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 registrationwww.clinicaltrials.gov, NCT00703820. Registered 24 June 2008.
Highlights
One-third of children with acute myeloid leukemia (AML) experience disease relapse despite risk-adapted intensive multiagent chemotherapy with or without hematopoietic cell transplantation (HCT) [1]
Patient and donor eligibility Children with intermediate-risk AML who were in first complete remission after completion of 4 or 5 courses of chemotherapy as part of the randomized controlled phase 3 clinical trial (NCT00703820) and who had a killer immunoglobulin–like receptor (KIR)–-human leukocyte antigen (HLA)-mismatched parent were eligible for adoptive transfer of haploidentical natural killer (NK) cells
Hematopoietic cell transplantation from KIR–HLA-mismatched donors is associated with a marked event-free survival benefit in patients with AML [2,3,4], but the benefit of NK cell infusion as a consolidation therapy remains unclear for children with AML
Summary
One-third of children with acute myeloid leukemia (AML) experience disease relapse despite risk-adapted intensive multiagent chemotherapy with or without hematopoietic cell transplantation (HCT) [1]. The inhibitory KIRs 2DL1 (CD158a), 2DL2/3 (CD158b), and 3DL1 (CD158e1) are such surface receptors and allow adoptively transferred donor NK cells to exert potent antileukemic effects if the cognate HLA class I ligands are absent in the recipients [3]. This potency has been demonstrated in preclinical experiments [2], as well as in clinical studies, without causing graft-versus-host disease [3, 4]. Patients may alternatively receive lympho-depleting chemotherapy followed by adoptive transfer of purified NK cells from an alloreactive donor, resulting in homeostatic lymphocyte proliferation with transient donor NK cell expansion in recipients [7]
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