A Phase 1 Trial of CIML NK Cell Infusion for Myeloid Disease Relapse After Hematopoietic Cell Transplantation

This research study is studying cytokine induced memory-like natural killer (CIML NK) cells combined with IL-2 in adult patients (18 years of age or older) with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS) and Myeloproliferative Neoplasms (MPN) who relapse after haploidentical hematopoietic cell transplantation (haplo-HCT) or HLA matched stem cells. This study will also study CIML NK cell infusion combined with IL-2 in pediatric patients (12 years of age or older) with AML, MDS, JMML who relapse after stem cell transplantation using HLA-matched related donor or related donor haploidentical stem cells.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Juvenile Myelomonocytic Leukemia; Myeloproliferative Neoplasm
• Intervention / Treatment: Biological: CIML NK; Drug: Fludarabine; Drug: Cyclophosphamide

Detailed Description

This research study is a Phase I clinical trial, which tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies. "Investigational" means that the intervention is being studied.

The U.S. Food and Drug Administration (FDA) has not approved CIML NK Cell Infusion as a treatment for relapsed disease.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Roman M. Shapiro, MD; Phone Number: 617-632-3470; Email: roman_shapiro@dfci.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Principal Investigator: Susanne Baumeister, MD
      • Contact: Susanne Baumeister, MD; Phone Number: (617) 632-4687; Email: susanne_baumeister@dfci.harvard.edu
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Dana Farber Cancer Institute
      • Principal Investigator: Roman Shapiro, MD
      • Contact: Roman Shapiro, MD; Phone Number: 617) 632-3470; Email: roman_shapiro@dfci.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

1. Inclusion Criteria:

   1.1 Relapse or post-transplant persistence of AML, MDS (including JMML) or MPN (CMML, myelofibrosis or MDS/MPN). Disease relapse or persistence will be defined as any measurable disease by morphology, flow-cytometry, validated tests for minimal residual disease or disease-defining mutations in the bone marrow, or non-immune privileged extramedullary sites.

   1.2 Persistence of disease within 4 weeks before planned NK cell infusion and at least 2 weeks after completion of immune suppression taper as long as it is > 2 months after stem cell transplantation for both adult and pediatric patients. If 2 weeks after completion of the immune suppression taper is still within 2 months of the most recent stem cell transplant, then chemotherapy with Fludarabine/Cyclophosphamide would need to start no earlier than at least 2 months after the transplant. For adults, disease persistence after a second transplant is allowed as long as the most recent transplant was a haploidentical or HLA matched stem cell transplant. In the pediatric cohort, disease persistence or recurrence after a second transplant is allowed as long as the most recent transplant was a haploidentical or matched related donor SCT.

   1.3 Available original donor (same donor as used for the most recent haploidentical or HLA matched stem cell transplant for adults, or for the most recent matched related donor or related haploidentical donor for pediatrics) that is willing and eligible for non-mobilized collection.

   1.4 Age ≥12 years.

   1.5 ECOG performance status ≤2. For For patients in the pediatric cohort, this corresponds to a Lansky (patients <16 years) or Karnofsky (≥16years) performance status of ≥50.

   1.6 T cell chimerism ≥20% donor-derived within the 4 weeks prior to cell infusion.

   1.7 Patient with ≤80% bone marrow involvement within 4 weeks prior to cell infusion. Medications like hydroxyurea, decitabine or cytarabine are allowed to control rising blasts between study enrollment and cell infusion.

   1.8 No systemic corticosteroid therapy for GVHD (≤ 5mg of prednisone or equivalent dose of systemic steroids for non-GVHD, non-autoimmune indications are allowed) for at least 4 weeks prior to cell infusion. Patients on systemic GVHD prophylaxis medications such as tacrolimus or sirolimus need to be off these medications for at least 4 weeks prior to cell infusion.

   1.9 No other systemic medications/treatments (e.g. ECP) for GVHD for at least 4 weeks prior to cell infusion.

   1.10 Ability of the patient or legal guardian to understand and the willingness to sign a written informed consent document.

   1.11 Adequate organ function within 2 weeks of NK cell infusion as defined below:

   • Total bilirubin: ≤1.5 x institutional upper limit of normal (ULN) (except Gilbert's or disease-related hemolysis, then <3 x ULN)
   • AST(SGOT)/ALT(SGPT): ≤3 x institutional ULN
   • Serum creatinine ≤2.0mg/dL
   • O2 saturation: ≥90% on room air
   • LVEF >40%. If there is no clinical evidence of a change in cardiovascular function from the time of pre-transplantation ECHO, then there is no need to repeat it. Otherwise, an ECHO will need to be repeated within 2 weeks of NK cell infusion.

   1.12 Negative pregnancy test for women of childbearing potential only.

   1.13 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.

2. Exclusion Criteria:

2.1 Extramedullary relapse involving immuno-privileged sites (e.g. CNS, testes, eyes). Other sites of extramedullary relapse (e.g. leukemia cutis, granulocytic sarcoma) are acceptable.

2.2 Participants who have had 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 or standard chemotherapy administered more than 14 days ago. Use of hydroxyurea, hypomethylating agents, low-dose cytarabine or venetoclax to control counts within 4 weeks prior to cell infusion is permitted with study PI approval but would need to be stopped 1 day prior to administration of Fludarabine and Cyclophosphamide preceding the NK cell infusion (provided that there are no ongoing AEs attributed to these agents that would preclude start of lymphodepletion in the view of the investigator). Patients on standard of care FLT-3, IDH1, and IDH2 inhibitors can stay on this treatment. Therapy with BCR-ABL inhibitors or bcl-2 inhibitors must be stopped 2 weeks before NK cell infusion and may be resumed after the end of the DLT period.

2.3 Prior history of Donor Lymphocyte Infusion (DLI) within 8 weeks of CIML NK infusion. DLI that was given before this time period and that did not result in any GVHD requiring systemic treatment is not an exclusion criterion.

2.4 Prior history of severe (grade 3 or 4) acute GVHD, or ongoing active GVHD requiring systemic treatment.

2.5 Solid organ transplant recipient. Prior allogeneic HLA matched or mismatched stem cell transplant is allowed in the pediatric cohort. Prior HLA matched related donor or HLA matched unrelated donor stem cell transplant is allowed in the adult cohort.

2.6 History of allergic reactions attributed to compounds of similar chemical or biologic composition to IL-2 or other agents used in study.

2.7 Autoimmune disease: 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.

2.8 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.

2.9 Patients who develop a critical illness prior to NK cell infusion that would contraindicate the administration of Fludarabine and Cyclophosphamide conditioning. Patients who recover from such illness may still be eligible, but this must be reviewed with the study PI. A repeat bone marrow examination may be required depending on the timing of recovery. Patients who become critically ill on the planned day of NK cell infusion are excluded if the NK cell infusion cannot be given within 48 hours of the planned day 0.

2.10 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 Flu/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.

2.11 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.

2.12 Individuals with active uncontrolled hepatitis B or C, HIV, or HTLV-1 are ineligible as they are at high risk of lethal treatment-related hepatotoxicity after HSCT.

2.13 Individuals with a history of a different malignancy are ineligible except for the following circumstances: 1. History of other malignancy and have had complete remission of disease for at least 2 years; 2. Diagnosed and treated within the past 2 years for: nonmetastatic melanoma, surgically resected (not needing systemic chemotherapy) squamous cell carcinoma of skin and nonmetastatic prostate cancer not needing systemic chemotherapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CIML NK; CIML NK cells will be administered intravenously on day 0.; Fludarabine will be administered as IV infusion once daily for 3 doses beginning on day -5.; Cyclophosphamide will be administered as IV infusion on days -5 and -4.	Biological: CIML NK; CIML NK cells have enhanced ability to recognize and kill leukemia targets; Drug: Fludarabine; Fludarabine is a chemotherapy agent; Drug: Cyclophosphamide; Cyclophosphamide (CP), also known as cytophosphane among other names, is a chemotherapy agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety	To determine the maximum tolerated dose (MTD) of CIML NK cell infusion followed by low-dose IL-2	6 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LFS and OS	To determine the rate of leukemia-free survival (LFS) and overall survival (OS) at day 100 and at 1 year post cell CIML NK cell infusion plus IL-2	100 Days, 1 Year
ORR (Objective Response Rate)	To determine complete remission (CR/CRi) rate after CIML NK cell infusion plus IL-2	28 days
Acute GVHD (Incidence, Severity)	To determine the incidence and severity of acute GVHD rates after CIML NK cell infusion plus IL-2	100 Days, 6 Months
Chronic GVHD (Incidence, Severity)	To determine the incidence and severity of chronic GVHD rates after CIML NK cell infusion plus IL-2	1 Year

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: The Leukemia and Lymphoma Society
• Investigators: Principal Investigator: Susanne Baumeister, MD, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• Shapiro RM, Birch GC, Hu G, Vergara Cadavid J, Nikiforow S, Baginska J, Ali AK, Tarannum M, Sheffer M, Abdulhamid YZ, Rambaldi B, Arihara Y, Reynolds C, Halpern MS, Rodig SJ, Cullen N, Wolff JO, Pfaff KL, Lane AA, Lindsley RC, Cutler CS, Antin JH, Ho VT, Koreth J, Gooptu M, Kim HT, Malmberg KJ, Wu CJ, Chen J, Soiffer RJ, Ritz J, Romee R. Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse. J Clin Invest. 2022 Jun 1;132(11):e154334. doi: 10.1172/JCI154334.

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2019
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: July 17, 2019
• First Submitted That Met QC Criteria: July 17, 2019
• First Posted (Actual): July 18, 2019

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Leukemia
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Hemic and Lymphatic Diseases; Leukemia; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Myeloproliferative Disorders; Organic Chemicals; Hydrocarbons; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Cyclophosphamide; fludarabine
• Other Study ID Numbers: 19-265

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: BCH - Contact the Technology & Innovation Development Office at www.childrensinnovations.org or email TIDO@childrens.harvard.edu BIDMC - Contact the Beth Israel Deaconess Medical Center Technology Ventures Office at tvo@bidmc.harvard.edu BWH - Contact the Partners Innovations team at http://www.partners.org/innovation DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu MGH - Contact the Partners Innovations team at http://www.partners.org/innovation
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No