estimated tumor doubling time of less than one month. * Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Prolymphocytic Leukemia are eligible after initial therapy if chemotherapy sensitive. * Patients must have undergone an autologous transplant ≤ 12 months prior to transplant on this study or have received multi-agent or immunosuppressive chemotherapy within 3 months of the preparative regimen. Performance Status, Organ Function, Contraception Use * Karnofsky score ≥ 70% (Appendix II) * Adequate organ function within 14 days (30 days for cardiac and pulmonary) of registration on-study defined as: * Renal: creatinine ≤ 2.0 mg/dL, for patient with a creatinine \> 1.2 mg/dL or a history of renal dysfunction an estimated glomerular filtration rate ≥ 40 mL/min/1.73 m2 is required * ALT, AST and alkaline phosphatase ≤ 5 x upper limit of normal and total bilirubin ≤ 2.5 mg/dL except for patients with Gilbert's syndrome or hemolysis * Pulmonary function: DLCO, FEV1, FVC ≥ 40% predicted, and absence of O2 requirements. * Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction ≥ 40%. * Sexually active females of childbearing potential and males with partners of child-bearing potential must agree to use adequate birth control during study treatment. * Voluntary written consent
Exclusion criteria
* Untreated active infection * History of HIV infection * Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy * Prior allogeneic transplantation * Less than 3 months from myeloablative conditioning for autologous transplantation (if applicable) * Evidence of progressive disease by imaging modalities or biopsy - persistent PET activity, though possibly related to lymphoma, is not an exclusion criterion in the absence of CT changes indicating progression. * CML in blast crisis * Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressing on salvage therapy. * Active central nervous system malignancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Survived | 2 years | Count of patients who survived 2 years post intervention |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Treatment Related Mortality (TRM) | 6 months | Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints. |
| Number of Participants Who Experienced Relapse | 1 year | Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints. |
| Number of Participants With Incidence of Bacterial, Viral and Fungal Infections | 1 year | Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints. |
| Number of Participant With Detectable Treg Cells at d14 | 14 days | The proportion of patients with detectable Treg cells at day 14 post infusion |
| Number of Participants With Immune Reconstitution | Assessed at Day 4, weekly for 8 weeks | The proportion of patients with immune reconstitution. Continuous endpoints will be described by medians, ranges and interquartile ranges as well as means and standard deviations if normally distributed. |
| Number of Participants Experiencing Treg Cell Infusion Toxicity | 48 hours post infusion | Incidence of Adverse Events |
| Number of Participants With Grade II-IV aGVHD | Assessed weekly until day 100, then day 180, 360 | Probability of grade II-IV aGVHD |
| Percentage of Donor Cell Chimerism | Day +100 | The incidence of chimerism in patients treated |
| Number of Participants Survived One Year Post-transplant | 1 year | The probability of survival, one year post-treatment |
| Number of Participants With Neutrophil Recovery | Day 42 | The incidence of neutrophil recovery, that is return of neutrophil counts to ≥ 5 X 10\^8/L in treated patients |
| Number of Participants With Platelet Recovery | 1 year | The incidence of platelet recovery (return of platelet counts to \> 20,000/μL) in treated patients |
| Number of Participants With Chronic GVHD | 1 year | The incidence of chronic GVHD in treated patients after one year |
| Length of Treg Survival | 24 hours post infusion | Length of Treg survival after infusion of Treg. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treg Infusion The Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Treg Infusion |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 3 |
| other Total, other adverse events | 2 / 3 |
| serious Total, serious adverse events | 2 / 3 |
Outcome results
Primary
Number of Participants Survived
Count of patients who survived 2 years post intervention
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treg Infusion | Number of Participants Survived | 1 Participants |
Secondary
Length of Treg Survival
Length of Treg survival after infusion of Treg.
Time frame: 24 hours post infusion
Population: Samples were not analyzed, and so data not available for reporting.
Secondary
Number of Participants Experiencing Treatment Related Mortality (TRM)
Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treg Infusion | Number of Participants Experiencing Treatment Related Mortality (TRM) | 0 Participants |
Secondary
Number of Participants Experiencing Treg Cell Infusion Toxicity
Incidence of Adverse Events
Time frame: 48 hours post infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treg Infusion | Number of Participants Experiencing Treg Cell Infusion Toxicity | 2 Participants |
Secondary
Number of Participants Survived One Year Post-transplant
The probability of survival, one year post-treatment
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treg Infusion | Number of Participants Survived One Year Post-transplant | 2 Participants |
Secondary
Number of Participants Who Experienced Relapse
Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treg Infusion | Number of Participants Who Experienced Relapse | 1 Participants |
Secondary
Number of Participants With Chronic GVHD
The incidence of chronic GVHD in treated patients after one year
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treg Infusion | Number of Participants With Chronic GVHD | 0 Participants |
Secondary
Number of Participants With Grade II-IV aGVHD
Probability of grade II-IV aGVHD
Time frame: Assessed weekly until day 100, then day 180, 360
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treg Infusion | Number of Participants With Grade II-IV aGVHD | 2 Participants |
Secondary
Number of Participants With Immune Reconstitution
The proportion of patients with immune reconstitution. Continuous endpoints will be described by medians, ranges and interquartile ranges as well as means and standard deviations if normally distributed.
Time frame: Assessed at Day 4, weekly for 8 weeks
Population: Samples were not analyzed, and so data not available for reporting.
Secondary
Number of Participants With Incidence of Bacterial, Viral and Fungal Infections
Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.
Time frame: 1 year
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treg Infusion | Number of Participants With Incidence of Bacterial, Viral and Fungal Infections | Bacterial | 1 Participants |
| Treg Infusion | Number of Participants With Incidence of Bacterial, Viral and Fungal Infections | Viral | 2 Participants |
| Treg Infusion | Number of Participants With Incidence of Bacterial, Viral and Fungal Infections | Fungal | 0 Participants |
Secondary
Number of Participants With Neutrophil Recovery
The incidence of neutrophil recovery, that is return of neutrophil counts to ≥ 5 X 10\^8/L in treated patients
Time frame: Day 42
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treg Infusion | Number of Participants With Neutrophil Recovery | 2 Participants |
Secondary
Number of Participants With Platelet Recovery
The incidence of platelet recovery (return of platelet counts to \> 20,000/μL) in treated patients
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treg Infusion | Number of Participants With Platelet Recovery | 2 Participants |
Secondary
Number of Participant With Detectable Treg Cells at d14
The proportion of patients with detectable Treg cells at day 14 post infusion
Time frame: 14 days
Population: Samples were not analyzed, and so data not available for reporting.
Secondary
Percentage of Donor Cell Chimerism
The incidence of chimerism in patients treated
Time frame: Day +100
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treg Infusion | Percentage of Donor Cell Chimerism | 72 percentage of donor cells |