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Cell Therapy (CIML NK Cells) for the Treatment of Recurrent Myeloid Disease after Donor Blood Stem Cell Transplant

Trial Status: Active

This phase I trial studies the side effects and best dose of cell therapy (CIML NK cells) in treating patients with myeloid disease that has come back (recurrent) after undergoing a donor blood stem cell transplant. Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. CIML NK cells may recognize and kill cancer cells. Aldesleukin may stimulate white blood cells, including natural killer cells, to kill myeloid cells. Giving CIML NK cells with aldesleukin may increase the levels of NK cells and kill more myeloid cells.

Inclusion Criteria

  • Histologically or cytologically confirmed relapse of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) (chronic myelomonocytic leukemia [CMML] or myelofibrosis or MDS/MPN with >= 5% blasts in the marrow)
  • Relapse at >= 2 months after first related donor haploidentical stem cell transplantation
  • Available original donor (same donor as used for the initial stem cell transplant) that is willing and eligible for non-mobilized collection
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Recipient donor T cell chimerism >= 20% within the 4 weeks prior to cell infusion
  • Patient with =< 50% bone marrow involvement within 4 weeks prior to cell infusion
  • No systemic corticosteroid therapy for GVHD (=< 5 mg of prednisone or equivalent dose of systemic steroids for non-GVHD, non-autoimmune indications for at least 4 weeks prior to cell infusion)
  • No other systemic medications/treatments (e.g. extracorporeal photopheresis [ECP]) for GVHD for at least 4 weeks prior to cell infusion
  • Ability to understand and the willingness to sign a written informed consent document
  • Total bilirubin: =< 1.5 x institutional upper limit of normal (ULN) (except Gilbert’s or disease-related hemolysis, then < 3 x ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
  • Creatinine clearance: =< 1.5 x institutional ULN
  • Oxygen (O2) saturation: >= 90% on room air
  • Left ventricular ejection fraction (LVEF) > 40%
  • Negative pregnancy test for women of childbearing potential only
  • The effects of CIML NK cells and IL-2 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after the last IL-2 dose administration

Exclusion Criteria

  • Extramedullary relapse involving immuno-privileged sites (e.g. central nervous system [CNS], testes, eyes). Other sites of extramedullary relapse (e.g. leukemia cutis, granulocytic sarcoma) are acceptable
  • Participants who have had anti-tumor chemotherapy or other investigational agents within 4 weeks prior to cell infusion (6 weeks for nitrosoureas or mitomycin C), or immunotherapy within 8 weeks prior, or those who have not recovered from adverse events due to agents administered more than 4 weeks prior. Use of hydroxyurea to control counts within 4 weeks prior to cell infusion is permitted
  • Prior history of treatment with anti-CTLA-4 or anti-PD-1 pathway therapy, or CD137 agonist therapy for post-transplant relapse
  • Prior history of donor lymphocyte infusion (DLI)
  • Prior history of severe (grade 3 or 4) acute GVHD, or ongoing active GVHD requiring systemic treatment
  • Organ transplant (allograft) recipient
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to IL2 or other agents used in study
  • Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s granulomatosis]) and motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and Myasthenia gravis). Patients with Hashimoto’s thyroiditis are eligible to go on study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because of the unknown teratogenic risk of CIML NK cells and IL-2 and with the potential for teratogenic or abortifacient effects by fludarabine (Flu)/cyclophosphamide (Cy) chemotherapy regimen. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CIML NK cells and IL-2, breastfeeding should be discontinued if the mother is treated on this study
  • Human immunodeficiency virus (HIV)-positive participants are ineligible because of the potential for pharmacokinetic interactions with anti-retroviral agents used in this study. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy
  • Individuals with active uncontrolled hepatitis B or C are ineligible as they are at high risk of lethal treatment-related hepatotoxicity after hematopoietic stem cell transplantation (HSCT)


Brigham and Women's Hospital
Status: ACTIVE
Contact: Rizwan Romee
Phone: 617-632-3470
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Rizwan Romee
Phone: 617-632-3470


I. To determine the safety (maximum tolerated dose [MTD]) of donor-derived cytokine-induced memory-like natural killer cells (CIML NK) cell infusion with low dose aldesleukin (interleukin [IL]-2) in patients relapsed after haploidentical donor stem cell transplantation.


I. To determine complete remission (CR/complete remission with incomplete blood count recovery [CRi]) rate at day 43 (6 weeks) after the CIML NK cell infusion.

II. To determine the rate of leukemia-free survival (LFS) and overall survival (OS) at day 100 and 1 year post CIML NK cell infusion.

III. To determine the day 100 incidence and severity of acute graft versus host disease (GVHD) rates after CIML NK cell infusion.

IV. To determine the 1 year incidence and severity of chronic GVHD rates after CIML NK cell infusion.


I. To evaluate the number, phenotype, and function of memory-like natural killer (NK) cells following adoptive transfer.

II. To assess serum cytokine, chemokine and soluble NKG2D ligand levels, before and after CIML NK cell infusion.

III. To assess functional responses and gene expression of memory-like NK cells and graft-derived NK cells to leukemia targets.

IV. To assess the impact of CIML NK cell infusion on immune reconstitution

V. To assess leukemia blasts and the bone marrow (BM) (and or extramedullary disease site[s] if applicable) microenvironment pre-therapy and at first relapse to identify mechanisms of immunoevasion and assess association with mutations and clonal architecture.

VI. To determine the impact of mutational landscape and KIR genotype and KIR ligand mismatches on blast clearance/remission induction and disease relapse.


Patients receive fludarabine phosphate intravenously (IV) over 1 hour once daily (QD) on days -6 to -2 and cyclophosphamide IV over 2 hours QD on days -5 and -4 in the absence of disease progression or unacceptable toxicity. Patients then receive donor-derived CIML NK IV over 15-30 minutes on day 0. Patients also receive aldesleukin subcutaneously (SC) every other day (QOD) on days 0-12 for a total of 7 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Rizwan Romee

  • Primary ID 19-265
  • Secondary IDs NCI-2019-07889
  • ID NCT04024761