Pediatric stem-cell recipients had considerably better survival and a reduced System.Drawing.Bitmap disease progression when matched with donors who had a specific natural killer (NK)-cell protein, investigators reported.
Survival improved by 60% and disease progression decreased by 62% in 313 sufferers who received allogeneic hematopoietic originate cells containing killer-cell immunoglobulin-like receptor 2DL1 (KIR2DL1). Patients benefited regardless of the indication for transplantation, treatment background, and completeness of HLA fit.
The results add to lab evidence that NK cells articulating KIR2DL1 had increased activity towards cancer cells, reported Wing Leung, MD, PhD, of St . Jude Children’s Research Hospital in Memphis, Tenn., and colleagues online within the Journal of Clinical Oncology.
“This approach should dramatically improve the outcome of patients undergoing bone tissue marrow transplantation, regardless of their age or even underlying condition, ” Leung mentioned in a statement. “NK cells furthermore play an important role in autoimmune disorders, chronic infections, and other situations, so these results will likely have an effect beyond cancer. ”
Improving Donor Selection
Clinical application of hematopoietic stem cell transplantation (HSCT) has grown and offers a potential cure for a number of malignancies, genetic diseases, and other problems. Despite advances in transplantation science, matching between donor and recipient remains critical to success. Researchers in several laboratories have explored potential markers that could improve donor choice beyond HLA matching.
Routine typing of KIRs has been proposed as a means to improve donor choice, the authors noted. KIRs are living on the surface of NK cells and certain cytotoxic T cells. Latest clinical studies have shown that inhibitory and activating KIRs play a role within the success of HSCT for malignant and nonmalignant conditions.
To date, 15 members of the KIR family have been identified, including KIR2DL1, which is found in 90% to 95% of healthy individuals. KIR2DL1 inhibits NK cell activity and “educates” NK cells in recognizing ligand group 2 HLA-C Lys80 (C2).
Some studies have suggested that the existence of donor KIR2DL1 and absence of recipient C2 (receptor-ligand mismatch) predict more favorable outcomes, but results from different transplantation centers have been inconsistent, the authors continued.
Recently, Leung and colleagues reported that KIR2DL1 alleles with arginine in position 245 of the transmembrane domain name (KIR2DL1-R 245 ) are stronger than those with cysteine (KIR2DL1-C 245 ). Continuing that line of research, investigators examined the influence of donor KIR2DL1-R 245 and KIR2DL1-C 245 on outcomes after allogeneic HSCT.
The authors performed allotyping for KIR2DL1 using DNA samples from donors for 313 patients who underwent allogeneic HSCT at St . Jude from January 2000 to January 2010. The particular patients had a median age of nine. 9 years at transplantation, and indications for HSCT were hematologic malignancies in 231 cases, strong tumors in 25, and nonmalignant conditions in 57.
Among the 256 patients with malignancies, 143 (56%) were in remission at the time of transplantation and the rest had persistent disease. Of the entire study population, 175 (56%) patients received conditioning regimens that included total-body irradiation, which was myeloablative in 76% of cases.
Contributor were matched siblings in 27% of cases, matched unrelated contributor in 31%, and haploidentical contributor in 41%.
The particular authors found that 215 of 313 donors were homozygous for KIR2DL1-R 245 , twenty two were homozygous for KIR2DL1-C 245 , and 76 had been heterozygous.
Recipients of KIR2DL1-R 245 had a significantly lower hazard for death after transplantation as compared with recipients of stem cells from homozygous KIR2DL1-C 245 donors (hazard ratio zero. 4, 95% CI 0. 25-0. 64, P =0. 0001), as did sufferers who received stem cells from heterozygous donors (HR 0. 42, 95% CI 0. 25-0. 71, P =0. 0013).
Survival failed to differ between patients who received homozygous KIR2DL1-R 245 stem cells and those who seem to received stem cells from heterozygous donors.
Limiting the analysis to the 231 patients with hematologic malignancies, Leung and colleagues found that patients who received stem cells from homozygous or even heterozygous KIR2DL1-R 245 donors still fared considerably better than those patients who received stem cells from homozygous KIR2DL1-C 245 contributor ( P =0. 0007).
Similar results surfaced from analyses of specific sorts of hematologic malignancies and analyses of sibling donors, unrelated donors, and haploidentical donors.
Progression-free survival in the 256 patients with malignancies was significantly better when they received stem cells from homozygous KIR2DL1-R 245 donors or heterozygous donors as compared with patients who received originate cells from homozygous KIR2DL1-C 245 donors (HR 0. 42, 95% CI zero. 26-0. 68, L =0. 0003; HR zero. 48, 95% CI 0. 28-0. 82, P =0. 0075).
An analysis limited to patients with hematologic malignancies yielded similar results, as do an analysis by type of hematologic malignancy.
Are the Results Enough to Move Forward?
The test for KIR2DL1 is available at most clinical laboratories, as well as the allotyping can be performed at the same time as HLA matching of a donor sample, based on Anna Pawlowska, MD, of City of Hope in Duarte, Calif.
“Based on these amazing results, I think KIR testing ought to be performed and reviewed at the time of donor selection and included with other factors think about a donor, ” Pawlowska mentioned via email. “KIR testing using the current method has been done from City of Hope since 2005. ”
The results are interesting but require validation in a well-designed prospective study, said Edward Copelan, MD, of Carolinas Healthcare Anatomy’s Levine Cancer Institute in Charlotte now, N. C.
“Typing was performed retrospectively at a one institution in pediatric patients, ” Copelan, who was not involved in the study, told MedPage Nowadays by email. “The patient population is heterogeneous pertaining to underlying disease, disease stage, transplant preparative regimen, donor type, as well as the use of T-cell depletion, complicating multivariate analysis. ”
“Many of the subset analyses were performed in small numbers of patients, and larger numbers of patients are needed for proper analysis of these specific circumstances, ” Copelan added. “In comparison to this study, many studies of KIR effect on relapse have shown an impact in acute meyloid leukemia but not in acute lymphoblastic leukemia.
“Lastly, it is unclear whether these results in pediatric patients can be applied to adults. ”
The study was supported by the NIH.
Leung and co-authors reported no conflicts appealing.
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