Donor Natural Killer Cells after Donor Peripheral Blood Stem Cell Transplant in Treating Younger Patients with Hematologic Malignancies

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IBiomarker/Laboratory analysis, Treatment4 to 3511-C-0073
NCI-2013-01476, 110073, P09561, NCT01287104

Trial Description



This phase I trial studies the side effects and best dose of donor natural killer cells after donor peripheral blood stem cell transplant in treating younger patients with hematologic malignancies. Giving chemotherapy 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. The donated stem cells may replace the patient’s immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor’s natural killer cells after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can make an immune response against the body’s normal cells. Removing the T cells from the donor cells before transplant and giving tacrolimus and cyclosporine after the transplant may stop this from happening.

Further Study Information


I. Assess the feasibility and toxicity of infusing escalating doses of unrelated or related donor-derived activated natural killer (NK) cell donor lymphocyte infusions (NK-DLI) on days 21 ± 3 days, and 49 ± 7 days following allogeneic human leukocyte antigen (HLA)-matched T cell depleted (TCD) peripheral blood stem cell transplantation (PBSCT) in patients with high risk hematological malignancies (leukemias and lymphomas).

II. Determine if TCD allogeneic HLA-matched PBSCT + NK-DLI results in rapid, sustained donor lymphoid engraftment (> 95% at day 100) and acceptable rates of acute graft-versus-host-disease (aGVHD) (< 25% incidence of grade 3 or grade 4).


I. Investigate the incidence of chronic (cGVHD) in patients receiving related or unrelated donor HLA-matched allogeneic PBSCT followed by NK-DLI.

II. Investigate the incidence of viral infection and/or reactivation in patients receiving HLA-matched allogeneic PBSCT followed by NK-DLI.

III. Compare disease-free (DFS) and overall survival (OS) of patients treated on this protocol with our previous experience using T cell-replete matched sibling PBSCT in similar patient populations.

IV. Correlate post-transplant NK cell, B cells and T cells numbers with select immunologic parameters including interleukin (IL)-7 and IL-15 levels.

V. Retrospectively investigate the impact of killer-cell inhibitory receptor (KIR) expression and KIR reactivity on progression free survival in patients enrolled on this study.

OUTLINE: This is a dose-escalation study of NK-DLI.

INDUCTION CHEMOTHERAPY: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days 1-3; etoposide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV continuously over 96 hours on days 1-4; cyclophosphamide IV over 30 minutes on day 5; and prednisone orally (PO) on days 1-5. Patients with leukemia receive non-myeloablative chemotherapy comprising fludarabine phosphate IV over 30 minutes and cytarabine IV over 4 hours on days 1-5. Treatment repeats every 22-28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

PREPARATIVE REGIMEN: Patients receive non-myeloablative chemotherapy comprising fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -2. Patients with acute myeloid leukemia (AML) receive myeloablative chemotherapy comprising fludarabine phosphate IV over 30 minutes and busulfan IV over 3 hours on days -5 to -2. Patients with acute lymphoblastic leukemia (ALL) undergo total-body irradiation (TBI) twice daily (BID) on days -6 to -4 and receiving myeloablative chemotherapy comprising cyclophosphamide IV over 2 hours on days -3 to -2.

GVHD PROPHYLAXIS: Patients with unrelated donor recipients receive tacrolimus IV continuously over 12 hours and then PO every 12 hours or cyclosporine IV over 2 hours or PO every 12 hours on days -1 to 100 with taper to day 180.

TRANSPLANT: Patients undergo allogeneic cluster of differentiation (CD)34+ PBSCT on day 0.

NK CELL INFUSION: Patients receive NK cells IV over 10-20 minutes on day 21. Treatment repeats every 28 days for up to 2 courses in the absence of unacceptable toxicity.

After completion of study treatment, patients are followed up at days 100, 150, 180, 270, and 365, and then every 3 months for 1 year, every 6 months for 1 year, and then annually for at least 2 years.

Eligibility Criteria

Inclusion Criteria:

Hematologic malignancies diagnoses:

Acute lymphoblastic leukemia (ALL) with a history of bone marrow relapse in clinical remission (CR) #2 or greater, or in CR#1 if prior induction failure; or with an M1 marrow if unable to achieve CR

Philadelphia chromosome positive ALL patients who:

  • Have progressed through or relapsed following tyrosine kinase inhibitor (TKI) therapy or conventional myeloablative therapy OR
  • Are ineligible to receive tyrosine kinase inhibitor (TKI) therapy AND myeloablative hematopoietic stem cell transplant (HSCT)

Acute myelogenous leukemia (AML) with a history of bone marrow relapse in remission CR #2 or greater; or with an M1 marrow if unable to achieve CR; or in CR#1 if prior induction failure; or any of the following high-risk categories:

  • FMS-like tyrosine kinase 3/internal tandem duplication positive (FLT3/ITD+) with high allelic ratio > 0.4 (HR FLT3/ITD+) regardless of low risk features
  • Presence of monosomy 7, monosomy 5, or deletion (del)5q, without inversion (inv)(16)/t(16;16) or t(8;21) cytogenetics or nucleophosmin (NPM) or CCAAT enhancer-binding protein (CEBP) alpha mutations
  • AML without inv(16)/t(16;16), t(8;21), NPM, CEPB alpha mutations, monosomy 7, monosomy 5, del5q, or HR FLT3/ITD+, but with evidence of residual AML (>= 0.1%) at end of induction I

Hodgkin’s and non-Hodgkin’s lymphoma with refractory disease or relapse after at least one salvage regimen, or after autologous stem cell transplant

Juvenile myelomonocytic leukemia (JMML) with < 10% blasts in marrow and blood, who are not eligible for effective standard therapies

Chronic myelogenous leukemia (CML) with history of blast crisis (ALL/AML) or progressive disease failing tyrosine-kinase inhibitor (TKI)

All previous cytotoxic chemotherapy must be completed at least 2 weeks prior to study entry; any prior non-hematologic vital organ toxicity (cardiac, pulmonary, hepatic, renal) of any previous therapy must have resolved to grade 1 or less, unless specified elsewhere


  • There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects; or
  • Subjects receiving standard ALL maintenance chemotherapy will not require washout

All previous immunologic or molecularly targeted therapy must be completed at least 2 weeks prior to study entry; any prior non-hematologic toxicity of any previous therapy must have resolved to grade 1 or less, unless specified elsewhere, or except breakpoint cluster region/tyrosine-protein kinase ABL1 (BCR-ABL) tyrosine kinase in patients who have Philadelphia chromosome positive (Ph+) ALL, where there will be no washout period

Prior investigational therapy must be completed at least 30 days prior to study entry

Patients with prior autologous or allogeneic transplant are eligible; patients must be > 100 days post transplant and have no evidence of active GVHD

Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2; or Karnofsky of >= 60, or for children =< 10 years of age, Lansky >= 60

Life expectancy > 3 months

Availability of HLA-matched or unrelated donors; related donors must be 5 or 6/6 antigen matched; unrelated donors must be at least 9/10 allele matched

Left ventricular ejection fraction >= 45% by multigated acquisition scan (MUGA) or echocardiogram (ECHO), fractional shortening >= 28% by ECHO

Diffusing capacity of the lung for carbon monoxide (DLCO) >= 40% of the expected value corrected for alveolar volume and hemoglobin (hgb) for reduced intensity transplant and DLCO >= 55% for myeloablative regimen; for children who are unable to cooperate for pulmonary function tests (PFTs), the criterion is, no evidence of dyspnea at rest, no exercise intolerance, and no requirement for supplemental oxygen therapy

Serum total bilirubin < 2 mg/dl; patients with Gilbert syndrome are excluded from the requirement of a normal bilirubin

Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal

Age-adjusted normal serum creatinine according to the following or a creatinine clearance >= 60 ml/min/1.73 m^2

Age =< 5 years: maximum serum creatinine 0.8 mg/dl

Age > 5 and =< 10 years: maximum serum creatinine 1.0 mg/dl

Age > 10 and =< 15 years: maximum serum creatinine 1.2 mg/dl

Age > 15 years: maximum serum creatinine 1.5 mg/dl

Absolute neutrophil count (ANC) must be > 750/mm^3 (unless due to underlying disease in which case there is no grade restriction)

Platelet count must be >= 75,000/mm^3 (not achieved by transfusion) unless due to underlying disease in which case there is no grade restriction)

Lymphopenia, cluster of differentiation (CD)4 lymphopenia, leukopenia, and anemia will not render patients ineligible

Ability to give informed consent; for patients < 18 years of age their legal guardian must give informed consent; pediatric patients will be included in age-appropriate discussion in order to obtain verbal assent

Durable power of attorney form completed (patients >= 18 years of age only)

Female patients (and when relevant their male partners) must be willing to practice birth control (including abstinence) during and for two months after treatment, if of childbearing potential

DONOR: Weight >= 15 kilograms and for unrelated donors, >= 18 years

DONOR: HLA-matched related or unrelated allogeneic donors; genotypically HLA identical twins may serve as stem cell donors; related donors must be 5 or 6/6 antigen matched; unrelated donors must be 9/10 allele matched

DONOR: For donors <18 years of age, he/she must be the oldest suitable donor, their legal guardian must give informed consent, the donor must give verbal assent, and he/she must be cleared by social work and a mental health specialist to participate

DONOR: For donors >= 18 years of age, ability to give informed consent

DONOR: Adequate peripheral venous access for apheresis or consent to use a temporary central venous catheter for apheresis; donor selection will be in accordance with National Institutes of Health (NIH)/Clinical Center (CC) Department of Transfusion Medicine (DTM) criteria and, in the case of an unrelated donor, the National Marrow Donor Program (NMDP) standards and Food and Drug Administration (FDA) 21 Code of Federal Regulations (CFR) 1271

Exclusion Criteria:

Uncontrolled infection

Active central nervous system (CNS) malignancy as defined by:

Lymphoma: tumor mass on computed tomography (CT) scan or leptomeningeal disease

Leukemia: CNS 2 or CNS 3 classification

Lactating or pregnant females

Human immunodeficiency virus (HIV) positive

Hepatitis B surface antigen (HBsAg) positive or hepatitis C antibody positive with elevated liver transaminases; all patients with chronic active hepatitis (including those on treatment) are ineligible

Patients who require systemic corticosteroid or other immunosuppressive therapy for GVHD; immunosuppressive therapy must be stopped at least 28 days prior to protocol course 1 day 1 (C1D1); steroids for physiologic replacement, for ALL maintenance or topical agents and/or inhaled corticosteroids are permitted

High risk of inability to comply with transplant protocol, or inability to give appropriate informed consent in the estimation of the principal investigator (PI), social work, psychiatry, or the stem cell transplant team

Fanconi anemia

Clinically significant systemic illness (e.g. serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the PI would likely compromise the patient’s ability to tolerate protocol therapy or significantly increase the risk of complications

DONOR: History of medical illness that in the estimation of the PI or DTM/NMDP physician poses prohibitive risk to donation including, but not limited to, stroke, hypertension that is not controlled with medication, or heart disease; individuals with symptomatic angina or a history of coronary bypass grafting or angioplasty will not be eligible

DONOR: Anemia (hemoglobin [Hb] < 11 gm/dl) or thrombocytopenia (< 100,000/ul)

DONOR: Identical twins will be excluded

DONOR: Breast feeding or pregnant females; donors of childbearing potential must use an effective method of contraception during the time they are receiving filgrastim

DONOR: High risk of inability to comply with protocol requirements as determined by the principal investigator and donor center team

DONOR: Positive screening test for transfusion-transmissible infection in accordance with DTM or NMDP donation standards, including HIV-positive, hepatitis B surface antigen (HBsAg) positive or hepatitis C antibody positive

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

NCI - Center for Cancer Research

  • National Cancer Institute
Nirali N. Shah, Principal Investigator

Trial Sites



Mark O Hatfield-Warren Grant Magnuson Clinical Center

Nirali N. Shah
Ph: 301-451-0390

Nirali N. Shah
Principal Investigator

Link to the current record.
NLM Identifier NCT01287104

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