Natural Killer Cells Before and After Donor Stem Cell Transplant in Treating Patients With Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia

PRIMARY OBJECTIVE:

I. To evaluate safety, tolerability and identify the maximum tolerated dose (MTD) of expanded natural killer (NK) cells to be used in patients with myeloid malignancies undergoing a haploidentical stem-cell transplant.

SECONDARY OBJECTIVES:

I. To determine survival of NK cells in vivo post-transplant. II. To determine the function of NK cells post-transplant and compare with a retrospective control treated with no NK cells.

III. To estimate the proportion of patients with engraftment/graft failure. IV. To estimate the non-relapse mortality (NRM) at day 100 post-transplant. V. To estimate the cumulative incidence of grade III-IV aGVHD (acute graft-versus-host disease) at day 100.

VI. To assess the rate of chronic graft-versus-host disease (GVHD) within the first year post transplantation.

VII. To assess immune reconstitution post-transplant. VIII. To assess disease response, disease-free survival (DFS) and overall survival (OS) after transplantation.

IX. To perform a retrospective comparison of patients treated on the study with NK cells will be performed with a Center for International Blood and Marrow Transplant Research (CIBMTR) control of similar patients who did not receive NK cells.

OUTLINE: This is a phase I, dose-escalation study of NK cells followed by a phase II study. Patients are assigned to 1 of 2 conditioning regimens.

MYELOABLATIVE CONDITIONING REGIMEN: Patients receive high-dose melphalan intravenously (IV) over 30 minutes on day -7, fludarabine IV over 1 hour on days -7 to -4, undergo total-body irradiation (TBI) on day -3, and NK cells IV over 30 minutes on day -2 or -1.

NON-MYELOABLATIVE CONDITIONING REGIMEN: Patients receive melphalan IV over 30 minutes on day -7, fludarabine IV over 1 hour on days -7 to -4, undergo TBI on day -3, and receive NK cells IV over 30 minutes on day -2 or -1.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell (PBSC) or bone marrow transplant on day 0.

POST-TRANSPLANT CYCLOPHOSPHAMIDE AND GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4, tacrolimus IV beginning on day 5 for 2 weeks and then orally (PO) for approximately 4 months, and mycophenolate mofetil PO thrice daily (TID) beginning on day 5 for approximately 6-7 months.

NK CELLS: Patients receive NK cells IV over 30 minutes on days 7 and 28-90.

After completion of study treatment, patients are followed up for 2 years.

• Allogeneic Hematopoietic Stem Cell Transplantation (Procedure), also known as Allogeneic, Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT, Stem Cell Transplantation, Allogeneic: Undergo allogeneic PBSC or bone marrow transplant
• Bone Marrow Transplantation (Procedure), also known as Blood and Bone Marrow Transplant, BMT, Bone Marrow Grafting, Bone Marrow Transplant, Marrow Transplantation: Undergo allogeneic PBSC or bone marrow transplant
• Cyclophosphamide (Drug), also known as (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719: Given IV
• Fludarabine (Drug), also known as Fluradosa: Given IV
• Laboratory Biomarker Analysis (Other): Correlative studies
• Melphalan (Drug), also known as Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813: Given IV
• Mycophenolate Mofetil (Drug), also known as CellCept, MMF: Given PO
• Natural Killer Cell Therapy (Biological): Given IV
• Peripheral Blood Stem Cell Transplantation (Procedure), also known as PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplant, Peripheral Stem Cell Transplantation: Undergo allogeneic PBSC or bone marrow transplant
• Tacrolimus (Drug), also known as FK 506, Fujimycin, Hecoria, Prograf, Protopic: Given IV and PO
• Total-Body Irradiation (Radiation), also known as SCT_TBI, TBI, Total Body Irradiation, Whole Body Irradiation, Whole-Body Irradiation: Undergo TBI

Primary outcomes

• Number of Participants With Dose Limiting Toxicities (DLTs) [Up to day 70 post-transplant]: Number of participants that experienced dose limiting toxicities.

Secondary outcomes

• 100-day Treatment Related Mortality [Up to 100 days post-transplant]: Number of participants who died within 100 days post-transplant.
• Overall Survival [Up to 2 years]: Number of participants with overall survival after 2 years.

Sex: All, ages: 2 Years to 65 Years

Inclusion Criteria:

* Eligibility for pediatric patients will be determined in conjunction with an MD Anderson Cancer Center (MDACC) pediatrician; patients age 2-17 years old may be enrolled after at least 4 adults (ages 18-65 years old) have been treated without toxicity
* Patient with no matched related donor who has a related haploidentical donor identified (=< 7/8 allele match at the A, B, C, DR loci) who is willing to undergo a bone marrow harvest and an NK cell collection approximately 2 weeks of the recipient's admission for transplant; the donor must be 16 years of age or older and weigh at least 110 pounds
* Patients with one of the following diseases: acute myeloid leukemia (AML): a. first complete remission with high-risk features defined as: (i) greater than 1 cycle of induction therapy required to achieve remission; (ii) preceding myelodysplastic syndrome (MDS); (iii) presence of FLT3 mutations or internal tandem duplication or other mutations associated with poor-risk AML (e.g. DNMT3A, TET2); (iv) French-American-British Classification (FAB) M6 or M7 classification; (v) adverse cytogenetics: -5, deletion (del) 5q, -7, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 or complex karyotype (> 3 abnormalities); (vi) treatment-related AML, or b. second or greater remission; patients beyond second remission have to be in complete remission (CR) at transplant to be eligible, or c. primary induction failure with partial response to therapy who achieve adequate cytoreduction
* Patients with myelodysplastic syndromes (MDS): a. de novo MDS with intermediate or high-risk International Prognostic Scoring System (IPSS) scores; patients with intermediate-1 features should have failed to respond to hypomethylating agent therapy, or b. patients with treatment-related MDS
* Chronic myeloid leukemia (CML): a. failed to achieve cytogenetic remission or have cytogenetic relapse after treatment with at least 2 tyrosine kinase inhibitors, or b. accelerated phase or blast phase at any time
* Performance score of at least 70% by Karnofsky or 0 to 1 by Eastern Cooperative Oncology Group (ECOG) (age >= 12 years), or Lansky Play-performance scale of at least 70% or greater (age < 12 years)
* Serum creatinine clearance equal or more than 50 ml/min (calculated with Cockcroft-Gault formula)
* Bilirubin equal or less than 1.5 mg/dl except for Gilbert's disease
* Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) equal or less than 200 IU/ml for adults
* Conjugated (direct) bilirubin less than 2 x upper limit of normal
* Left ventricular ejection fraction equal or greater than 40%
* Diffusing capacity of the lung for carbon monoxide (DLCO) equal or greater than 50% predicted corrected for hemoglobin; for children =< 7 years of age who are unable to perform pulmonary function tests (PFT), oxygen saturation >= 92% on room air by pulse oximetry
* Patient or patient's legal representative, parent(s) or guardian should provide written informed consent; assent of a minor if participant's age is at least seven and less than eighteen years

Exclusion Criteria:

* Human immunodeficiency virus (HIV) positive; active hepatitis B or C
* Uncontrolled infections; principal investigator (PI) is the final arbiter of this criterion
* Liver cirrhosis
* Central nervous system (CNS) involvement within 3 months
* Positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization
* Inability to comply with medical therapy or follow-up

Participant flow

Outcome results

• Number of Participants With Dose Limiting Toxicities (DLTs) (Primary), Count of participants, Participants: Phase I: NK Cell Dose Level 1_10^4 0; Phase I: NK Cell Dose Level 2_10^5 0; Phase I: NK Cell Dose Level 3_10^6 0; Phase I: NK Cell Dose Level 4_ 10^7 0; Phase I: NK Cell Dose Level 5_3x10^7 0; Phase I: NK Cell Dose Level 6_10^8 0; Phase II: NK Cell Dose Level 5_3x10^7 0; Phase II: NK Cell Dose Level 6_10^8 0; Donor 0
• 100-day Treatment Related Mortality (Secondary), Count of participants, Participants: Phase I: NK Cell Dose Level 1_10^4 1; Phase I: NK Cell Dose Level 2_10^5 0; Phase I: NK Cell Dose Level 3_10^6 0; Phase I: NK Cell Dose Level 4_ 10^7 0; Phase I: NK Cell Dose Level 5_3x10^7 0; Phase I: NK Cell Dose Level 6_10^8 0; Phase II: NK Cell Dose Level 5_3x10^7 0; Phase II: NK Cell Dose Level 6_10^8 3; Donor 0
• Overall Survival (Secondary), Count of participants, Participants: Phase I: NK Cell Dose Level 1_10^4 1; Phase I: NK Cell Dose Level 2_10^5 1; Phase I: NK Cell Dose Level 3_10^6 1; Phase I: NK Cell Dose Level 4_ 10^7 0; Phase I: NK Cell Dose Level 5_3x10^7 0; Phase I: NK Cell Dose Level 6_10^8 0; Phase II: NK Cell Dose Level 5_3x10^7 1; Phase II: NK Cell Dose Level 6_10^8 5; Donor 0

Adverse events

Time frame: Up to 2 years.

Serious adverse events by term

Other adverse events by term

• Results publication: Ciurea SO, Kongtim P, Soebbing D, Trikha P, Behbehani G, Rondon G, Olson A, Bashir Q, Gulbis AM, Indreshpal K, Rezvani K, Shpall EJ, Bassett R, Cao K, Martin AS, Devine S, Horowitz M, Pasquini M, Lee DA, Champlin RE. Decrease post-transplant relapse using donor-derived expanded NK-cells. Leukemia. 2022 Jan;36(1):155-164. doi: 10.1038/s41375-021-01349-4. Epub 2021 Jul 26. PMID 34312462

• Study Protocol and Statistical Analysis Plan (PDF, 2020-05-14)

• Samer Srour, Principal investigator, M.D. Anderson Cancer Center

NIH grants: P01CA049639