In patients with acute leukemia, detection of minimal residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) correlates with risk of relapse. However, the level of MRD that is most likely to preclude cure by HCT is unclear, and the benefit of further chemotherapy to reduce MRD before HCT is unknown. In 122 children with very-high-risk acute lymphoblastic leukemia (ALL; n = 64) or acute myeloid leukemia (AML, n = 58), higher MRD levels at the time of HCT predicted a poorer survival after HCT (P = .0019); MRD was an independent prognostic factor in a multivariate analysis (P = .0035). However, the increase in risk of death associated with a similar increment of MRD was greater in ALL than in AML, suggesting that a pretransplantation reduction of leukemia burden would have a higher impact in ALL. At any given MRD level, survival rates were higher for patients treated in recent protocols: the 5-year overall survival for patients with ALL was 49% if MRD was detectable and 88% if it was not and the corresponding rates for patients with AML were 67% and 80%, respectively. Although MRD before HCT is a strong prognostic factor, its impact has diminished and should not be regarded as a contraindication for HCT.

We evaluated 190 children with very highrisk leukemia, who underwent allogeneic hematopoietic cell transplantation in 2 sequential treatment eras, to determine whether those treated with contemporary protocols had a high risk of relapse or toxic death, and whether non-HLA-identical transplantations yielded poor outcomes. For the recent cohorts, the 5-year overall survival rates were 65% for the 37 patients with acute lymphoblastic leukemia and 74% for the 46 with acute myeloid leukemia; these rates compared favorably with those of earlier cohorts (28%, n ‫؍‬ 57; and 34%, n ‫؍‬ 50, respectively). Improvement in the recent cohorts was observed regardless of donor type (sibling, 70% vs 24%; unrelated, 61% vs 37%; and haploidentical, 88% vs 19%), attributable to less infection (hazard ratio [HR] ‫؍‬ 0.12; P ‫؍‬ .005), regimen-related toxicity (HR ‫؍‬ 0.25; P ‫؍‬ .002), and leukemiarelated death (HR ‫؍‬ 0.40; P ‫؍‬ .01). Survival probability was dependent on leukemia status (first remission vs more advanced disease; HR ‫؍‬ 0.63; P ‫؍‬ .03) or minimal residual disease (positive vs negative; HR ‫؍‬ 2.10; P ‫؍‬ .01) at the time of transplantation. We concluded that transplantation has improved over time and should be considered for all children with very high-risk leukemia, regardless of matched donor availability. (Blood. 2011;118(2):223-230)

As survivors of pediatric allogeneic hematopoietic stem cell transplantations (HSCTs) increase in number, it is increasingly important to evaluate their well-being. We conducted this prospective cohort study to evaluate the cumulative incidence and risk factors for late sequelae of HSCT. Comprehensive surveillance tests were performed annually on every participant, regardless of signs and symptoms, to obtain accurate information on the time-of-onset of each late event to allow hazard function analyses. All participants included in this report had been followed for at least 3 years after HSCT. With a median follow-up of 9 years and a current age of 18.5 years, only 20 of the 155 participants (13%) had no late sequelae; 18 survivors (12%) had 1 chronic health condition, 71 (46%) had 2-4 conditions, and 46 (30%) had 5-9 conditions. Risk factors for increasing number of chronic conditions included young age at the time of HSCT, female sex, high radiation dose, and history of chronic graft-versus-host disease. The cumulative incidence at 10 years for common late events was as follows (ordered by the median time-of-onset): osteonecrosis 13.8%, chronic renal insufficiency 26.8%, hypothyroidism 45.1%, growth hormone deficiency 31.2%, female hypogonadism 57.4%, osteopenia 47.7%, cataracts 43.4%, pulmonary dysfunction 63.2%, and male hypogonadism 20.3%. Coexistence of multiple late sequelae was common in HSCT survivors. Our findings provide a basis for more effective patient counseling, optimal surveillance, and early intervention.

A B S T R A C T PurposeKiller-cell immunoglobulin-like receptors (KIRs) that regulate natural-killer cells are highly polymorphic. Some KIR2DL1 alleles encode receptors that have stronger signaling function than others. We tested the hypothesis that the clinical outcomes of allogeneic hematopoietic stem-cell transplantation (HSCT) could be affected by donor KIR2DL1 polymorphism. Patients and MethodsAll 313 pediatric patients received allogeneic HSCT at a single institution. Donor KIR2DL1 functional allele typing was retrospectively performed using single nucleotide polymorphism assay. ResultsPatients who received a donor graft containing the functionally stronger KIR2DL1 allele with arginine at amino acid position 245 (KIR2DL1-R 245 ) had better survival (P ϭ .0004) and lower cumulative incidence of disease progression (P ϭ .001) than those patients who received a donor graft that contained only the functionally weaker KIR2DL1 allele with cysteine at the same position (KIR2DL1-C 245 ). The effect of KIR2DL1 allelic polymorphism was similar in patients with acute myeloid leukemia or acute lymphoblastic leukemia among all allele groups (P Ն .71). Patients who received a KIR2DL1-R 245 -positive graft with HLA-C receptor-ligand mismatch had the best survival (P ϭ .00003) and lowest risk of leukemia progression (P ϭ .0005) compared with those who received a KIR2DL1-C 245 homozygous graft. ConclusionDonor KIR2DL1 allelic polymorphism affects recipient outcomes after allogeneic HSCT. These findings have substantial implications for prognostication and donor selection.

Background Novel therapies are needed for children with relapsed or refractory leukemia. We therefore tested the safety and feasibility of haploidentical natural killer cell therapy in this patient population. Procedure Twenty-nine children who had relapsed or refractory leukemia were treated with chemotherapy followed by the infusion of haploidentical NK cells. Cohort 1 included 14 children who had not undergone prior allogeneic hematopoietic cell transplantation (HCT), whereas Cohort 2 included 15 children with leukemia that had relapsed after HCT. Results Twenty-six (90%) NK donors were KIR mismatched (14 with one KIR and 12 with 2 KIRs). The peak NK chimerism levels were >10% donor in 87% of the evaluable recipients. In Cohort 1, 10 had responsive disease and 12 proceeded to HCT thereafter. Currently, 5 (36%) are alive without leukemia. In Cohort 2, 10 had responsive disease after NK therapy and successfully proceeded to second HCT. At present, 4 (27%) are alive and leukemia-free. The NK cell infusions and the IL-2 injections were well-tolerated. Conclusions NK cell therapy is safe, feasible, and should be further investigated in patients with chemotherapy-resistant leukemia.