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Programmed death 1 (PD-1) activation triggers an immune checkpoint resulting in inhibition of T cells that leads to peripheral tolerance. Some PD-1 polymorphisms have been described and associated with the development of autoimmune diseases or cancer predisposition, but there are few data concerning the relevance of such polymorphisms on the clinical outcome after allogeneic hematopoietic stem cell transplant (alloHSCT). We analyzed the distribution of the SNPs PD-1.1G/A (rs36084323) and PD-1.3G/A (rs11568821) genotypes of the donor in a cohort of 1485 alloHSCT from HLA-identical sibling donors. We found an increased risk of grades II to IV graft-versus-host disease (GvHD) in patients receiving grafts from donors homozygous for the G allele at the rs36084323 SNP (P = 0.033; hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.1 to 4.8) and also from donors homozygous for the A allele at the rs11568821 position (P < 0.001; HR 4.5, 95%CI 2.0 to 10.1). In contrast, the PD-1 genotype of the donor did not show association with overall survival or relapse incidence. These results suggest that the PD-1 genotype of the donor plays an important role for the development of acute GvHD after alloHSCT from HLA-identical sibling donors. [ABSTRACT FROM AUTHOR]

The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08–0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients. [ABSTRACT FROM AUTHOR]

We analyze the impact of cyclosporine (CsA) levels in the development of acute graft-versus-host disease (aGVHD) after reduced intensity conditioning allogeneic hematopoietic transplantation (allo-RIC). We retrospectively evaluated 156 consecutive patients who underwent HLA-identical sibling allo-RIC at our institution. CsA median blood levels in the 1st, 2nd, 3rd and 4th weeks after allo-RIC were 134 (range: 10-444), 219 (54-656), 253 (53-910) and 224 (30-699) ng/mL; 60%, 16%, 11% and 17% of the patients had median CsA blood levels below 150 ng/mL during these weeks. 53 patients developed grade 2-4 aGVHD for a cumulative incidence of 45% (95% CI 34-50%) at a median of 42 days. Low CsA levels on the 3rd week and sex-mismatch were associated with the development of GVHD. Risk factors for 1-year NRM and OS were advanced disease status (HR: 2.2, ρ = 0.02) and development of grade 2-4 aGVHD (HR: 2.5, ρ < 0.01), while there was a trend for higherNRMin patients with a low median CsA concentration on the 3rd week (ρ = 0.06). These results emphasize the relevance of sustaining adequate levels of blood CsA by close monitoring and dose adjustments, particularly when engraftment becomes evident. CsA adequate management will impact on long-termoutcomes in the allo-RIC setting. [ABSTRACT FROM AUTHOR]

The graft- versus-host disease (GVHD) characteristics of 150 consecutive patients undergoing reduced intensity conditioning allogeneic (allo-RIC) transplants and 88 patients undergoing myeloablative conditioning regimen were analysed. All patients received the same GVHD prophylaxis and peripheral blood stem cells from a human leucocyte antigen identical sibling. The cumulative incidence of acute GVHD (aGVHD) was 67% and 44% in the myeloablative and allo-RIC regimen groups, respectively ( P < 0·001), and was 39% vs. 29%, respectively ( P = 0·043), for grades 2–4 aGVHD. Only conditioning type (myeloablative versus allo-RIC) significantly influenced the incidence of aGVHD in multivariate analysis: Hazard ratio (HR) = 2·16 [95% confidence interval (CI): 1·52–3·07], P < 0·0001. The cumulative incidence of chronic GVHD (cGVHD) was 63% and 71% among myeloablative and allo-RIC patients respectively ( P = 0·084). This trend was because of the higher incidence of limited cGVHD, but not extensive cGVHD among allo-RIC recipients [HR = 3·3 (95% CI: 1·42–8·08), P = 0·0017]. Moreover, among patients who developed cGVHD, the cumulative incidence of limited cGVHD was significantly lower in the myeloablative group than in the allo-RIC group (7% vs. 25%, P = 0·007). Duration of immunosuppression was shorter among allo-RIC patients (35·5% vs. 68·8% required systemic immunosuppression 36 months after transplant, P = 0·028). Although prospective controlled trials are required to further evaluate the effect of the conditioning regimen on GVHD, our results suggest that RIC modifies the incidence and characteristics of both acute and cGVHD after allogeneic transplantation, and decreases the immunosuppression requirements in long-term follow up when compared with myeloablative conditioning. [ABSTRACT FROM AUTHOR]

Disparity for the minor histocompatibility antigen HA-1 between patient and donor has been associated with an increased risk of acute graft-versus-host disease (GvHD) after allogeneic human leucocyte antigen (HLA)-identical sibling donor stem cell transplantation (SCT). However, no data concerning the impact of such disparity on chronic GvHD, relapse or overall survival are available. A retrospective multicentre study was performed on 215 HLA-A2-positive patients who received an HLA-identical sibling SCT, in order to determine the differences in acute and chronic GvHD incidence on the basis of the presence or absence of the HA-1 antigen mismatch. Disease-free survival and overall survival were also analysed. We detected 34 patient–donor pairs mismatched for HA-1 antigen (15·8%). Grades II–IV acute GvHD occurred in 51·6% of the HA-1-mismatched pairs compared with 37·1% of the non-mismatched. The multivariate logistic regression model showed statistical significance (P: 0·035, OR: 2·96, 95% CI: 1·07–8·14). No differences were observed between the two groups for grades III–IV acute GvHD, chronic GvHD, disease-free survival or overall survival. These results confirmed the association between HA-1 mismatch and risk of mild acute GvHD, but HA-1 mismatch was not associated with an increased incidence of chronic GvHD and did not affect relapse or overall survival. [ABSTRACT FROM AUTHOR]

To assess the influence of graft-versus-host disease (GVHD) on the outcome of patients with advanced haematological malignancies (AHM) who received a primary, unmodified allogeneic peripheral blood progenitor cells transplant (allo-PBT) from a human leucocyte antigen (HLA) identical sibling donor, we analysed 136 patients with myeloid neoplasms (n = 70) or lymphoproliferative disorders (n = 66), transplanted at 19 Spanish institutions. Median age was 35 years (range 1–61). The cumulative incidence of relapse for all patients was 34% (95% CI, 26–42%), 41% (95% CI, 33–49) for patients without GVHD and 14% (95% CI, 3–25) (P = 0·001) for patients with acute and chronic GVHD. After a median follow-up of 11 months (range 2–49), 60 (44%) patients remained alive with an actuarial probability of overall survival and disease-free survival (DFS) at 30 months of 31% (95% CI, 21–41%) and 28% (95% CI, 17–39%) respectively. In patients surviving > 100 d, the low incidence of relapse in those with acute and chronic GVHD led to a DFS of 57% (95% CI, 38–76%) compared with a DFS of 34% (95% CI, 17–51%) in the remaining patients (P = 0·03). Our results indicate a reduced incidence of relapse for patients with AHM receiving an unmodified allo-PBT and developing acute and chronic GVHD, which results in an improved DFS. [ABSTRACT FROM AUTHOR]

CTLA-4 (cytotoxic T-lymphocyte antigen-4) plays a pivotal role in inhibiting T cell activation through competitive interaction with B7 molecules and interruption of costimulatory signals mediated by CD28. Polymorphisms on the CTLA-4 gene have been previously associated with autoimmune diseases, predisposition to leukemic relapse, and with graft-versus-host disease (GVHD) or relapse after allogeneic transplant. As CTLA-4 is expressed on T-lymphocytes, the aim of this study was to determine whether the donor CTLA-4 CT60 genotype also influences clinical outcome even after T cell depletion with CD34-positive selection. We studied 136 patient-donor pairs. Overall survival (OS) was worse for those patients who received grafts from a donor with the CT60 AA genotype rather than from a donor with the AG or GG genotype (35.6% vs 49.4%; P = .043). This association was confirmed through multivariate analysis, which identified the donor CT60 genotype as an independent risk factor for OS (P = .008; hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.23-4.08). The donor CT60 AA genotype was also associated with lower disease-free survival, this being related to an increased risk of relapse (P = .001; HR: 3.41, 95% CI: 1.67-6.96) and a trend toward higher transplant-related mortality. These associations were stronger when considering only patients in the early stage of disease. Our results suggest that graft-versus-leukemia (GVL) activity after T cell depletion is conditioned by the donor CTLA-4 genotype. [ABSTRACT FROM AUTHOR]

Minor histocompatibility antigen (miHA) mismatches have been related to graft-versus-host disease (GVHD) after allogeneic stem cell transplantation, but this association remains controversial due to the lack of consistency in the results obtained by different groups. The CTLA-4 genotype of the donor has been reported to be relevant in the appearance of acute GVHD. We explored the effect of the donor's CTLA-4 genotype in the incidence of acute GVHD associated with HA-1, HA-8, or H-Y miHA mismatches in a large cohort of 1295 patients receiving an allogeneic transplant from an HLA-identical sibling donor. The incidence of acute GVHD was higher if the donor and recipient were mismatched for HA-1, HA-8, or H-Y, but only when the donor had the CTLA-4 rs231775 AA genotype (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.27 to 3.75; P  = .005; HR, 2.11, 95% CI, 1.06 to 4.18; P  = .033; and HR, 1.50; 95% CI, 1.05 to 2.15; P  = .025, respectively). In contrast, this increased risk of developing acute GVHD was not found when the donor presented the CTLA-4 rs231775 AG or GG genotypes. We conclude that the immune response to specific miHA mismatches is modulated by the CTLA-4 genotype of the donor. [ABSTRACT FROM AUTHOR]

Abstract: Refractory acute graft-versus-host disease (aGVHD) remains an important cause of mortality after allogeneic stem cell transplantation. No standard therapy exists once steroids fail to obtain a good response. In 2006, our group published a series of patients who received inolimomab, an anti–interleukin-2 receptor monoclonal antibody, as salvage therapy with initial encouraging results. In this update, we analyzed a larger group of patients with prolonged follow-up. Ninety-two consecutive patients were treated with inolimomab at our center between April 1999 and December 2011. Overall response rate was 42% (complete response in 14%) on day +30. Predictors of failure to respond in the multivariate analysis were overall aGVHD grade IV, instauration of inolimomab before day 15 of aGVHD diagnosis, and severe lymphopenia. Patients without gastrointestinal involvement appeared to do better, with a 70% response rate compared with 39% in patients with gastrointestinal involvement (P = .06). However, the 2-year overall survival rate was of 18% for the entire cohort (95% confidence interval, 10% to 26%) and 33% for day 30 responders (95% confidence interval, 25% to 40%) and Acute GVHD was the main cause of death (49%) followed by opportunistic infections (27%). Results of this update show that although inolimomab is a well-tolerated drug with a moderate number of short-term responses, it is associated with long-term survival in only one-third of responding patients. These data highlight the need to investigate new rescue treatments with sustained effect and the importance of reporting long-term outcomes in GVHD studies. [Copyright &y& Elsevier]

Neurological complications (NC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are common and life-threatening in most cases. They may involve either the central (CNS) or peripheral nervous system (PNS). The aim of this study was to describe incidence and characteristics of NC after reduced-intensity conditioning allo-HSCT (allo-RIC), an unexplored setting. For this purpose, we reviewed 191 consecutive patients who underwent this procedure at our institution between January 1999 and December 2006. The median follow-up for survivors was 48 months (3-98 months). RIC included fludarabine (Flu) 150mg/m2 in combination with busulfan (Bu) 8-10mg/kg (n=61), melphalan (Mel) 70-140mg/m2 (n=119), cyclophosphamide (Cy) 120mg/kg (n=7), or low-dose total body irradiation (TBI) 2Gy (n=4). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A (CsA) in combination with methotrexate (MTX; n=134) or mycophenolate mofetil (MMF; n=52). Twenty-seven patients (14%) developed a total of 31 NC (23 CNS and 8 PNS) for a 4-year cumulative incidence of 16% (95% confidence interval [CI] 11-23). CNS complications included nonfocal encephalopathies in 11 patients, meningoencephalitis in 5 patients, and stroke or hemorrhage in 4. PNS complications consisted of 5 cases of mononeuropathies and 3 cases of polyneuropathies. Drug-related toxicity was responsible for 10 of the 31 events (32%) (8 caused by CsA). Interestingly, 14 of the 23 CNS events (61%) and only 1 of the 8 PNS complications (13%) appeared before day +100 (P =.01). Overall, patients presenting NC showed a trend for higher 1-year nonrelapse mortality (NRM) (37% versus 20%, P =.08). In patients with CNS involvement, 1-year NRM was significantly worse (42% versus 20%, P =.02). CNS NC also had a negative impact on 4-year overall survival (OS; 33% versus 45%, P =.05). In conclusion, our study showed that NC are observed after allo-RIC and have diverse features. NC affecting the CNS have earlier onset and worse outcome than those involving the PNS. [Copyright &y& Elsevier]

Abstract: Many patients receiving allogeneic stem cells develop chronic graft-versus-host disease (cGVHD), which remains as the main cause of morbidity and mortality. Although the first line of therapy is generally with steroids, it is not well known how to manage refractory cases. Those patients are usually treated with alternative experimental agents. Sirolimus (Rapamycin), a new immunosuppressive agent, inhibits signal transduction and cell cycle progression after binding to FKBP12. We report a retrospective analysis with sirolimus in transplant recipients with cGVHD refractory to previous immunosuppressive therapy. Forty-seven patients with refractory or relapsed cGVHD were treated with the combination of sirolimus and calcineurin inhibitors (n = 33), mycophenolate (n = 9), or prednisone (n = 5). Thirty-eight of 47 (81%) patients had clinical responses (complete = 18, partial = 20). The main toxicity was mild renal failure, particularly at the start of therapy. Four patients who presented thrombotic microangiopathy were managed with plasmapheresis and the discontinuation of sirolimus and calcineurin inhibitors. Statistical analysis showed the type of cGVHD onset and presirolimus clinical status as the main variables influencing the response to treatment. The Kaplan-Meier estimate of survival was 57.4% at 3 years. The current study shows the efficacy and safety of sirolimus in refractory cGVHD patients. Further investigation is warranted to elucidate the role of sirolimus in cGVHD, and find the best combination (sirolimus + calcineurin inhibitors versus others) for therapeutic use. [Copyright &y& Elsevier]

Abstract: Enlimomab, an anti-interleukin-2 receptor (anti-IL-2R) monoclonal antibody, may be useful in the treatment of steroid-refractory acute graft-versus-host disease (aGVHD) by inhibiting 1 of its putative immunopathogenic pathways. We retrospectively analyzed 40 consecutive patients who received enlimomab as salvage treatment for steroid refractory aGVHD at a single institution between June 1999 and December 2004. Enlimomab was given intravenously at a dose of 11 mg/d for 3 consecutive days, followed by 5.5 mg/d for 7 consecutive days and then 5.5 mg every other day for 5 doses. No infusion-related side effects were noted. Twenty-three patients (58%) responded, including 15 (38%) complete and 8 (20%) partial responses. Median overall survival was 294 days (58-996 days) for responders versus 14 days for nonresponders (P < .001), with a 1 year probability of 59% vs 0% for overall survival (P < .0001). Patients without gastrointestinal (GI) involvement showed a higher response rate (100% versus 50% for those without versus with GI involvement, P = .03) In addition, patients who showed some response by day 15 had a higher overall survival (73 ± 12% vs 24 ± 12%, respectively, P = .02). The results of this study suggest that enlimomab may be an effective salvage therapy for patients with steroid-refractory aGVHD, particularly for those without GI disease, and supports further studies with this agent in prospective controlled trials. [Copyright &y& Elsevier]