HLA-identical Hematopoietic Stem Cell Research Articles

Long-Term Immune Recovery After Hematopoietic Stem Cell Transplantation for ADA Deficiency: a Single-Center Experience

Unconditioned hematopoietic stem cell transplantation (HSCT) is the recommended treatment for patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency with an HLA-matched sibling donor (MSD) or family donor (MFD). Improved overall survival (OS) has been reported compared to the use of unrelated donors, and previous studies have demonstrated that adequate cellular and humoral immune recovery can be achieved even in the absence of conditioning. Detailed insight of the long-term outcome is still limited. We aim to address this by studying a large single-center cohort of 28 adenosine deaminase-deficient patients who underwent a total of 31 HSCT procedures, of which more than half were unconditioned. We report an OS of 85.7% and event-free survival of 71% for the entire cohort, with no statistically significant differences after procedures using related or unrelated HLA-matched donors. We find that donor engraftment in the myeloid compartment is significantly diminished in unconditioned procedures, which typically use a MSD or MFD. This is associated with poor metabolic correction and more frequent failure to discontinue immunoglobulin replacement therapy. Approximately one in four patients receiving an unconditioned procedure required a second procedure, whereas the use of reduced intensity conditioning (RIC) prior to allogeneic transplantation improves the long-term outcome by achieving better myeloid engraftment, humoral immune recovery, and metabolic correction. Further longitudinal studies are needed to optimize future management and guidelines, but our findings support a potential role for the routine use of RIC in most ADA-deficient patients receiving an HLA-identical hematopoietic stem cell transplant, even when a MSD or MFD is available.

386 - Cryptogenic Organizing Pneumonia Following HLA Identical Hematopoietic Stem Cell Transplantation for Sickle Cell Disease: A Case Series of Three Pediatric Patients

386 - Cryptogenic Organizing Pneumonia Following HLA Identical Hematopoietic Stem Cell Transplantation for Sickle Cell Disease: A Case Series of Three Pediatric Patients

High pre-transplant TREC levels indicate good prognosis after hematopoietic stem cell transplantation

BackgroundThymus-dependent T-cell reconstitution plays a role in immune recovery after stem cell transplantation (HSCT). High pre-HCST thymic function has been associated with higher survival, lower incidence of acute and chronic graft versus host disease (GVHD) and lower incidence of infections. The aim of this study was to analyze the relationship between pre-HSCT peripheral blood levels of T-cell receptor excision circles (TREC) and post-HSCT clinical events in recipients of HLA-identical hematopoietic stem cell transplants.MethodDelta deletion signal joint TRECs (sjTRECs) formed by the dREC-yJa rearrangement were quantified by real time PCR in peripheral blood lymphocytes of 62 HSCT recipients.ResultsUnivariate analysis revealed an association between low TREC levels and a higher incidence of grade II-IV acute GVHD (p=0.026), bacterial infection (p=0.005) and cytomegalovirus infection (p=0.033), whereas high TREC levels were associated with higher overall survival (p=0.028). In the multivariate analysis, low pre-HSCT TREC levels remained independently associated with lower survival (p=0.032; RR 2.6), occurrence of grade II-IV acute GVHD (p=0.031; RR: 2.5), bacterial infection (p=0.006, RR: 6.6) and cytomegalovirus infection (p=0.039; RR:2.8).ConclusionOur results corroborate the concept that pre-HSCT recipient´s thymic function is an important predictor of risk for acute grade II-IV GVHD and infection.

Transplantation in patients with SCID: mismatched related stem cells or unrelated cord blood?

AbstractPediatric patients with SCID constitute medical emergencies. In the absence of an HLA-identical hematopoietic stem cell (HSC) donor, mismatched related-donor transplantation (MMRDT) or unrelated-donor umbilical cord blood transplantation (UCBT) are valuable treatment options. To help transplantation centers choose the best treatment option, we retrospectively compared outcomes after 175 MMRDTs and 74 UCBTs in patients with SCID or Omenn syndrome. Median follow-up time was 83 months and 58 months for UCBT and MMRDT, respectively. Most UCB recipients received a myeloablative conditioning regimen; most MMRDT recipients did not. UCB recipients presented a higher frequency of complete donor chimerism (P = .04) and faster total lymphocyte count recovery (P = .04) without any statistically significance with the preparative regimen they received. The MMRDT and UCBT groups did not differ in terms of T-cell engraftment, CD4+ and CD3+ cell recoveries, while Ig replacement therapy was discontinued sooner after UCBT (adjusted P = .02). There was a trend toward a greater incidence of grades II-IV acute GVHD (P = .06) and more chronic GVHD (P = .03) after UCBT. The estimated 5-year overall survival rates were 62% ± 4% after MMRDT and 57% ± 6% after UCBT. For children with SCID and no HLA-identical sibling donor, both UCBT and MMRDT represent available HSC sources for transplantation with quite similar outcomes.

Clinical Applications for Biomarkers of Acute and Chronic Graft-versus-Host Disease

Acute and chronic graft-versus-host disease (aGVHD, cGVHD) are serious complications of allogeneic hematopoietic cell transplantation. The complex pathophysiology of these disease processes is associated with immune system activation, the release of cytokines and chemokines, and alterations in cell populations. The blood levels of specific protein and cellular levels in patients with GVHD have correlated with the development, diagnosis, and prognosis of GVHD. Here, we review the most promising biomarkers for aGVHD and cGVHD with clinical relevance. The utility of GVHD biomarkers in clinical care of allogeneic hematopoietic cell transplantation recipients needs to be proven through clinical trials, and potential approaches to trial design are discussed.

Diarrhea during the Conditioning Regimen Is Correlated with the Occurrence of Severe Acute Graft-versus-Host Disease through Systemic Release of Inflammatory Cytokines

Graft-versus-host disease (GVHD) is a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although many indicators have been used to predict GVHD, the prediction of GVHD remains very difficult. Determining how to predict the occurrence of acute GVHD (aGVHD) as exactly as possible has been a huge challenge so far. Systemic release of inflammatory cytokines during the conditioning regimen and early-phase post-HSCT plays a crucial role in the generation of aGVHD; additionally, the conditioning regimen causes the damage to the intestinal tract. Diarrhea is a common symptom of intestinal tract damage during the conditioning regimen. We therefore performed a prospective study to investigate the relationship between diarrhea related to the conditioning regimen, systemic release of inflammatory cytokines during the conditioning regimen and the early-phase post-HSCT, and the development of aGVHD. This study demonstrated that duration of diarrhea was >5.5 days, with a maximal volume >8.72 mL/kg and a mean volume of diarrhea for days -3 to 0 >7.94 mL/kg were risk factors of grade II to IV aGVHD. Diarrhea with any 1 risk factor was defined as severe diarrhea. Furthermore, this study first confirmed that the correlation between diarrhea and aGVHD was related to the serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 during the conditioning regimen and during the early phase after transplantation. Our study demonstrated that diarrhea related to the conditioning regimen could be used as a marker for the prediction of aGVHD and further explain the possible mechanism underlying the linkage described here. Therefore, for the patients with severe diarrhea related to the conditioning regimen, low-dose glucocorticoid may be used to reduce the levels of inflammatory cytokine release by a damaged intestinal tract, and possibly further reduce the occurrence of aGVHD. For these patients, prophylaxis of aGVHD may be need to be adjusted individually.

Immunomonitoring of graft‐versus‐host minor histocompatibility antigen correlates with graft‐versus‐host disease and absence of relapse after graft

After HLA-identical hematopoietic stem cell transplantation, minor histocompatibility (mH) antigen alloreactivity plays a dominant role in the development of graft-versus-host disease (GVHD) and graft versus leukemia (GVL). We have analyzed the mH alloreactivity (enzyme-linked immunospot [ELISpot] for interferon-gamma[IFN-gamma] assay) from 24 donor/recipient pairs over a period of 2 years of follow-up and correlated such alloreactivity with the development of GVHD or absence of relapse. Circulating specific T cells anti-mH with multimer HLA-peptides were also studied. We show by ELISpot IFN-gamma assay that alloreactivity during the first 3 months from donor versus recipient or donor versus mismatched identified mH antigens is associated with acute GVHD and GVL effect. In addition, we demonstrate that the donor-versus-recipient reactivity observed after the third month is highly associated with chronic GVHD and GVL (p = 0.0007). Finally, we show by multimer HLA-peptide assay that mH epitope-specific T cells present after 3 months are statistically related to the GVL effect. Our results provide a robust method to monitor mH antigen graft-versus-host reaction and suggest that current identified mH have predictive value on GVHD and GVL.

Primary Exploration of Relationship of HLA-Cw typing with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Objective To determine the effects of HLA-Cw typing on graft-versus-host disease and re-lapse after allogeneic hematopoietic stem cell transplantation. Methods HLA - Cw typing was performed in HLA identical allogeneic hematopoietic stem cell transplantation,including 9 patients with allogeneic peripheral blood stem cell transplantation(allo-PBSCT) and 10 patients with umbilical cord blood(UCBT) respectively. A-cute GVHD data were compared between the groups with different HLA-Cw typing results (matched and un-matched). Results In 16 HLA-Cw matched patients,15 cases got engrafted(94%) ,and 11 patients had Ⅰ～Ⅱ acute GVHD and 2 patients had Ⅲ acute GVHD. Fifteen patients had chronic GVHD but no patients had re-lapse. In 3 HLA-Cw unmatched patients,2 patients had Ⅲ acute GVHD and died in early stage and 1 patient had early relapse. When cases were classified into two groups accoring to HLA-Cw typing results, there is statisti-cally significant difference in both Ⅰ～Ⅱ and Ⅲ acute GVHD between these two groups (P < 0. 05). Conclu-sion In hematopoietic stem cell transplantation cases, HLA-Cw matching may be helpful to reduce GVHD. The results suggest that HLA typing is important for the prognosis of hematopoietic stem cell transplantation in addi-tion to HLA-A, B, DR/DQ matching. Key words: HLA-Cw typing; Allogeneic ; Hematopoietic stem cell transplantation; Graft-versus-host disease

Mesenchymal Stem Cells Derived from Different Donors as Salvage Therapy for Resistant Severe Acute Graft-Versus-Host Disease

Severe Acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation(allo-HSCT), especially severe intestinal aGVHD, is associated with a high morbidity and mortality rate and is a major threat to a successful outcome. Currently, corticosteroids are still the first-line treatment for established aGVHD with a response rate of 30–50%; however, patients who fail on standard therapy have poor outcome, and therapeutic options avail able for them are limited. Mesenchymal stem cells (MSCs) are multipotent cells able to differentiate into different tissues and also have immunomodulatory effects, inhibit T-cell proliferation in mixed lymphocyte cultures, prolong skin allograft survival. Recently, Le Blanc and Fan B et al. respec tively reported their experience of using vitro expanded MSCs to treat severe, resistant aGVHD of the gut and liver, and the results showed rapid improvement after infusion of MSC. Thus, MSC may be used for the treatment of severe acute GVHD. The purpose of our study was to evaluate further the efficacy of ex vivo expanded MSC as the salvage therapy for severe refractory acute GVHD. Between February, 2006, and July, 2007, four patients with gastrointestinal grade III to IV acute GVHD after sibling HLA-identical hematopoietic stem cell transplantation, who didn't respond to steroid therapy (≥2mg per kg per day) for more than seven days, or with progression at least within 72 hours were treated with MSC. The study was approved by the Ethics Committee at Guangdong Provincial People's Hospital. All patients and the MSC donors gave them written informed consent. Eleven infusions of MSCs were given Fone patient had one infusion, others had two or more infusions. All of them, the first-infusion MSCs were derived from their HLA-identical sibling donors, and the second or more MSCs were derived from different HLA-mismatched unrelated donors. The median dose given to patients was 0.5×106 cells per kg(range: 0.3 to 0.8×106 cells per kg). Median time from tansplantation of haemopoietic stem cells to infusion of MSCs was 58 days (range 28–63days). No patients had acute side-effects either during or after infusion. Total response rate was 100%. Two patients achieved complete response and the others achieved partial response. Four patients with gut aGVHD, two of them achieved complete response after the first dose infusion, and the other two achieved partial response and good partial response after the second and the third infusion, respectively. Otherwise, two of four patients with liver aGVHD, achieved partial response and complete response after the second and the third infusion. The median time from first infusion of MSCs to primary response time and fully response time was 3 days and 23 days(range: 2 to 5 days; 10 to 72 days) after MSC transfusion, respectively. Two patients had died of multiple cerebral infarction and the other one died of multiorgan failure. Just case 2 was alive and developed gut chronic GVHD. At last follow-up (July 31, 2008), the patient was in stable state and his immunosuppressive therapy is being tapped. In conclusion, our preliminary results support the hypothesis that MSC derived from either bone marrow or umbilical cord blood, HLA-identical or HLA-mismatched, single donor's or multiple donors' MSCs can be used safely and has encouraging efficacy in the treatment of patients with severe acute GVHD who was refractory to conventional immunosuppressive threapy, although our result may have been influenced by the small number of patients studies and the short observation period, however, in view of the dismal outcome in patients with grades III–IV acute GVHD, MSC seems promising.

Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia

Individual differences in drug efficacy or toxicity can be influenced by genetic factors. We investigated whether polymorphisms of pharmacogenes that interfere with metabolism of drugs used in conditioning regimen and graft-versus-host disease (GvHD) prophylaxis could be associated with outcomes after HLA-identical hematopoietic stem cell transplantation (HSCT). Pharmacogenes and their polymorphisms were studied in 107 donors and patients with leukemia receiving HSCT. Candidate genes were: P450 cytochrome family (CYP2B6), glutathione-S-transferase family (GST), multidrug-resistance gene, methylenetetrahydrofolate reductase (MTHFR) and vitamin D receptor (VDR). The end points studied were oral mucositis (OM), hemorrhagic cystitis (HC), toxicity and venoocclusive disease of the liver (VOD), GvHD, transplantation-related mortality (TRM) and survival. Multivariate analyses, using death as a competing event, were performed adjusting for clinical factors. Among other clinical and genetic factors, polymorphisms of CYP2B6 genes that interfere with cyclophosphamide metabolism were associated with OM (recipient CYP2B6(*)4; P=0.0067), HC (recipient CYP2B6(*)2; P=0.03) and VOD (donor CYP2B6(*)6; P=0.03). Recipient MTHFR polymorphisms (C677T) were associated with acute GvHD (P=0.03), and recipient VDR TaqI with TRM and overall survival (P=0.006 and P=0.04, respectively).Genetic factors that interfere with drug metabolisms are associated with treatment-related toxicities, GvHD and survival after HLA-identical HSCT in patients with leukemia and should be investigated prospectively.

HLA-identical haematopoietic stem cell transplantation for acute leukaemia in children: less relapse with higher biologically effective dose of TBI

To examine relapse, survival and transplant-related complications in relationship to disease- and pre-treatment-related characteristics, we evaluated 132 children, who consecutively received an allogeneic HLA-identical SCT for acute leukaemia in our centre: ALL in first remission (n=24), ALL in second remission (n=53) and AML in first remission (n=55). The source of the stem cells was bone marrow in all but three cases. Most patients (89%) were pre-treated with cyclophosphamide and an age-related dose of TBI. Initially, GVHD prophylaxis consisted of long-course MTX only (n=24), later short-course MTX and CsA (n=102) was given. All patients were nursed in strictly protective isolation and received total gut decontamination to suppress their potentially pathogenic enteric microflora. The 5-year probability of overall survival was 63, 53 and 74% for ALL1, ALL2 and AML1, respectively (median follow-up: 10.6 years). The overall transplant-related mortality was 6%. The incidence of acute GVHD was 17%; 6% was grades II-IV. A higher total biologically effective TBI dose (BED) resulted in a decreased relapse frequency (P=0.034) and increased overall survival. AML patients with acute GVHD got no relapse (P=0.02); this was not the case in ALL patients. Fractionated TBI regimens with higher BED should be evaluated in prospective studies.

Persistent Centre Effect but Improvement of Leukemia-Free Survival of HLA Identical Hematopoietic Stem Cell Transplantation for Adults with AML in First CR in Europe over the Period 1987–2005 an Analysis on Behalf of the ALWP of EBMT.

Background. Among major European centres which had undertaken more than 30 bone-marrow transplantations(BMT) between Jan 1, 1987, and Dec 31, 1995, the outcome of allogenic BMT for acute myeloid leukemia (AML) in first complete remission has been shown to be influenced by the centre in which the procedure is done. To determine whether similar variation exists 10 years later, we analysed leukaemia free survival (LFS), relapse incidence (RI) and treatment related mortality (TRM) across the same 13 transplant centres.Methods. Thirteen centres were included in the analysis which enrolled 515 patients (aged 16–55 years), between 1987 and 1995, for acute myeloid leukaemia in first complete remission and 455 patients were enrolled between 1996 and 2005. Patients were followed from the date of transplantation to the time of event (Relapse and/or deaths). Regression models taking into account centre effect was adapted to the outcome and adjusted for relevant covariatesFindings The overall results at 5 years were 57% (95% CI 54–61) for leukaemia-free survival (LFS), 22% (19–25) for relapse incidence (RI), and 21% (18–24) for treatment related mortality (TRM) with a range for centres of 41–67%, 13–41%, and 13–41%, respectively. LFS at 5 years before 1995 was significantly lower 54% than after 1995 62% (p=0.02). Relapse Incidence at 5 years before 1995 was not significantly lower 23% than after 1995 21% (p=0.34). Treatment-related mortality incidence at 5 years before 1995 was not significantly lower 25% than after 1995 21% (p=0.13). Analysis showed the centre effect to be highly significant for LFS and TRM, but not for RI.Interpretation These findings show that the results of BMT have improved over time in Europe. At the same time this study confirms a significant centre-specific variation in the success of bone transplantation in Europe. This effect has persisted despite advances in transplantation, which have lead to improvements in patient outcomes (leukaemia free survival and Treatment Related Mortality). Further studies are needed to elucidate the causes of this variation, with the goal of developing strategies to minimize the centre effect and ensure the best possible outcomes for all transplant recipients.

HLA Identical Hematopoietic Stem Cell Transplantation for Acute Leukemia in Children - A Single Center Experience.

Between 1980 and 2002, 132 children and adolescents (median age 8.5 years, range 1.1 to 17.3) got an allogeneic HLA-identical hematopoietic stem cell transplantation (SCT) from a sibling donor for acute leukemia. The patients suffered from ALL in 1st remission (n=24), ALL in 2nd remission (n=53) and AML in 1st remission (n=55). The mean follow-up time after SCT was 11.5 years (range 1.3 to 23.3 years). The source of the stem cells was bone marrow in all but 3 cases of cord blood-derived stem cells. The number of nucleated marrow cells in the graft varied between 0.5 and 6.8x108/kg (median 2.75x108/kg). Most patients, 118 of 132, were pre-treated with a total body irradiation (TBI) and cyclophosphamide-based regimen. TBI doses were 1x 7 Gy for children of 3 and 4 years, 1x 7.5 Gy for >4 and <10 years, and 1x 8 Gy (before 1990) and 2x 6 Gy on two consecutive days (after 1990) for children older than 10 years. Initially, graft-versus-host disease (GvHD) prophylaxis consisted of long-course methotrexate (MTX) only (n=24), later a short-course MTX-Cyclosporine A prophylaxis was given (n=102). All patients were nursed in strict protective isolation, using positive-pressure laminar-air flow cubicles or rooms, and got total gut decontamination with non-absorbable antimicrobials. Engraftment, transplant-related complications, relapse of the disease and survival were evaluated retrospectively in relation to disease- and transplant-related characteristics. None of the patients failed to engraft. The mean 5-year probability of overall survival was 63%, 53% and 74% for ALL1, ALL2 and AML1 patients, respectively. Transplant-related mortality was 6%. The incidence of acute GvHD in evaluable cases was 17% (21/124), of whom 7 (6%) got grade II to IV. Chronic GvHD occurred in 10 patients out of 125 evaluable patients (8%). The mean 5-year probability of relapse was 35%, 49% and 26% for ALL1, ALL2, and AML1 patients, respectively. Most relapses (70%) occurred within the first year post-SCT. The patient age and dose of TBI were significantly related with post-transplant relapse (p=0.007). Overall survival was significantly higher in children that received a higher dose of TBI (see figure). Overall, acute GvHD was not significantly associated with relapse, but none of the AML patients (n=9) with acute GvHD got a relapse (likelihood ratio test, p=0.02), which was not the case for ALL first or second remission patients. This retrospective single-center study on HLA-identical SCT for acute leukemia in 132 consecutively enrolled children confirms the beneficial role of slight to moderate acute GvHD in the suppression of relapse of AML, and draws attention to the potential antileukemia effect of a high (fractionated) dose of TBI in the conditioning. [Display omitted]

Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT)

Results of reduced intensity conditioning regimen (RIC) in the HLA identical haematopoietic stem cell transplantation (HSCT) setting have not been compared to those after myeloablative (MA) regimen HSCT in patients with acute myeloblastic leukaemia (AML) over 50 years of age. With this aim, outcomes of 315 RIC were compared with 407 MA HSCT recipients. The majority of RIC was fludarabine-based regimen associated to busulphan (BU) (53%) or low-dose total body irradiation (24%). Multivariate analyses of outcomes were used adjusting for differences between both groups. The median follow-up was 13 months. Cytogenetics, FAB classification, WBC count at diagnosis and status of the disease at transplant were not statistically different between the two groups. However, RIC patients were older, transplanted more recently, and more frequently with peripheral blood allogeneic stem cells as compared to MA recipients. In multivariate analysis, acute GVHD (II-IV) and transplant-related mortality were significantly decreased (P=0.01 and P<10(-4), respectively) and relapse incidence was significantly higher (P=0.003) after RIC transplantation. Leukaemia-free survival was not statistically different between the two groups. These results may set the grounds for prospective trials comparing RIC with other strategies of treatment in elderly AML.

A defined donor activating natural killer cell receptor genotype protects against leukemic relapse after related HLA-identical hematopoietic stem cell transplantation

Killer cell immunoglobulin-like receptors (KIRs) recognize different groups of Human Leukocyte Antigen (HLA) class I alleles and are expressed by natural killer (NK) cells and some T lymphocytes. NK cell cytotoxicity is triggered by failure to recognize the appropriate HLA class I ligand on target cells. Recently, it has been shown that HLA class I ligand incompatibility in the graft-versus-host (GvH) direction is associated with a better outcome in haploidentical hematopoietic stem cell transplantation (HSCT). Since KIR genotypes are very diverse in the population, we explored whether or not the donor KIR genotype could affect the graft-versus-leukemia (GvL) effect in the related HLA-identical HSCT setting. We determined the KIR and HLA genotypes of 65 HLA-identical patient-donor siblings. We found that the presence of two activating KIRs, 2DS1 and 2DS2, in the donor was significantly associated with a decreased leukemic relapse rate (P=0.03; OR=0.18; 95% CI: 0.037-0.88). Moreover, the probability of relapse at 5 years was significantly lower for patients who received a graft from a donor with the 2DS1(+)2DS2(+) genotype than for those who received a transplant from other donors (17 vs 63%, respectively; P=0.018). In conclusion, this study suggests that a joint effect of these two selected activating KIRs in the donor might confer some protection against leukemic relapse.

A Defined Donor Activating Natural Killer Cell Receptor Phenotype Protects Against Leukemic Relapse after HLA-Identical Hematopoietic Stem Cell Transplantation.

Objective: Killer immunoglobulin-like receptors (KIRs) on Natural Killer (NK) cells recognize groups of HLA class I alleles. Failure to recognize the appropriate KIR ligand on a HLA class I-mismatched cell triggers NK cytotoxicity. Because KIR and HLA genes are located on different chromosomes matching for HLA does mostly not result in matched KIR genes in related HLA-identical hematopoietic stem cell transplantation (HSCT). Moreover, KIR genotypes are very diverse in the population and therefore we explored whether this KIR diversity could have any Graft-versus-Leukemia (GvL) effect in related, HLA-identical HSCT.Methods: A total of 65 consecutive patients with leukemia (AML, CML, ALL) who received a first transplant at our institution, were included in the analysis. The median age of the patients was 34 years. The conditioning regimen included TBI + cytosine arabinoside + cyclophosphamide in the majority of the patients (85%). The source of stem cells was bone marrow (72%) or peripheral blood (28%). The NK KIR genotype (6 inhibiting and 5 activating KIRs) and molecular HLA compatibility (locus A, B, C, DRB1, DQB1, DPB1) were studied in all patients and their sibling donors.Results and conclusion: Our analysis showed that the combined presence of the activating KIR receptors 2DS1 and 2DS2 on the donor NK cells is of major importance in protection against leukemic relapse in HLA-identical HSCT. In the patient group with a KIR2DS1(+)2DS2(+) donor, relapse was significantly lower (2/15; 13%) compared to all other donors (23/50; 46%) (P=0.01). Additionally, we found a direct relationship between the number of HLA class I - activating KIR interactions and relapse. The more activating KIR receptor-HLA-C ligand interactions possible, the less relapse observed (P=0.05). However, we cannot exclude at this moment that a hitherto unknown ligand (such as a viral protein or a tumor associated or -specific protein) could substitute for a HLA class I antigen. HLA class I down-regulation is frequently observed on leukemic cells and decreases the interaction with inhibitory NK receptors. The presence of sufficient donor activating NK receptors to overcome the remaining inhibition is likely the mechanism that mediates the elimination of residual leukemic cells.

Serum cytokine levels and acute graft-versus-host disease after HLA-identical hematopoietic stem cell transplantation

Serum cytokine levels and acute graft-versus-host disease after HLA-identical hematopoietic stem cell transplantation

Serum cytokine levels and acute graft-versus-host disease after HLA-identical hematopoietic stem cell transplantation

Objective The aim of this study was to investigate whether the serum levels of soluble interleukin-2R (sIL-2R), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-6, IL-10, and transforming growth factor-β 1 (TGF-β 1) were associated with the development of acute graft-vs-host disease (aGVHD). Patients and methods Serum cytokine levels were sequentially measured by sandwich enzyme-linked immunosorbent assay in 13 patients who had received full-match allogeneic hematopoietic stem cell transplantation (HSCT). Results Serum sIL-2R and IL-10 levels from the 1st to the 15th week post transplantation were significantly higher in the group that developed aGVHD than in the group without aGVHD. sIL-2R levels increased in direct correlation to engraftment and at onset of aGVHD, whereas IL-10 levels increased transiently following HSCT. The mean TNF-α concentration in the first weeks after transplantation was augmented in the group that developed aGVHD. Furthermore, a decrease in TGF-β 1 levels after engraftment was significantly associated with aGVHD. No correlation was found between aGVHD and the other cytokines. Conclusions These results support the idea that a balance between cytokines derived from type 1 and type 2 T-helper cells may be important in the development and control of aGVHD. Although sIL-2R, TNF-α, IL-10, and TGF-β 1 levels have been correlated with aGVHD, sIL-2R levels at engraftment may provide a better parameter for early detection of aGVHD after allogeneic HSCT.

CD34+ cell dose predicts relapse and survival after T-cell-depleted HLA-identical haematopoietic stem cell transplantation (HSCT) for haematological malignancies.

Seventy-eight patients with haematological malignancies, received T-cell-depleted stem cell transplants and cyclosporin followed by delayed add-back of donor lymphocytes to prevent leukaemia relapse. The source of stem cells was bone marrow in 50 patients and granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood in 28 patients. In univariate analysis, only the CD34+ cell dose (but not the stem cell source or the T lymphocyte dose) and disease status were predictive for transplant-related mortality, relapse and survival. Patients receiving >/= 3 x 106 CD34+ cells/kg had an overall actuarial survival of 68% compared with 52%, 35% and 10%, respectively, for cell doses of 2-2.99, 1-1.99 and < 1 x 106/kg. Multivariate analysis of risk factors for relapse identified disease risk and CD34+ cell dose as the only factors. Relapse was 62.5% in 38 patients at high risk of relapse vs. 25% for 40 patients at intermediate or low risk. CD34+ cell doses of >/= 3 x 106/kg were associated with a 13.5% relapse vs. 48% for recipients of lower doses. This favourable effect of CD34+ cell dose on relapse was apparent in both high- and intermediate- plus low-risk groups. Our results support the potential benefit of a high stem cell dose in lowering transplant-related mortality (TRM) and in reducing relapse after allogeneic marrow or blood stem cell transplants.