Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 473-476 ◽  
Author(s):  
Maria Ester Bernardo ◽  
Eugenia Piras ◽  
Adriana Vacca ◽  
Giovanna Giorgiani ◽  
Marco Zecca ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Hematopoietic Stem

Abstract Sixty thalassemia patients (median age, 7 years; range, 1-37) underwent allogeneic hematopoietic stem cell transplantation (HSCT) after a preparation combining thiotepa, treosulfan, and fludarabine. Before HSCT, 27 children were assigned to risk class 1 of the Pesaro classification, 17 to class 2, and 4 to class 3; 12 patients were adults. Twenty patients were transplanted from an HLA-identical sibling and 40 from an unrelated donor. The cumulative incidence of graft failure and transplantation-related mortality was 9% and 7%, respectively. Eight patients experienced grade II-IV acute GVHD, the cumulative incidence being 14%. Among 56 patients at risk, 1 developed limited chronic GVHD. With a median follow-up of 36 months (range, 4-72), the 5-year probability of survival and thalassemia-free survival are 93% and 84%, respectively. Neither the class of risk nor the donor used influenced outcome. This treosulfan-based preparation proved to be safe and effective for thalassemia patients given allogeneic HSCT.

Impact of Cytogenetics on Outcome of Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation for Adults with AML.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 830-830 ◽  
Author(s):  
Martin Tallman ◽  
Gordon Dewald ◽  
Hillard Lazarus ◽  
Sharavi Gandham ◽  
Gene Nelson ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cumulative Incidence ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Kaplan Meier

Abstract Matched unrelated donor hematopoietic stem cell transplantation (MUD HSCT) is a potentially curative treatment for patients with acute myeloid leukemia (AML). The graft-versus-leukemia (GVL) effect may be potent enough to overcome the otherwise poor prognosis associated with AML though its efficacy for high risk cytogenetic subgroups is uncertain. To test this hypothesis, we analyzed outcomes by cytogenetic risk group in 324 patients in first complete remission (CR1), and 440 in CR2 undergoing NMDP-facilitated MUD HSCT between 1988–2002. Using the SWOG/ECOG classification of cytogenetic risk groups (Slovak et al. Blood, 2000) cytogenetics were classified as favorable in 14% of patients, intermediate in 71% and unfavorable in 16%. 56% of the patients were male and 42% were > 35 years at HSCT. 76% of patients and donors were matched at HLA-A, -B and -DRB1, 17% were mismatched at one or more loci and 7% were potentially matched (serologically matched at HLA-A and -B and potentially allele matched at -DR). Disease Status N Kaplan-Meier Estimate for Survival at 5 years Kaplan-Meier Estimate for Disease-Free Survival at 5 years Cumulative Incidence for 100 Day Transplant-Related Mortality Cumulative Incidence for Relapse at 5 years * p-value indeterminate; ** p=0.01 CR1 324 32 ± 6% 32 ± 5% 32 ± 5% 18 ± 4%     Intermediate 227 33 ± 7% 32 ± 7% 31 ± 6% 16 ± 5%*     Unfavorable 85 31 ± 11% 31 ± 10% 29 ± 10% 23 ± 9%* CR2 440 36 ± 5% 35 ± 5% 25 ± 4% 16 ± 3%     Favorable 93 46 ± 10% 44 ± 10% 25 ± 9% 10 ± 6%**     Intermediate 313 33 ± 6% 32 ± 5% 27 ± 5% 16 ± 4%**     Unfavorable 34 37 ± 17% 38 ± 16% 15 ± 12% 32 ± 15%** These data suggest that with the exception of the 5-year relapse rate, results of cytogenetics have little apparent influence on the outcome for patients undergoing MUD HSCT for AML in CR1. In CR2, results in patients with favorable cytogenetics appear to be better than those with intermediate or unfavorable cytogenetics, but are not statistically significantly different. Effective GVL and protection against relapse is observed, even in high risk cytogenetic subgroups. In this retrospective study, other prognostic factors may influence the outcome, but overall survival for patients with unfavorable cytogenetics appears at least as good as previously reported for matched sibling HSCT.

Favorable Outcome Of Hematopoietic Stem Cell Transplantation Using a Targeted Once-Daily IV Busulfan Fludarabine Etoposide Regimen In Pediatric and Infant ALL Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4553-4553
Author(s):  
Hyoung Jin Kang ◽  
Ji Won Lee ◽  
Sung jin Kim ◽  
Seung Hwan Lee ◽  
Kyung-Sang Yu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cumulative Incidence ◽  
Conditioning Regimen ◽  
Favorable Outcome ◽  
Hematopoietic Stem ◽  
Once Daily

Conditioning regimens for pediatric acute lymphoblastic leukemia (ALL) usually include total body irradiation (TBI), but TBI may result in serious sequelae such as growth impairment, endocrinologic and metabolic problem, and secondary malignancies. Busulfan based conditioning regimen with cyclophosphamide has been used as an alternative to TBI based regimen in many diseases including pediatric ALL. Etoposide has been widely used in hematopoietic stem cell transplantation (HSCT) for lymphoid and myeloid malignancy because of its anti-leukemic effect, and a conditioning regimen containing busulfan, cyclophosphamide and etoposide (BuCyVP) was used in many studies including pediatric patients. But, toxicities have been reported in some studies using BuCyVP regimen. Recently, a reduced toxicity myeloablative regimen using busulfan and fludarabine showed promising results. Also, therapeutic drug monitoring (TDM) and administration of targeted dose of busulfan has been recommended to improve the outcome of HSCT. In this study, we evaluated the outcome of HSCT using a targeted once-daily intravenous (IV) busulfan fludarabine etoposide (BuFluVP) regimen in pediatric and infant ALL. The conditioning regimen was composed of busulfan, fludarabine (40 mg/m2 once daily i.v. on days -8 ∼ -3) and etoposide (20 mg/kg once daily i.v. on days -4 ∼ -2). Busulfan (≥ 1 year-120 mg/m2 and < 1 year-80 mg/m2) was administered once daily as the first dose on day -8, and targeted dose of busulfan was used according to the TDM results on day -7 ∼ -5. A total of 33 patients were evaluated. Donor-type neutrophil engraftment was achieved in all patients. Veno-occlusive disease occurred in 5 (15.2%) patients, but all of them were successfully treated. Grade II-IV acute GVHD developed in 11 patients (grade 2 in 9 patients, grade 3 in 1 and grade 4 in 1 patient) and the cumulative incidence was 33.6%. Chronic GVHD developed in 3 patients (2 extensive and 1 limited). Three patients died of treatment-related mortality (TRM) and the cumulative incidence was 9.1%. The causes of TRM were adenoviral pneumonia in 1, respiratory syncytial viral (RSV) pneumonia in 1 and interstitial lung disease in 1 patient. Relapse occurred in 3 patients and cumulative incidence was 9.1%. Overall survival (OS) and event free survival (EFS) of all patients were 84.9% and 81.8%, respectively. EFS showed no difference according to the type of HSCT (77.8% in related BMT/PBSCT, 82.4% in unrelated BMT/PBSCT, and 85.7% in CBT, P=0.95). Eleven patients (33.3%) were infants at diagnosis, and OS of these patients was 81.8%. Our study demonstrated that HSCT using a targeted once-daily IV BuFluVP regimen showed favorable outcome and could be one option for HSCT in pediatric and infant ALL. Disclosures: No relevant conflicts of interest to declare.

Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation

2019 ◽  
Vol 37 (5) ◽  
pp. 375-385 ◽  
Author(s):  
Mareike Frick ◽  
Willy Chan ◽  
Christopher Maximilian Arends ◽  
Raphael Hablesreiter ◽  
Adriane Halik ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Increased Risk

Purpose Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT). Methods We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS). Results A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434). Conclusion Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.

Impact of Conditionning Regimen in Allogeneic Hematopoietic Stem Cell Transplantation for Children with Acute Myeloid Leukemia in First Complete Remission: Total-Body Irradiation and Cyclophosphamide Versus Busulfan and Cyclophosphamide - A Report from The Societe Francaise de Greffe de Moelle et de Therapie Cellulaire.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 617-617 ◽  
Author(s):  
Jean-Hugues Dalle ◽  
Luc Caty ◽  
Regis Peffault ◽  
Alexandra Salmon ◽  
Valerie Mialou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Hematopoietic Stem

Abstract Goal: Compare results after allogeneic HSCT for AML in CR1 in pediatric population after myeloablative conditioning regimen either based on TBI or busulfan. Patients and Methods: Retrospective analysis from French registry including all consecutive patients under 18 years of age (n=131) from Dec’1979 and Oct’2004 transplanted for AML in CR1 with either sibling (n=104) or matched unrelated donor and given either multi-fractionated TBI 12Gy and cyclophosphamide 120mg/kg (TBI-Cy) or Busulfan 16mg/kg and Cyclophosphamide 200mg/kg (BuCy200). Results were analysed according to EBMT statistical analysis guidelines i.e. OS and EFS were analyzed by KM method and Log-rank test for comparison where TRM and relapse incidence were analyzed by cumulative incidence method and Gray test for comparison. Multivariate analyses were performed using proportional hazard model for the distribution of competitive risks defined by Fine and Gray. Results: 131 patients (female: 51.5%) were included. Median age at initial diagnosis was 11y (0.5 to 17.8). Median time from diagnosis to transplantation was 4.2 months. Eighty-three patients received BuCy200 and 48 patients were transplanted after TBI-Cy. Patient subgroups were comparable for age, gender, sex mismatch, source of graft (BMT vs PBSC), donor type (geno-identical vs 10/10 matched unrelated donor vs other), cytogenetical analysis and WBC at initial diagnosis, and for donor-recipient CMV status (−/+ vs others). Both 5 year-overall and event-free survival rates appeared significantly better in BuCy200 group than in TBI-Cy group with 73.3% vs 56.1% (p=0.02) and 67+/−7% vs 38+/−9% (p=0.002), respectively. TRM incidence at day 365 was dramatically better in BuCy200 group than in TBI-Cy group with 4,7% vs 26.1% of TRM rate (p=0.002), respectively. Even though there were no statistical significant differences for both acute and chronic GVHD cumulative incidences whatever given conditioning regimen, there was a trend for obtaining lesser GVHD in BuCy200 group: day 100 grade II-IV aGVHD cumulative incidence was 13% vs 37% and 2 year extensive cGVHD was 9 vs 19% for BuCy200 and TBI-Cy group, respectively. At 5 years, there was a trend for less relapse in BuCy200 group than in TBI-Cy 16+/−3% vs 32+/−6% (p=0.09), respectively. Conclusion: This study demonstrates the superiority of BuCy200 on TBI-Cy conditioning regimen for paediatric patients presenting with AML in CR1 and undergoing allogeneic hematopoietic stem cell transplantation from either matched related or unrelated donor. These results, obtained from a larger cohort, confirm and update those published by our group in 1994. Figure 1: Overall survival Figure 1:. Overall survival

scholarly journals Post-Transplant High-Dose Cyclophosphamide Overcomes the Detrimental Effect of a Single-Locus HLA Mismatched in Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4576-4576
Author(s):  
Patricia Ferraz ◽  
Arturo Pereira ◽  
María Suárez-Lledó ◽  
Gonzalo Gutiérrez-García ◽  
Francesc Fernández-Avilés ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Detrimental Effect ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis

Abstract Background: Allogeneic hematopoietic stem cell transplantation (alloSCT) from unrelated donors mismatched (MMUD) at a single HLA-A, -B, -C, or -DRB1 locus (7/8) were previously reported to be associated with lower overall survival (OS) and disease-free survival (DFS), higher treatment-related mortality (TRM), and more acute graft-versus-host disease (GVHD) compared to 8/8 matched unrelated (MUD) allografts. Despite these risks, 7/8 MMUD grafts remain a viable option for alloSCT, particularly in patients who lack suitable donors or in those with aggressive hematologic malignancies for whom the risks of disease progression due to delays in identifying optimal donors is offset in part by the benefits of earlier transplantation with a 7/8 MMUD alloHCT. According to the published experience of post-transplant cyclophophamide (PTCy) in the context of haploidentical alloSCT, this GVHD prophylaxis strategy could potentialy overcome the detrimental effect of a single-locus HLA MMUD. Methods: We retrospectively analyzed 72 consecutive adult patients (median age 53y, range 18-69) who received 7/8 MMUD (n=44) or 8/8 MUD (N=28) alloSCT with PTCy in our institution. Unrelated donor selection was performed according to standard criteria, including high resolution typing for alleles at HLA-A, -B, -Cw, DRB1 and DQB1. For those patients in whom an 8/8 HLA-matched related or unrelated donor was not available, a search was performed based on a single HLA-mismatch. Results: Acute myeloid or lymphoblastic leukemia accounted for 51% of all hematologic diseases, myelodisplastic syndrome for 17%, chronic lymphoproliferative or myeloproliferative disorders for 28%, and severe aplastic anemia for 4%. Disease Risk Index (DRI) was intermediate in 51%, high 16% and very high 6%. Forty-four percent of patients had a HCT-CI ≥3. All patients, except 6 have received peripheral blood stem cells (PBSC). Fludarabine-based conditioning regimens were used in all patients (fludarabine-busulphan in 61%); of them, myeloablative (MAC) in 34 patients (47%) and RIC in 38 (53%). GVHD prophylaxis consisted on PTCy 50mg/kg IV on days 3 and 4 after transplant followed by one (tacrolimus or mycophenolate mofetil, MMF) (n=62, 86%) or 2 (n=10, 14%) immunossuppresor drugs. All but two patients engrafted and the median time to neutrophil (>500/mL) and platelet (>20,000/mL) recovery were 18 days (range 11-30) and 18 days (10-47), respectively. Thirteen patients (18%) developed an invasive pulmonary Aspergillosis, 20 (27%) had severe bacterial infection, 40 (56%) CMV reactivation, 5 (7%) cytomegalic disease and 3 EBV reactivation. The cumulative incidences of 1-year TRM, 100-days acute grade II-IV, 100-days grade III-IV GHVD, and 1-year moderate-severe chronic GHVD were 19%, 24%, 13%, and 11%, respectively. The cumulative incidence of relapse at 1-year was 16%. After a median follow-up for surviving patients of 12 months (2-60), 2-year OS, DFS, and survival free of moderate/severe chronic GVHD and relapse (cGRFS) were 64%, 61%, and 49%, respectively. Univariate analysis of variables that could influence OS, PFS, and cGRFS, including age, donor/patient sex, comorbidity, DRI, conditioning type, 1 vs. 2 immunosuppressors, and HLA 7/8 vs. 8/8 did not show any statistical differences. At 6 and 12 months after alloSCT, 42% and 73% of patients alive and without relapse were free of immunosuppressor drugs and prednisone. Conclusions: This study suggests that PTCy after unrelated PBSC alloSCT results in a low incidence of acute and chronic GVHD with encouraging survival outcomes even in the context of 7/8 HLA-mismatched transplant. An immunosuppressive schema of intermediate intensity such as PTCy followed by single-agent tacrolimus may provide an adequate GVHD prophylaxis and could be a good alternative to ATG in both MMUD and MUD transplants. Confirmatory and comparative studies are warranted to examine the effect of this approach on alloSCT outcomes. Disclosures Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Martinez:BMS: Research Funding; Takeda: Consultancy.

scholarly journals Haploidentical Hematopoietic Stem Cell Transplantation for Malignant Infantile Osteopetrosis and Intermediate Osteopetrosis:A Retrospective Analysis of a Single-Center

2021 ◽  
Author(s):  
Guanghua Zhu ◽  
Ang Wei ◽  
Bin Wang ◽  
Jun Yang ◽  
Yan Yan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Survival Rate ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
High Survival ◽  
Hematopoietic Stem

Abstract ObjectiveTo evaluate the clinical efficacy of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for treatment of malignant infantile osteopetrosis (MIOP) and intermediate osteopetrosis.MethodsChildren with MIOP and IOP who underwent haplo-HSCT in Beijing Children’s Hospital, Capital Medical University, from January 2010 to May 2018 were retrospectively analyzed. Data relating to the clinical manifestations, engraftment, and prognosis of the children were extracted from medical records. ResultsTwenty-seven patients, including 18 males and 9 females, with an onset age of 12 (0.04-72) months, were enrolled in this study. The median time from diagnosis to transplantation was 4 (1-23) months. All patients received haplo-HSCT with myeloablative conditioning regimen (including fludarabine, busulfan, and cyclophosphamide). The graft versus host disease (GVHD) prophylaxis was based on anti-human T lymphocyte porcine immunoglobulin /anti-human thymus globulin, methotrexate, and mycophenolate mofetil. The median observation time was 55.2 (0.3-126.2) months. By the end of follow-up, twenty patients survived and seven patients died. The five years overall survival rate was 73.9%. Acute GVHD degree I-II was observed in 20 patients, degree III in 1 patient and without degree IV. Chronic GVHD was observed in 11 patients (40.7%). It was controlled by anti-GVHD therapy.ConclusionHaplo-HSCT was effective for MIOP and IOP, with high survival rate and significantly improved of clinical symptoms. For the patients with vision impairment before HSCT, the improvement was slow after transplantation. The incidence of GVHD was high but mild, and could be effectively controlled after appropriate treatment. These data provided that haplo-HSCT was feasible in the treatment of MIOP and IOP.

Impact of Activating Killer Immunoglobulin-Receptor Genotype of the Donor on Outcome of Unrelated Donor - Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5206-5206
Author(s):  
Sebastian Giebel ◽  
Izabela Nowak ◽  
Tomasz Kruzel ◽  
Jerzy Wojnar ◽  
Miroslaw Markiewicz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Function of NK cells is regulated by a balance between inhibitory and activating signals transmitted through killer immunoglobulin-like receptors (KIR). The goal of the present analysis was to evaluate the impact of donor activating KIR genotype (KIR2DS1 and KIR2DS2 loci) on outcome of unrelated donor-hematopoietic stem cell transplantation (URD-HSCT). Fourty-two URD-HSCT recipients with haematological malignancies, aged 28 (14–48) years (male/female - 26/16) were included in the analysis. The conditioning regimen was myeloablative and based on chemotherapy alone (n=33) or total body irradiation (n=9). Graft-vs-host disease (GVHD) prophylaxis consisted of cyclosporin, methotrexate, and pre-transplant anti-thymocyte globulin. Patients were grouped according to their donors’ activating KIR genotype including two loci: KIR2DS1 and KIR2DS2. The overall survival at 2.5 years with respect of the donors’ activating KIR genotype was as follows: KIR2DS1(−)DS2(−) (n=15) − 82% (+/−12%), KIR2DS1(+)DS2(−) (n=9) − 78% (+/−14%), KIR2DS1(−)DS2(+)− (n=7) 86% (+/−13%), KIR2DS1(+)DS2(+) (n=11) − 0%. The OS rate differed significantly between KIR2DS1(+)DS2(+) group and the remaining patients: 0% vs. 82% (+/−7%), p=0.03. The difference resulted mainly from higher cumulative incidence of non-relapse mortality in the KIR2DS1(+)DS2(+) group: 100% vs. 18% (+/−8%), p=0.098. The reasons of death in patients with KIR2DS1(+)DS2(+) donors were chronic GVHD (n=4) and acute GVHD (n=1). We conclude that the concomitance of both KIR2DS1 and KIR2DS2 in the donor is associated with high risk of mortality following URD-HSCT, resulting mainly from the incidence of severe GVHD. Whether this effect is associated with the activity of NK cells or KIR-bearing T lymphocytes requires further investigation.

Impaired Survival after Unrelated Hematopoietic Stem Cell Transplantation from KIR2DS1 and KIR2DS2 Positive Donors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3113-3113
Author(s):  
Sebastian Giebel ◽  
Tomasz Czerw ◽  
Izabela Nowak ◽  
Jerzy Wojnar ◽  
Tomasz Kruzel ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Unrelated Donor ◽  
Hematopoietic Stem

Abstract The function of NK cells is regulated by a balance between signals transmitted via actvating and inhibitory receptors, including killer-immunoglobulin-like receptors (KIRs). Activating KIRs (KIR2DS1 and KIR2DS2) are also present on subsets of T cells, which has recently been demonstrated to play a role in several autoimmune conditions. The goal of this analysis was to determine the relationship between donor activating KIRs genotype and outcome after unrelated donor hematopoietic stem cell transplantation (URD-HSCT). Seventy five patients (age 30y; range 14–57) with hematological malignancies treated with URD-HSCT in a single centre between 2000 and 2006 were included in the analysis. Donors were selected using DNA-high resolution typing for both HLA class I and II alleles. KIR2DS1 and KIR2DS2 genes were examined in all donors. Additionally, in 16 cases a subpopulation of KIR2DS2/DL2/DL3-positive T cells in peripheral blood was monitored in donors as well as in recipients for 6 months after transplantation. The conditioning regimen was myeloablative and based on chemotherapy alone (n=56) or TBI (n=19). Graft-vs-host disease (GVHD) prophylaxis was uniform and consisted of cyclosporin, methotrexate, and pre-transplant anti-thymocyte globulin. Twenty-five % of donors were positive for both KIR2DS1 and KIR2DS2 gene, 18% were positive for KIR2DS1 only, 25% - for KIR2DS2 only, and 32% were negative for both KIR2DS1 and KIR2DS2. In univariate and multivariate analysis, including other potential risk factors, the presence of both KIR2DS1 and KIR2DS2 genes of the donor was associated with decreased overall survival (0% vs. 80%, RR 3.2, p=0,01) and disease free survival (0% vs. 64%, RR 2.5, p=0,03), compared to the remaining subgroups. Furthermore, simultanous KIR2DS1 and KIR2DS2 positivity resulted in increased GVHD-related mortality (70% vs. 8%, p=0.01) in univariate analysis (incidence of both acute and chronic GVHD contributed to this effect). KIR2DS2/DL2/DL3-positive T cells were detected in 3/16 donors before URD-HSCT and in all recipients between day +28 and +180 after URD-HSCT. KIR-positive T cells were particularily frequent (32%–42% of all CD3 cells) in three patients who developed acute GVHD, and for whom the donors were KIR2DS2-positive. We conclude that the simultaneous presence of both KIR2DS1 and KIR2DS2 in the donor is associated with decreased survival following URD-HSCT. The mortality may result from higher incidence of lethal GVHD. Preliminary observation suggests the role of KIR-bearing T lymphocytes in this effect.

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