Acute Myeloid Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
non-myeloablative haploidentical transplant, hematopoietic cell transplant, natural killer cells, adoptive cellular therapy
Brief summary
This is a phase II multi-institutional therapeutic study of NK-cell based nonmyeloablative haploidentical transplantation for the treatment of high-risk acute myeloid diseases. Enrollment will use a two-stage design. Stage 1 will enroll 15 patients unless an early stopping rule is met. If 9 or more of these first 15 patients achieve leukemia free neutrophil engraftment at day +28 accrual will move to stage 2. In stage 2, an additional 28 patients will be enrolled for a total of 43 patients. Patients will be followed for disease response for 2 years.
Detailed description
A reduced intensity conditioning using Fludara, Cytoxan, and irradiation will start on day -22, followed by infusion of donor NK (natural killer) cells on day-17, 6 doses of interleukin-2 (IL-2) to promote NK expansion (day -17 to day -7), 2 doses of ATG for additional immunosuppression to promote engraftment (day -5 to -4), and infusion of a TCR α/β-depleted same donor graft on day 0.
Interventions
Preparative Regimen: 1\) fludarabine 40 mg/m\^2 x 4 doses on Days -22 through -19 pretransplant, 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pretransplant, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pretransplant,
BIOLOGICALNK Cells
CD3\^- CD19\^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant.
DRUGInterleukin-2
Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion
BIOLOGICALCD34 Graft/Anti-thymocyte globulin
Single donor filgrastim mobilized CD34+ selected peripheral blood stem cell graft (minimum cell dose of 5 x 10\^6/kg) on day 0. Rabbit anti-thymocyte globulin (ATG) will be administered on day -1 (0.5 mg/kg) and day +1 and +2 (2.5 mg/kg) pretransplant per institutional guidelines. ATG dosing not identical for all patients.
BIOLOGICALDonor TCR α/β-depleted Graft/ATG
Single donor TCR α/β-depleted filgrastim-mobilized peripheral blood stem cells (PBSC) graft (minimum cell dose of 5 x 10\^6/kg) on day 0. ATG will be administered on days -6 and -5 (3mg/kg) for most patients.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) RAEB-1 or RAEB-2 fitting within one of the following disease groups: * Primary induction failure (PIF): Patients who have not achieved a complete remission (CR) after two induction cycles of cytotoxic therapy (i.e. 7+ 3, MEC, FLAG, etc.) and having ≤ 10,000 absolute circulating blasts measured at least 21 days from prior therapy. Hydroxyurea may be used to control blasts count. Demethylating agents do not count as induction therapy; however early re-induction therapy based on residual disease on a day 14 BM will count as a 2nd cycle * Relapsed Disease with low disease burden (AML or MDS with ≤ 10,000 absolute circulating blasts. No re-induction attempts are required, but a maximum of 2 reinduction attempts are allowed to be eligible. * CR3 or greater: This will include CRp defined as CR without platelet recovery to 100,000/mcL. * CR1 or CR2 with high risk features: Includes therapy induced, prior MDS or MPD, high risk cytogenetic or molecular phenotype with no available donor (sibling or unrelated adult) Patients with known prior central nervous system (CNS) involvement are eligible provided that it has been treated and CSF is clear for at least 2 weeks prior to enrollment. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment. * Available related HLA-haploidentical adult donor by at least Class I serologic typing at the A&B locus * Karnofsky score \> 50% * Adequate organ function within 28 days of study registration defined as: * Hepatic: AST ≤ 3 x upper limit of institutional normal, total bilirubin ≤ 2.0 mg/dl * Renal: estimated glomerular filtration rate (GFR) ≥ 50 mL/min/1.73m\^2 * Pulmonary: Oxygen saturation ≥ 90% on room air and DLCOcor ≥ 40% * Cardiac: Ejection Fraction ≥ 35% and no uncontrolled angina, severe uncontrolled ventricular or arterial arrhythmias, or any evidence of acute ischemia or active conduction system abnormalities (rate controlled atrial fibrillation is not an exclusion) * Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to NK cell infusion (except for those prescribed as part of the study) * Women of child bearing potential must have a negative pregnancy test within 28 days prior to study registration and agree to use adequate birth control during study treatment * Voluntary written consent
Exclusion criteria
* Biphenotypic leukemia * Allogeneic transplant for AML within previous 6 months * New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that has not been evaluated with bronchoscopy, if feasible. Infiltrates attributed to infection must be stable/improving (with associated clinical improvement) after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections). * Uncontrolled bacterial, fungal or viral infections including HIV - chronic asymptomatic viral hepatitis is allowed * Known hypersensitivity to any of the study agents * Received any investigational drugs within the 14 days before 1st dose of fludarabine * Requires agents other than hydroxyurea to control blast count Donor Selection: * Related donor (sibling, parent, offspring, parent or offspring of an HLA identical sibling) 12-75 years of age. (It is recognized individual institutions may have differing donor age guidelines. This is acceptable as long as no donor is younger than 12 years or older than 75 years). * Body weight of at least 40 kilograms * In general good health as determined by the medical provider * HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus * Able and willing to have up to 4 separate apheresis collections * Not pregnant * Voluntary written consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Donor Neutrophil Engraftment | Day 28 | The rate of donor neutrophil engraftment in the absence of leukemia at day +28 will be determined. Successful neutrophil engraftment is defined as an absolute donor-derived neutrophil count of \>500 cells/μl. Leukemia free is defined as \<5% bone marrow blasts, absence of blasts with Auer rods; absence of extramedullary disease; but cytogenetic or molecular minimal residual disease is allowed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Disease Free Survival | At 6 Months | — |
| Number of Participants With Treatment Related Mortality (TRM) | At 6 Months | Cumulative incidence will be used to estimate TRM. |
| Number of Participants Who Relapse | 2 Years | Cumulative incidence will be used to estimate relapse. |
| Number of Participants With Early In Vivo Expansion of Natural Killer (NK) Cells | Day 12 | Successful in vivo donor NK cell expansion will be defined by measuring an absolute circulating donor-derived NK cell count of \>100 cells/μl in patient's peripheral blood 12 days after infusion. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CD34+ Selection Schema : High-Risk Acute Myeloid Disease Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and filgrastim mobilized CD34+ selected peripheral blood stem cell graft from the same donor.
Preparative Regimen:
1\) fludarabine 40 mg/m\^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3\^- CD19\^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | 7 |
| TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor.
Preparative Regimen:
1\) fludarabine 40 mg/m\^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3\^- CD19\^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | 17 |
| TCR α/β Depletion and ATG at Different Time Schema Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor.
Preparative Regimen:
1\) fludarabine 40 mg/m\^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3\^- CD19\^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered (3 mg/kg/day) pre-tx on different days per institutional guidelines | 1 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Early Death | 1 | 0 | 0 |
| Overall Study | Not evaluable | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | CD34+ Selection Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion and ATG at Different Time Schema | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 6 Participants | 1 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 11 Participants | 0 Participants | 14 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 0 Participants | 6 Participants |
| Sex: Female, Male Male | 6 Participants | 12 Participants | 1 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 25 / 25 |
| serious Total, serious adverse events | 19 / 25 |
Outcome results
Primary
Number of Participants With Donor Neutrophil Engraftment
The rate of donor neutrophil engraftment in the absence of leukemia at day +28 will be determined. Successful neutrophil engraftment is defined as an absolute donor-derived neutrophil count of \>500 cells/μl. Leukemia free is defined as \<5% bone marrow blasts, absence of blasts with Auer rods; absence of extramedullary disease; but cytogenetic or molecular minimal residual disease is allowed.
Time frame: Day 28
Population: CD34 Schema - out of 7 patients, 2 patients were NA due to leukemia, 1 died, and 1 was not evaluable so 3 were analyzed (4 were not).~TCRα/β Schema - out of 17 patients, 6 patients were NA due to leukemia, 2 were not evaluable.~TCRα/β Schema + ATG - 1 patient was given ATG at a different time so their results were reported separately
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CD34+ Selection Schema : High-Risk Acute Myeloid Disease | Number of Participants With Donor Neutrophil Engraftment | 3 Participants |
| TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | Number of Participants With Donor Neutrophil Engraftment | 7 Participants |
| TCR α/β Depletion and ATG at Different Time Schema | Number of Participants With Donor Neutrophil Engraftment | 1 Participants |
Secondary
Number of Participants Who Relapse
Cumulative incidence will be used to estimate relapse.
Time frame: 2 Years
Population: CD34 Graft - of 7, 1 patient not evaluable, 2 patients did not clear disease, 2 died before 2 years.~TCRα/β Schema - of 17, 7 didn't achieve remission, 2 died before 2 years, 2 were not evaluable.~TCRα/β Schema + ATG at different time - 1 patient received ATG at different time, results reported separately.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CD34+ Selection Schema : High-Risk Acute Myeloid Disease | Number of Participants Who Relapse | 2 Participants |
| TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | Number of Participants Who Relapse | 6 Participants |
| TCR α/β Depletion and ATG at Different Time Schema | Number of Participants Who Relapse | 0 Participants |
Secondary
Number of Participants With Disease Free Survival
Time frame: At 6 Months
Population: CD34 Schema - of 7, 1 patient was not evaluable. TCRα/β Schema - of 17, 15 patients evaluable for DFS , 2 patients were not evaluable.~TCRα/β Schema + ATG at different time - 1 patient given ATG at different time so results reported separately
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CD34+ Selection Schema : High-Risk Acute Myeloid Disease | Number of Participants With Disease Free Survival | 1 Participants |
| TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | Number of Participants With Disease Free Survival | 6 Participants |
| TCR α/β Depletion and ATG at Different Time Schema | Number of Participants With Disease Free Survival | 1 Participants |
Secondary
Number of Participants With Early In Vivo Expansion of Natural Killer (NK) Cells
Successful in vivo donor NK cell expansion will be defined by measuring an absolute circulating donor-derived NK cell count of \>100 cells/μl in patient's peripheral blood 12 days after infusion.
Time frame: Day 12
Population: CD34 Graft - of 7, 1 NA due to missing data/tests not performed, 1 not evaluable.~TCRα/β Schema - of 17 patients, 15 were evaluable for outcome measure criteria, 2 were not evaluable.~TCRα/β Schema + ATG at different time - 1 given ATG at different time, results reported separately.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CD34+ Selection Schema : High-Risk Acute Myeloid Disease | Number of Participants With Early In Vivo Expansion of Natural Killer (NK) Cells | 1 Participants |
| TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | Number of Participants With Early In Vivo Expansion of Natural Killer (NK) Cells | 6 Participants |
| TCR α/β Depletion and ATG at Different Time Schema | Number of Participants With Early In Vivo Expansion of Natural Killer (NK) Cells | 1 Participants |
Secondary
Number of Participants With Treatment Related Mortality (TRM)
Cumulative incidence will be used to estimate TRM.
Time frame: At 6 Months
Population: CD34 Schema - of 7 patients, 1 was not evaluable. TCRα/β Schema - of 17 patients, 8 died of disease, 2 did not have TRM at 6 months, 2 were not evaluable.~TCRα/β Schema + ATG at different time - 1 patient given ATG at different time, results reported separately.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CD34+ Selection Schema : High-Risk Acute Myeloid Disease | Number of Participants With Treatment Related Mortality (TRM) | 2 Participants |
| TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | Number of Participants With Treatment Related Mortality (TRM) | 5 Participants |
| TCR α/β Depletion and ATG at Different Time Schema | Number of Participants With Treatment Related Mortality (TRM) | 0 Participants |