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

Phase 1

Completed

Conditions: Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Acute Erythroid Leukemia
Blasts Under 20 Percent of Bone Marrow Nucleated Cells
Myelodysplastic Syndrome
Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Therapy-Related Acute Myeloid Leukemia
Therapy-Related Myelodysplastic Syndrome
Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Acute Megakaryoblastic Leukemia
Acute Myeloid Leukemia

Interventions: Biological: Aldesleukin
Biological: Allogeneic CD56-positive CD3-negative Natural Killer Cells
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Drug: Busulfan
Drug: Fludarabine Phosphate
Other: Laboratory Biomarker Analysis
Procedure: Peripheral Blood Stem Cell Transplantation
Other: Pharmacological Study

Registration Number: NCT01823198

Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 63

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (NK cells, PBSC transplant)	Aldesleukin	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.
Treatment (NK cells, PBSC transplant)	Allogeneic CD56-positive CD3-negative Natural Killer Cells	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.
Treatment (NK cells, PBSC transplant)	Allogeneic Hematopoietic Stem Cell Transplantation	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.
Treatment (NK cells, PBSC transplant)	Laboratory Biomarker Analysis	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.
Treatment (NK cells, PBSC transplant)	Peripheral Blood Stem Cell Transplantation	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.
Treatment (NK cells, PBSC transplant)	Pharmacological Study	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.
Treatment (NK cells, PBSC transplant)	Busulfan	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.
Treatment (NK cells, PBSC transplant)	Fludarabine Phosphate	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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