Donor Natural Killer Cells and Donor Stem Cell Transplant in Treating Patients With High Risk Myeloid Malignancies

NK Cells With HLA Compatible Hematopoietic Transplantation for High Risk Myeloid Malignancies

This phase I/II trial studies the side effects and best dose of donor natural killer cells when given together with donor stem cell transplant and to see how well they work in treating patients with myeloid malignancies that are likely to come back or spread. Giving chemotherapy, such as busulfan and fludarabine phosphate, before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells and natural killer cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Acute Erythroid Leukemia; Acute Megakaryoblastic Leukemia; Myelodysplastic Syndrome; High Risk Myelodysplastic Syndrome; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Therapy-Related Acute Myeloid Leukemia; Therapy-Related Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Blasts Under 20 Percent of Bone Marrow Nucleated Cells; Blasts Under 20 Percent of Peripheral Blood White Cells
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Biological: Aldesleukin; Drug: Fludarabine Phosphate; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Busulfan; Biological: Allogeneic CD56-positive CD3-negative Natural Killer Cells; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Detailed Description

PRIMARY OBJECTIVES:

I. Assess the safety of infusing ex vivo expanded natural killer (NK) cells in patients receiving busulfan-fludarabine phosphate (fludarabine) with an allogeneic human leukocyte antigen (HLA) matched hematopoietic transplantation for myeloid malignancies. Two sources of NK cells could be studied, depending on what donor source is available: cells from the HLA matched related donor or cells from an unrelated cord blood unit.

II. For each source of NK cells: the maximum tolerated cell dose; the phenotype and function of the ex vivo expanded NK cells and their survival in vivo; the rate of engraftment, graft-vs.-host disease (GVHD), immune reconstitution, relapse rates and survival for patients receiving this regimen will be determined.

OUTLINE: This is a phase I, dose-escalation study of NK cells followed by a phase II study.

Patients receive fludarabine phosphate intravenously (IV) over 1 hour and busulfan IV over 3 hours on days -13 to -10. Patients then receive allogeneic CD56-positive CD3-negative natural killer cells IV over 1 hour on day -8. Patients also receive aldesleukin subcutaneously (SC) once daily (QD) on days -8 to -4. Patients then undergo allogeneic peripheral blood stem cell (PBSC) transplant on day 0.

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Acute myeloid leukemia who fail to achieve complete remission with one course of induction chemotherapy or after relapse; patients must have less than 20% bone marrow or peripheral blood blasts

• Acute myeloid leukemia in first remission with any of the following high risk features defined as:

  • Adverse cytogenetics: -5, deletion (del) 5q, -7, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 or complex karyotype (> 3 abnormalities)
  • Preceding myelodysplastic or myeloproliferative syndrome
  • Presence of high risk molecular abnormalities including FLT3 mutations, DNMT3A, TET2; ras; kit
  • French-American-British (FAB) monosomy (M)6 or M7 classification
  • Treatment related acute myeloid leukemia (AML)
  • Residual cytogenetic or molecular abnormalities
• Myelodysplastic syndromes with intermediate, high or very high risk Revised International Prognostic Scoring System (R-IPSS) score, chronic myelomonocytic leukemia (CMML) or therapy related myelodysplastic syndromes (MDS)

• Chronic myeloid leukemia (CML) which:

  • Failed to achieve a cytogenetic remission to tyrosine kinase inhibitor treatment or has a cytogenetic relapse
  • Has ever been in accelerated phase or blast crisis
• Patient must have an identified HLA (A,B,C,DR) compatible related or unrelated donor who is age 16 years of age or older and weighs at least 110 pounds for the stem cell donation
• Zubrod performance status 0 to 2 or Karnofsky of at least 60
• Left ventricular ejection fraction >= 45%; no uncontrolled arrhythmias or uncontrolled symptomatic cardiac disease
• Forced expiratory volume in one second (FEV1) >= 50% of expected, corrected for hemoglobin
• Forced vital capacity (FVC) >= 50% of expected, corrected for hemoglobin
• Diffusing capacity of the lung for carbon monoxide (DLCO) >= 50% of expected, corrected for hemoglobin
• Bilirubin =< 1.5 mg/dl (unless Gilbert's syndrome)
• Serum glutamate pyruvate transaminase (SGPT) =< 200 IU/ml unless related to patient malignancy
• Hepatitis B surface antigen negative and hepatitis C antibody negative
• No evidence of chronic active hepatitis or cirrhosis
• Patients with a history of hepatitis C, but have a negative viral load, are eligible
• The protocol chairman will determine the eligibility of patients related to hepatic abnormalities
• Serum creatinine < 1.5 mg%
• Patient or patient's legal representative, parent(s) or guardian able to sign informed consent; patients aged 7 to < 18 to provide assent
• Pediatric patients (age 7-18 years) will be entered only after 3 adult patients have been entered without dose limiting toxicity

Exclusion Criteria:

• Uncontrolled infection, not responding to appropriate antimicrobial agents after seven days of therapy; the protocol principal investigator (PI) is the final arbiter of eligibility
• Pleural/pericardial effusion or ascites > 1 L
• Patients who are known to be human immunodeficiency virus (HIV)-seropositive
• Pregnancy: positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization
• Women of child bearing potential not willing to use an effective contraceptive measure while on study
• Patients who are known to have allergy to mouse proteins

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: Treatment (NK cells, PBSC transplant); Patients receive fludarabine phosphate IV over 1 hour and busulfan IV over 3 hours on days -13 to -10. Patients then receive allogeneic CD56-positive CD3-negative natural killer cells IV over 1 hour on day -8. Patients also receive aldesleukin SC QD on days -8 to -4. Patients then undergo allogeneic PBSC transplant on day 0.

Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Biological: Aldesleukin; Given SC; Other Names: Proleukin; 125-L-Serine-2-133-interleukin 2; r-serHuIL-2; Recombinant Human IL-2; Recombinant Human Interleukin-2; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo allogeneic PBSC transplant; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; PBSCT; Peripheral Stem Cell Transplant; Drug: Busulfan; Given IV; Other Names: Busulfex; Misulfan; Mitosan; Myeloleukon; Myelosan; 1, 4-Bis[methanesulfonoxy]butane; BUS; Bussulfam; Busulfanum; Busulphan; CB 2041; CB-2041; Glyzophrol; GT 41; GT-41; Joacamine; Methanesulfonic Acid Tetramethylene Ester; Methanesulfonic acid, tetramethylene ester; Mielucin; Misulban; Myeleukon; Mylecytan; Myleran; Sulfabutin; Tetramethylene Bis(methanesulfonate); Tetramethylene bis[methanesulfonate]; WR-19508; Biological: Allogeneic CD56-positive CD3-negative Natural Killer Cells; Given IV; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic PBSC transplant; Other Names: Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced Dose-limiting Toxicities (DLT)	Participants that experienced DLT related to the NK Cells post transplant at different dose levels.	Up to 42 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Participants that survived between day of transplant and day of death on different dose levels.	Up to 2 years
Number of Participants With Grade 3 Toxicities	Number of participants that had grade 3 toxicities up to day 42.	Up to day 42

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Richard E Champlin, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• University of Texas MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start (Actual): June 11, 2013
• Primary Completion (Actual): May 10, 2022
• Study Completion (Actual): May 10, 2022

Study Registration Dates

• First Submitted: March 28, 2013
• First Submitted That Met QC Criteria: March 28, 2013
• First Posted (Estimated): April 4, 2013

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 3, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Neoplastic Processes; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Cell Transformation, Neoplastic; Carcinogenesis; Chronic Disease; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Blast Crisis; Leukemia, Myeloid, Accelerated Phase; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Aldesleukin; Fludarabine; Fludarabine phosphate; Busulfan; Interleukin-2
• Other Study ID Numbers: 2012-0819 (Other Identifier: M D Anderson Cancer Center); NCI-2013-00993 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); RP110553-P3

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No