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The graft-versus-leukemia effect is mainly restricted to NIH-defined chronic graft-versus-host disease after reduced intensity conditioning before allogeneic stem cell transplantation.

Incidence on relapse and nonrelapse mortality (NRM) of chronic graft-versus-host disease (GVHD), per National Institutes of Health (NIH) criteria, is not well defined after reduced-intensity conditioning (RIC) regimens. We analyzed the association of chronic GVHD with the risk of relapse and NRM using Cox models in 177 consecutive patients who underwent transplantation for hematological malignancies after RIC. The cumulative incidence of chronic GVHD at 36 months was 74% when using Seattles criteria compared with 54% with NIH consensus. In Cox model, NRM was significantly higher in patients with late-onset, persistent and recurrent acute GVHD (hazard ratio (HR): 6, 25 and 11; P=0.014, P<0.0001, P<0.0001, respectively). The cumulative incidence of relapse was significantly decreased in patients with chronic GVHD compared with no GVHD group using either Seattles or NIH criteria (HR 0.43 and 0.38; P=0.022 and 0.016, respectively), whereas the presence of late-onset, persistent and recurrent acute GVHD was not associated with a decreased rate of relapse (HR: not significant, 0.70 and 0.71; P=not significant, P=0.73 and P=0.54, respectively). Chronic GVHD per NIH consensus definition is associated with the graft-versus-tumor effect, whereas all forms associated with acute features beyond day 100 are associated with NRM.

Use of Eculizumab in Patients With Allogeneic Stem Cell Transplant-Associated Thrombotic Microangiopathy: A Study From the SFGM-TC.

Background Thrombotic microangiopathy (TMA) occurring after allogeneic hematopoietic stem cell transplantation (HSCT) has a devastating prognosis. Response rates to current therapies (mainly plasma exchange) are unsatisfactory. Thrombotic microangiopathy after allogeneic HSCT shares similarities with atypical hemolytic uremic syndrome (aHUS) in the underlying pathomechanisms. Eculizumab has been associated with impressive results in aHUS. Materials and Methods We retrospectively analyzed 12 patients who received Eculizumab in France between 2010 and 2013 for severe post-HSCT TMA. Results All 12 patients had severe TMA with neurological and/or renal involvement. Fifty-eight percent were refractory to first-line plasma exchange. At the time of TMA diagnosis, infections were present in 50% of the patients and acute graft-versus-host disease in 33%. Patients were treated with Eculizumab according to the aHUS therapeutic scheme. With a median follow-up of 14 months, hematological response and overall survival were 50% and 33%, respectively. Active acute graft-versus-host disease at TMA diagnosis was the only factor associated with worse overall survival (P = 0.009). Discussion Response rate and overall survival after Eculizumab in our cohort compare favorably with previously published data in TMA after allogeneic HSCT. Prospective trials are warranted to confirm these results. Early initiation of Eculizumab may have a favorable effect on long-term renal function and further contribute to the prolongation of survival.

Fecal calprotectin and alpha-1 antitrypsin predict severity and response to corticosteroids in gastrointestinal graft-versus-host disease.

Diagnosis of gastrointestinal GVHD (GI-GVHD) is based on clinical symptoms and histologic findings. No biomarkers predicting responses to treatment are routinely available even though 30% to 50% of patients will not respond to corticosteroids. In this study, we aimed to evaluate fecal calprotectin, α-1-antitrypsin (α(1)-AT), and elastase at the time of first symptoms as diagnostic and prognostic tools for GI-GVHD in 72 consecutive patients, of whom 51 developed GI-GVHD. The prognostic value of markers was evaluated by their association with complete response (CR) and steroid-resistant (SR) GVHD. Calprotectin and α(1)-AT concentrations increased with GI-GVHD initial stages but patients with initial stage 1 GI-GVHD had similar marker levels to patients without GI-GVHD, so sensitivity to diagnose GI-GVHD was weak. In contrast, calprotectin and α(1)-AT were predictors for SR-GVHD and CR. Multiple regression modeling identified calprotectin and α(1)-AT concentration as independently predicting SR-GVHD together with initial stage > 2 GI-GVHD. Our results showed that fecal calprotectin and α(1)-AT levels at the time of diagnosis are predictive for responses to treatment but are not diagnostic markers for initial stage 1 to 3 GI-GVHD.

Pre-transplant prognostic factors of long-term survival after allogeneic peripheral blood stem cell transplantation with matched related/unrelated donors

Mobilized peripheral blood has become the predominant stem cell source for allogeneic hematopoietic cell transplantation. In this retrospective single center study of 442 patients with hematologic malignancies, we analyzed prognostic factors for long-term survival after peripheral blood stem cell transplantation from HLA-matched related or unrelated donors. To account for disease/status heterogeneity, patients were risk-stratified according to the Disease Risk Index. Five-year overall survival was similar after transplants with matched related and unrelated donors (45% and 46%, respectively; P=0.49). Because donor age ≥60 years impacted outcome during model building, we further considered 3 groups of donors: matched unrelated (aged <60 years by definition), matched related aged <60 years and matched related aged ≥60 years. In multivariate analysis, the donor type/age group and the graft CD34+ and CD3+ cell doses impacted long-term survival. Compared with matched unrelated donor transplant, transplant from matched related donor <60 years resulted in similar long-term survival (P=0.67) while transplant from matched related donor ≥60 years was associated with higher risks for late mortality (hazard ratio (HR) 4.41; P=0.006) and treatment failure (HR: 6.33; P=0.009). Lower mortality risks were observed after transplant with CD34+ cell dose more than 4.5×106/kg (HR: 0.56; P=0.002) and CD3+ cell dose more than 3×108/kg (HR: 0.61; P=0.01). The Disease Risk Index failed to predict survival. We built an “adapted Disease Risk Index” by modifying risks for myeloproliferative neoplasms and multiple myeloma that improved stratification ability for progression-free survival (P=0.04) but not for overall survival (P=0.82).

Matched unrelated or matched sibling donors result in comparable outcomes after non-myeloablative HSCT in patients with AML or MDS.

The impact of allelic HLA matching in patients with AML and myelodysplastic syndrome (MDS) who receive allogeneic PBSC after a reduced-intensity conditioning (RIC) regimen is unclear. From January 2000 to December 2010, 108 consecutive patients with AML (n=63) and MDS (n=45) received PBSC after RIC in our center, either from siblings (n=70) or from matched unrelated donors (MUD; 10/10 high resolution, n=38). Conditioning regimen was fludarabine based in 95% of patients and GvHD prophylaxis was mostly cyclosporine plus mycophenolate. Patient characteristics were similar between sibling and MUD for age (median 57 years), gender and disease distribution. Conditioning regimen (more anti-thymocyte globulin (ATG) in MUD), donor age (younger for MUD) and number of CD34+ cells infused (higher in MUD) were different. The median follow-up was 36 months (range 2–72). Engraftment, GvHD, TRM, relapse rate and OS at 3 years were comparable between sibling and MUD. After adjustment for age, cytogenetic risk, ATG and number of CD34+ cells infused, donor type still did not influence OS. In patients with AML or MDS, HSCT from MUD using PBSC after a RIC regimen led to similar outcomes than from Siblings.

Increased infection rate after preemptive rituximab treatment for Epstein-Barr virus reactivation after allogeneic hematopoietic stem-cell transplantation.

Background Preemptive rituximab (R) treatment decreases the incidence of Epstein-Barr virus (EBV) posttransplantation lymphoproliferative disease, but the extent of immune deficiency related to R in patients who received allogeneic hematopoietic stem-cell transplantation is unclear. The aim of our study was to evaluate the incidence of late infections and immune reconstitution after preemptive R treatment of EBV infection. Methods Seventy-eight patients receiving preemptive R between January 2005 and January 2010 were studied. Fifty-two of them could be matched with controls (not receiving R) according to administration of antithymoglobulin, stem-cell source and donor type, age and grade of acute graft-versus-host disease. Results Among the 78 patients with EBV reactivation treated with R, the 36-month cumulative incidence of bacterial, viral, and fungal infections was 64%, 59%, and 23%, respectively. When compared with controls, bacterial infection incidence was significantly higher in R patients (55% vs. 35%), and a slower reconstitution of B cells was observed. R patients had modest but not significantly higher nonrelapse mortality (35% vs. 15%) than controls. Conclusion R has dramatically decreased risks of posttransplantation lymphoproliferative disease but is followed by a prolonged and profound B-cell deficiency associated with an excess risk of bacterial infection and higher mortality. R should be given with caution, and immunoglobulin replacement should be provided to limit these excess risks.

Clinical severity scores in gastrointestinal graft-versus-host disease.

Background The clinical prognosis of gastrointestinal (GI) graft-versus-host disease (GvHD) is based on either a clinical staging system or histological or endoscopic findings. How these different scores correlate with each other and which have the greater impact on transplantation outcomes is, however, not clear. Methods Clinical, pathological, and endoscopic findings of the upper GI tract on 201 patients who underwent allogeneic hematopoietic stem cell transplantation were reviewed. The association between clinical, histological, and endoscopy grading was assessed by Kendall correlation coefficient. The agreement between grading systems was evaluated by kappa statistics. Factors associated with survival or steroid resistance were analyzed by proportional hazard models. Results At disease onset, no strong association was found between pathological and clinical grade at disease onset (&tgr;=0.034, P=0.6). In contrast, endoscopy score and clinical grades were strongly associated (&tgr;=0.37, P<0.001). The Kappa concordance coefficient (0.20) between histological and endoscopy scores was poor. However, by multivariate analysis all three scores significantly predicted survival rates Conclusions Clinical, histological, and endoscopic scores poorly correlated with each other when estimated at the GI-GvHD onset. However, all three severe initial scores independently predict poor outcome. Of interest, clinical and endoscopic scores predict resistance to steroids while pathological does not.

Equivalent outcomes using reduced intensity or conventional myeloablative conditioning transplantation for patients aged 35 years and over with AML

Allogeneic hematopoietic stem cell transplantation provides the best chance of long-term survival for patients with AML, but is associated with an unpredictable risk of treatment-related mortality. From January 2000 to December 2010, we compared the outcomes for patients with AML aged 35 and over using reduced-intensity conditioning (RIC, N=60) or conventional myeloablative conditioning (MAC) regimen (N=72) transplantation. The median follow-up was 47 months (10–134). The 4-year cumulative incidence of non-relapse mortality was 21%. After adjusting for cytogenetic risk, gender donor/recipient mismatch and CD34+ cells, non-relapse mortality was significantly lower with the RIC regimen (P=0.027). The 4-year cumulative incidence of relapse was 38% and no difference was observed in the adjusted relapse rate between the two groups. The 4-year OS rate was 46%. Using both Cox regression and inverse probability-of-treatment weighted (IPTW) method, a similar OS rate was found with both regimens (adjusted hazard ratios for conventional vs reduced of 1.14 (95% CI 0.67–1.93, P=0.64) with Cox regression, and 1.14 (95% CI 0.55–2.34, P=0.73) with IPTW). Until prospective trials are completed, this study supports the use of a reduced-intensity regimen prior to transplantation for patients with AML aged 35 and over.

Reconstitution of regulatory T-cell subsets after allogeneic hematopoietic SCT

Previous studies on regulatory T-cell (Treg) reconstitution after allogeneic hematopoietic SCT (HSCT) have suggested that, within the GVHD process, imbalance between effector T cells and Tregs may be more important than the absolute numbers of circulating Tregs. No study has analyzed naive vs memory Treg reconstitution in a longitudinal cohort with large numbers of patients. The reconstitution of total and subsets of Treg was prospectively analyzed by flow cytometry in 185 consecutive recipients at 3, 6, 12 and 24 months after allogeneic HSCT. The levels of total, naive and memory Tregs increased, mainly within the memory subset, but remained lower than healthy controls up to 2 years after transplantation. Reduced-intensity conditioning and peripheral blood (PBSC) as the source of stem cells were associated with better 3-month reconstitution. In multivariate analysis, PBSC, recipient age ⩽25 and no anti-thymoglobulin in the conditioning regimen were associated with a better Treg reconstitution. Naive Treg long-term reconstitution was mainly influenced by recipient age. Whereas prior acute GVHD impaired Treg reconstitution, Treg subsets (absolute numbers and frequencies relative to CD4+ T-cell subsets) at 3, 6 and 12 months after HSCT were not associated with the occurrence of a later episode of chronic GVHD.

Fecal calprotectin and α1-antitrypsin dynamics in gastrointestinal GvHD

In a previous study, the fecal biomarkers calprotectin and α1-antitrypsin (α1-AT) at symptom onset were reported to be significantly associated with the response to steroids in gastrointestinal GvHD (GI-GvHD). The purpose of this trial was to evaluate the dynamics of the fecal biomarkers calprotectin and α1-AT throughout the course of GvHD. Patients who were refractory to steroids had initially higher biomarker levels and in the course of GvHD demonstrated a continuous increase in fecal biomarkers. In contrast, the dynamics of calprotectin and α1-AT demonstrated low and decreasing levels in cortico-sensitive GvHD. In steroid-refractory patients who received a second line of treatment, the biomarker levels at the beginning of second-line treatment did not predict the subsequent response. Nevertheless, calprotectin levels progressively decreased in subsequent responders, whereas non-responders demonstrated continuously high levels of calprotectin. α1-AT values correlated to a lesser extent with the response to second-line treatment and remained elevated in both non-responders and responders. In conclusion, calprotectin monitoring can be of use in the management of immunosuppressive treatment in GI-GvHD.