A phase II clinical trial of adoptive transfer of haploidentical natural killer cells for consolidation therapy of pediatric acute myeloid leukemia

Abstract

Consolidation therapies for children with intermediate- or high-risk acute myeloid leukemia (AML) are urgently needed to achieve higher cure rates while limiting therapy-related toxicities. We determined if adoptive transfer of natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA)-mismatched donors may prolong event-free survival in children with intermediate-risk AML who were in first complete remission after chemotherapy. Patients received cyclophosphamide (Day - 7), fludarabine (Days - 6 through - 2), and subcutaneous interleukin-2 (Days - 1, 1, 3, 5, 7, and 9). Purified, unmanipulated NK cells were infused on Day 0, and NK cell chimerism and phenotyping from peripheral blood were performed on Days 7, 14, 21, and 28. As primary endpoint, the event-free survival was compared to a cohort of 55 patients who completed chemotherapy and were in first complete remission but did not receive NK cells. Donor NK cell kinetics were determined as secondary endpoints. Twenty-one patients (median age at diagnosis, 6.0 years [range, 0.1-15.3 years]) received a median of 12.5 × 106 NK cells/kg (range, 3.6-62.2 × 106 cells/kg) without major side effects. All but 3 demonstrated transient engraftment with donor NK cells (median peak donor chimerism, 4% [range, 0-43%]). KIR-HLA-mismatched NK cells expanded in 17 patients (81%) and contracted in 4 (19%). However, adoptive transfer of NK cells did not decrease the cumulative incidence of relapse (0.393 [95% confidence interval: 0.182-0.599] vs. 0.35 [0.209-0.495]; P = .556) and did not improve event-free (60.7 ± 10.9% vs. 69.1 ± 6.8%; P = .553) or overall survival (84.2 ± 8.5% vs. 79.1 ± 6.6%; P = .663) over chemotherapy alone. The lack of benefit may result from insufficient numbers and limited persistence of alloreactive donor NK cells but does not preclude its potential usefulness during other phases of therapy, or in combination with other immunotherapeutic agents. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT00703820 . Registered 24 June 2008.

Keywords: Acute myeloid leukemia; Child; Clinical trial; Natural killer cells.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by our institutional review board, and informed consent was obtained from parents or guardians, and assent from the patients, as appropriate.

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This manuscript does not include details, images, or videos relating to an individual person. Informed consent for publication according to institutional guidelines was obtained from parents or guardians, and assent from the patients, as appropriate.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Average natural killer (NK) cell engraftment (a) in peripheral blood plotted over time. KIR–HLA-mismatched NK cells expanded over time in 17 patients (b) and contracted in 4 patients (c). Donor NK cell chimerism was detected in 18 patients (d, gray line), of which 4 were noted to have rising levels over time (black line)

Fig. 2

Kaplan-Meier survival curves comparing the overall survival (a) and event-free survival (b) of 21 patients with NK cell infusion (dashed line) with that of 53 patients who completed 4 courses of chemotherapy but did not receive NK cell infusion (solid line)