Low‐dose methotrexate may preserve a stronger antileukemic effect than that of cyclosporine after modified donor lymphocyte infusion in unmanipulated haploidentical HSCT

To compare the impacts of low‐dose methotrexate (MTX) with cyclosporine (CSA) on graft‐versus‐host disease (GVHD) and graft‐versus‐leukemia (GVL) effect after haploidentical modified donor lymphocyte infusion (DLI). Fifty‐five consecutive patients who had relapsed acute leukemia after haploidentical hematopoietic stem cell transplantation (HSCT) and received modified DLI were retrospectively studied. Forty‐one patients received CSA and 14 received low‐dose MTX after DLI to prevent DLI‐associated GVHD. The incidence of acute GVHD and grade 2–4 acute GVHD in MTX group showed a trend toward being higher than in CSA group (61.0% vs. 37.3%, p = 0.198 and 61.0% vs. 35.5%, p = 0.155). However, no significant difference in the incidence of grade 3–4 acute GVHD between two groups (p = 0.982) was observed. Moreover, compared with CSA, patients treated with MTX had lower re‐relapse rate (38.1% vs. 80.8%, p = 0.029), better disease‐free survival (DFS) (51.9% vs. 15.6%, p = 0.06), and higher absolute lymphocyte counts at 30, 45, 60, and 90 d after modified DLI (p < 0.05). This study suggested that after haploidentical modified DLI, low‐dose MTX is at least as effective as CSA in the prevention of DLI‐associated GVHD and probably allowed stronger GVL effect than CSA. This phenomenon was probably due to a direct antitumor effect and a better reconstitution of lymphocytes after modified DLI induced by low‐dose MTX.     

Impact of cyclosporine‐A concentration in T‐cell replete haploidentical allogeneic stem cell transplantation

This paper aims to study whether cyclosporine‐A (CSA) levels have an impact on the clinical outcome of patients with T‐cell replete haploidentical allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We analyzed 140 consecutive patients who had been given T‐cell replete haploidentical allo‐HSCT in our institute to assess the effect of CSA concentration in the early stages of allo‐HSCT on clinical outcomes, such as hematopoietic recovery, acute graft vs host disease (aGVHD), infection, disease‐free survival (DFS), and overall survival (OS). The median concentrations of CSA in the blood in the 1st, 2nd, 3rd, and 4th week after allo‐HSCT were 218, 235, 263, and 270 ng/mL, respectively. Additionally, 46%, 40%, 27%, and 18% of the patients had CSA blood levels below 200 ng/mL during those weeks. In total, 39 patients developed aGVHD (grade II‐IV), for a cumulative incidence of 27.8%, at a median of 32 days. Patients having a low CSA concentration (below 200 ng/mL) in the 3rd week had a higher cumulative incidence of grade II‐IV aGVHD (P = .02). In addition, multivariate logistic regression analysis showed that low CSA concentration (below 200 ng/mL) in the 3rd week was an independent risk factor of grade II‐IV aGVHD (P = .02; odds ratio = 2.66; 95% CI, 1.15‐6.17). However, CSA levels during the first 4 weeks did not have a significant impact on the patients’ hematopoietic recovery, infection, DFS, and OS. Our data indicated that adequate management of CSA levels during the peri‐engraftment period might improve clinical outcomes for those with T‐cell replete haploidentical allo‐HSCT.     

The cell composition of infused donor lymphocyte has different impact in different types of allogeneic hematopoietic stem cell transplantation

Donor lymphocyte infusion (DLI) is often used to enhance the graft‐versus‐leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). In this study, we first evaluated the impact of the cell composition of a modified DLI (mDLI) on the prognoses of patients. A total of 194 patients undergoing allo‐HSCT were enrolled and received mDLI for various clinical reasons. The infused cellular components of the mDLI were examined by flow cytometry. The results showed that infusion with a lower dose of CD14⁺ cells (<0.33 × 10⁸/kg) was an independent risk factor for the occurrence of II–IV acute graft‐versus‐host disease (aGVHD) (HR = 0.104, p = 0.032) in human leukoctye antigen‐identical transplant patients. In addition, a dose of CD14⁺ cells greater than the 50th percentile was associated with a lower incidence of hematological relapse and longer disease‐free survival (DFS) after the mDLI (relapse: HR = 0.193, p = 0.007; DFS: HR = 0.259, p = 0.016). However, we also found that a greater number of CD14⁺ cells were an independent risk factor for II–IV aGVHD (HR = 1.758, p = 0.034) in haploidentical allo‐HSCT. In conclusion, our data were the first to demonstrate that the cell composition of a 56 mDLI played a distinct role in different types of allo‐HSCT. This finding provided a novel approach for the development of cellular therapies by manipulating the components of infused cells.     

Optimizing anti‐T‐lymphocyte globulin dosing to improve long‐term outcome after unrelated hematopoietic cell transplantation for hematologic malignancies

Prophylaxis of graft‐versus‐host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HCT) remains challenging. Because prospective randomized trials of in‐vivo T cell depletion using anti‐T‐lymphocyte globulin (ATLG) in addition to a calcineurin inhibitor and methotrexate (MTX) led to conflicting outcome results, we evaluated the impact of ATLG on clinical outcome, lymphocyte‐ and immune reconstitution survival models. In total, 1500 consecutive patients with hematologic malignancies received matched unrelated donor (MUD) HCT with cyclosporin and MTX (N = 723, 48%) or with additional ATLG (N = 777, 52%). In the ATLG cohort, grades III‐IV acute (12% vs 23%) and extensive chronic GVHD (18% vs 34%) incidences were significantly reduced (P < .0001). Nonrelapse mortality (27% vs 45%) and relapse (30% vs 22%) differed also significantly. Event‐free and overall survival estimates at 10 years were 44% and 51% with ATLG and 33% and 35% without ATLG (P < .002 and <.0001). A dose‐dependent ATLG effect on lymphocyte‐ and neutrophil reconstitution was observed. At ATLG exposure, lymphocyte counts and survival associated through a logarithmically increasing function. In this survival model, the lymphocyte count optimum range at exposure was between 0.4 and 1.45/nL (P = .001). This study supports additional ATLG immune prophylaxis and is the first study to associate optimal lymphocyte counts with survival after MUD‐HCT.     

A case–control study of bronchiolitis obliterans syndrome following allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans syndrome (BOS) is a significant complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, the pathogenesis and risks for the development of BOS have remained unclear. Therefore, a case–control study was conducted to investigate the risk factors for the development of BOS, which included the largest number of BOS cases; 196 patients with BOS were identified and compared with 1960 control recipients. The following were identified as significantly higher risk factors for the development of BOS: female recipients (OR 1.47, P = 0.019), ABO‐mismatch HSCT (minor mismatch, OR 1.67, P = 0.015; major mismatch, OR 1.73, P = 0.012; bidirectional mismatch, OR 1.96, P = 0.018), busulfan+cyclophosphamide‐based myeloablative conditioning (OR 1.74, P = 0.016), and acute graft‐versus‐host disease (GVHD) involving the skin (OR 1.55, P = 0.011). On the other hand, the risk for the development of BOS was significantly lower in patients receiving cord blood transplantation (OR 0.26, P = 0.0011). With respect to other target organs of chronic GVHD, ocular involvement was significantly associated with BOS (OR 2.53, P < 0.001). Prospective studies are required to elucidate the risk factors for the development of BOS, and future investigations should focus on finding a prophylactic approach against BOS based on these findings.     

Mycophenolate mofetil use after unrelated hematopoietic stem cell transplantation for prophylaxis and treatment of graft‐vs.‐host disease in adult patients in Japan

Our previous study of 301 patients who received hematopoietic stem cell transplantation (HSCT) from related donors demonstrated the efficacy of mycophenolate mofetil (MMF) for prophylaxis and treatment of graft‐vs.‐host disease (GVHD). In this study, we investigated the safety and efficacy of MMF in 716 adult patients who received unrelated HSCT. The incidences of Grade II–IV and III–IV acute GVHD in the prophylactic administration group were 38.3% and 14.3%, respectively. These rates were not statistically significant when evaluating the MMF dosage and graft source. The incidences of limited and extensive chronic GVHD were 16.6% and 11.1%, respectively. In the therapeutic administration group, 69.1% of the subjective symptoms for both acute and chronic GVHD improved. With respect to the adverse events, 75 infections and 50 cases of diarrhea were observed, and the frequency of these events increased with increasing MMF dose. The overall survival rate was 36.4% after a median follow‐up period of three yr. This study shows that MMF is safe and effective for the prevention and treatment of GVHD in patients who have received HSCT from unrelated donors.     

The use of a fludarabine‐based conditioning regimen in patients with severe aplastic anemia – a retrospective analysis from three Indian centers

Between 2001 and 2009, 121 patients with severe aplastic anemia (SAA) underwent hematopoietic stem cell transplantation (HSCT) using a conditioning protocol of fludarabine and cyclophosphamide at three Indian hospitals. Donors were HLA‐identical sibling or family donors. Seventy‐six patients were considered “high risk” as per criteria. The graft source included peripheral blood stem cells in 109 and G‐CSF‐stimulated bone marrow in 12. GVHD prophylaxis consisted of cyclosporine and mini‐methotrexate. Engraftment occurred in 117 (96.6%) while two had graft failure and two expired in the first two wk. Neutrophil engraftment was seen at 12.3 d (range: 9–19) while platelet engraftment occurred at 12.4 d (range: 8–32). Grade II–IV acute GVHD was seen in 26.7% and grade IV GVHD in 8.6%. Chronic GVHD occurred in 44% and was extensive in 10%. The five‐yr overall survival for the entire cohort is 75.8 ± 3.9% with a survival of 95.6 ± 3.1% in the low‐risk group (n = 45) and 64.0 ± 5.6% in the high‐risk group (n = 76). Conditioning with fludarabine and cyclophosphamide is associated with very good long‐term survival in patients undergoing HSCT for SAA.     

Improved outcomes using G‐CSF‐mobilized blood and bone marrow grafts as the source of stem cells compared with G‐PB after HLA‐identical sibling transplantation in patients with acute leukemia

This retrospective study compared the transplantation outcomes of 98 consecutive patients with acute leukemia. Allogeneic hematopoietic stem cell transplantation was performed using G‐CSF‐mobilized bone marrow and blood (G‐BM&PB) or G‐CSF‐mobilized peripheral blood (G‐PB) from HLA‐identical sibling donors. The G‐BM&PB and G‐PB groups displayed significantly different neutrophil recovery rates (medians of 15 vs. 14 d, respectively; p = 0.009) but similar platelet recovery rates. The cumulative incidences of grades II–IV acute graft‐versus‐host disease (aGVHD) in the G‐BM&PB and G‐PB cohorts were similar (16.2 ± 4.7% vs. 21.8 ± 7.4%, respectively; p = 0.676), but the incidences of grades III‐IV aGVHD were significantly different (5.5 ± 3.1% vs. 18.9 ± 7.1%, respectively; p = 0.042). The G‐BM&PB and G‐PB cohorts displayed similar cumulative incidences of chronic GVHD (cGVHD, 49.1 ± 5.7% vs. 42.7 ± 6.8%, respectively; p = 0.465), one‐yr cumulative incidences of treatment‐related mortality (16.5 ± 3.5% vs. 24.4 ± 4.1%, respectively; p = 0.220), and five‐yr cumulative incidences of relapse (13.9 ± 4.8% vs. 26.8 ± 7.2%, respectively; p = 0.113). The five‐yr probability of leukemia‐free survival (LFS) was significantly higher in the G‐BM&PB group than in the G‐PB group (77.8 ± 5.2% vs. 57.6 ± 8.6%, respectively; p = 0.023). Multivariate analysis identified G‐PB as an independent risk factor for grades III‐IV aGVHD and LFS. Our results suggest that HLA‐identical transplantation with G‐BM&PB results in superior clinical outcomes compared with G‐PB for patients with acute leukemia.     

A gut microbiota score predicting acute graft‐versus‐host disease following myeloablative allogeneic hematopoietic stem cell transplantation

Although studies have reported that intestinal microbiota are associated with acute graft‐versus‐host disease (aGVHD), they lacked a satisfactory method for predicting aGVHD. We collected stool and blood samples at day 15 posttransplant from 150 patients from two centers who underwent myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Stool microbiota were detected by 16S ribosomal RNA gene sequencing; inflammatory factors and T lymphocytes were detected by multiplex immunoassays and flow cytometry, respectively. A gut microbiota score (GMS) from a LASSO (least absolute shrinkage and selection operator) model was developed and validated to predict aGVHD. In the discovery cohort, the GMS could predict II‐IV aGVHD (area under the receiver operating characteristic [ROC] curve [AUC] = 0.904, P < .0001). Furthermore, the validation model was consistent with the discovery set (AUC = 0.887, P < .0001). Regulatory T/T‐helper 17 (Treg/Th17) cells ratio in the low GMS subgroup was higher compared with the high GMS (P = .012), and the validation set is consistent with the discovery set (P = .003). In addition, high cytokine levels were associated with high GMS. In conclusion, the GMS at neutrophil engraftment could predict aGVHD, and it was a potential and novel method. The GMS was associated with the inflammatory factor and Treg/Th17 balance.     

Feasibility of tacrolimus, methotrexate, and prednisolone as a graft-versus-host disease prophylaxis in non-T-cell-depleted haploidentical hematopoietic stem cell transplantation for children

In this study, we evaluated the feasibility of our graft-versus-host disease (GVHD) prophylaxis with tacrolimus, methotrexate, and prednisolone in non-T-cell-depleted haploidentical hematopoietic stem cell transplantation (HSCT) for children. Twenty-one consecutive patients including those with hematological malignancies (n = 11), solid tumors (n = 7), and non-malignancies (n = 3) were analyzed. Myeloablative and reduced intensity conditionings were carried out in 5 and 16 patients, respectively, and both of the regimens contained anti-human T-lymphocyte immunoglobulin. Twenty (95%) of the 21 patients achieved primary engraftment. Acute GVHD of grades II-IV and III-IV were observed in nine (47%) and one (5%) patient, respectively, all of which were controllable by steroids. Chronic GVHD was observed in eight (51%) of the 17 evaluable patients, and one of them developed steroid refractory chronic GVHD. Treatment-related mortality occurred in three patients (15%), as a result of acute pancreatitis, chronic GVHD, and EB virus associated lymphoproliferative disease. The median follow-up of the 13 survivors was 24 months, and the two-yr probability of overall survival was 68%. The Karnofsky performance scale score of the 13 survivors was 100%. These results indicated the feasibility of our GVHD prophylaxis in non-T-cell-depleted haploidentical HSCT for children.     

The safety and efficacy of acute graft‐versus‐host disease prophylaxis with a higher target blood concentration of cyclosporine around 500 ng/mL

Cyclosporine (CsA) is the most widely used immunosuppressive agent for the prevention of acute graft‐versus‐host disease (GVHD). In a previous report, the incidence of acute GVHD was decreased by increasing the target blood concentration of CsA during a continuous infusion from 300 to 500 ng/mL without excessive toxicities. To confirm these results, we retrospectively analyzed 69 patients who received a continuous infusion of CsA at a higher target CsA level between 450 and 550 ng/mL (CsA500 group) and compared the clinical outcome with 29 patients who received CsA with a lower target concentration between 250 and 350 ng/mL (CsA300 group). The target concentration was determined based on the status of background diseases. Multivariate analysis revealed that the incidence of grade III‐IV acute GVHD was significantly lower in the CsA500 group, although the incidence of grade II‐IV acute GVHD was not different. Toxicities were equivalently observed between the two groups. Concomitant administration of voriconazole or itraconazole and higher hematocrit were identified as independent significant factors for higher concentration/dose ratio of CsA. The average dose of CsA to maintain CsA level around 500 ng/mL was higher compared with the previous study (3.4 mg/kg vs. 2.7 mg/kg at three wk), probably due to the difference in measuring method of CsA concentration. We conclude that continuous infusion of CsA with a target level between 450 and 550 ng/mL is a feasible and effective GVHD prophylaxis, but caution should be paid for the difference in measuring method.     

Long‐term outcomes of antithymocyte globulin in patients with hematological malignancies undergoing myeloablative allogeneic hematopoietic cell transplantation: a systematic review and meta‐analysis

Antithymocyte globulin (ATG) has shown efficacy in preventing acute GVHD (aGVHD) in allogeneic hematopoietic cell transplantation (allo‐HCT), but its efficacy in chronic GVHD (cGVHD) and long‐term outcomes remains controversial. We conducted a systematic review and meta‐analysis to evaluate potential benefit and risk of prophylactic ATG use in myeloablative HCT. We searched Pubmed, EMBASE, Cochrane databases, and included 10 trials (two RCTs and eight retrospective) comparing ATG use vs. control with a total of 1859 patients. The median follow‐ups were over two yr. Outcomes assessed included overall cGVHD, extensive cGVHD, overall survival (OS), disease‐free survival, relapse, and causes of death. Our results showed ATG significantly decreased overall cGVHD (RR = 0.59; 95% CI: 0.53–0.66, p < 0.00001), extensive cGVHD (RR = 0.34; 95% CI: 0.25–0.47, p < 0.00001). Pooled results also showed ATG use was associated with a marginal increased risk of relapse (RR = 1.28; 95% CI: 1.01–1.63, p = 0.04), and a non‐inferior OS (HR = 0.86; 95% CI: 0.74–1.01, p = 0.06). We conclude prophylactic use of ATG exerts a favorable effect in reducing cGVHD without survival impairment in a long term, although a higher relapse rate is a major threat.     

Prevention of relapse using DLI can increase survival following HLA-identical transplantation in patients with advanced-stage acute leukemia: a multi-center study

A total of 123 consecutive patients with advanced‐stage, acute leukemia undergoing HSCT from HLA‐identical sibling donors were analyzed. A G‐CSF‐primed DLI was planned within day 60 post‐transplantation before hematologic relapse was diagnosed. Fifty of the 123 individuals received prophylactic DLI, and 73 individuals received no prophylactic treatment. The incidence of grades II–IV acute graft‐versus‐host disease (GVHD) was 17% for patients receiving DLI and 23% for patients not receiving DLI (p = 0.35). The incidence of chronic GVHD was 38% for patients receiving DLI and 17% for patients not receiving DLI (p = 0.021). The two‐yr cumulative incidence of relapse was significantly lower in patients who received prophylactic DLI (46%) compared with patients who did not receive prophylactic DLI (66%) (p = 0.02). The three‐yr probability of overall survival was higher in patients who received prophylactic DLI (36%) than in patients who did not receive prophylactic DLI (11%) (p = 0.001). The leukemia‐free survival was also higher in patients who received prophylactic DLI (29%) than in patients who did not receive prophylactic DLI (9%) (p = 0.001). Our comparisons suggest that the prophylactic use of DLI can significantly increase survival of patients with advanced‐stage, acute leukemia who receive HLA‐identical sibling HSCT.     

Limited benefit of pentostatin salvage therapy for steroid‐refractory grade III‐IV acute graft‐versus‐host disease

Corticosteroid‐refractory (SR) acute graft‐versus‐host disease (aGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Multiple agents have been evaluated in this setting, but the benefit of pentostatin has not been described well. We report a single‐center experience of pentostatin salvage therapy for SR aGVHD. Fifteen patients received pentostatin for SR aGVHD from March 2005 till March 2010 after failure to respond to methylprednisolone ≥2 mg/kg/d for at least seven d. All patients had grade III‐IV aGVHD prior to pentostatin therapy. Thirteen (87%), 10 (67%), and six (40%) patients had gastrointestinal (GI), skin, and liver involvement of aGVHD, respectively. Pentostatin was given at a median of 33 d after steroid therapy initiation. The dose of pentostatin was 1.4 mg/m² daily for three d, repeated every two wk. Eight (53%) patients also received additional therapies. Complete responses were noted in two patients (both in skin). However, one patient relapsed and did not respond to additional salvage treatment. Partial responses were seen in three patients. Fourteen died of GVHD‐related causes. This study suggested that pentostatin is of limited benefit in the treatment for SR grade III‐IV aGVHD.     

Impact on relapse of corticosteroid therapy after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia

Imahashi N, Inamoto Y, Seto A, Watanabe K, Nishiwaki S, Yanagisawa M, Shinba M, Yasuda T, Kuwatsuka Y, Atsuta Y, Kodera Y, Miyamura K. Impact on relapse of corticosteroid therapy after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia.
Clin Transplant 2010: 24: 772–777. © 2009 John Wiley & Sons A/S. Abstract: Corticosteroids are often used following allogeneic hematopoietic stem cell transplantation (HSCT) to control complications such as graft‐versus‐host disease (GVHD). However, there is some concern that corticosteroids may suppress the graft‐versus‐leukemia effect and increase leukemia relapse. To evaluate the effect of corticosteroids on relapse, we analyzed 112 adult patients who received their first allogeneic HSCT for acute myeloid leukemia at our institution between 1997 and 2007. Fifty‐seven patients (50.9%) received corticosteroid therapy. Patients who had corticosteroid therapy included higher proportion of patients who developed GVHD. In multivariate analysis, with corticosteroid administration entered as a time‐dependent covariate, corticosteroid administration was not a risk factor for relapse (p = 1.00, hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.53–1.88), but it was associated with higher non‐relapse mortality (NRM) (p < 0.001, HR 55.5, 95% CI 7.42–416) and lower overall survival (p < 0.001, HR 2.68, 95% CI 1.56–4.61). The higher NRM associated with corticosteroid administration was mainly due to the increased deaths caused by the complications themselves, which required corticosteroid therapy. The findings of this study indicate the importance of controlling complications after allogeneic HSCT. The strategy of refraining from indispensable corticosteroid therapy because of the excessive concerns about relapse should be avoided.     

Two decades of stem cell transplantation in patients with Fanconi anemia: Analysis of factors affecting transplant outcomes

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for the hematological complications of patients with Fanconi anemia (FA). Over the last two decades, HSCT outcomes have improved dramatically following the development of regimens tailored for FA patients. In this study, we analyzed genetic, clinical, and transplant data of 41 patients with FA who underwent HSCT at Hadassah Medical Center between November 1996 and September 2020. Overall survival (OS) was 82.9% with a median follow-up time of 2.11-years (95% CI, .48–16.56). Thirteen patients (31.7%) developed acute graft-versus-host disease (GVHD), three of them with grades 3-4. Nine patients developed chronic GVHD, five had extensive disease. Twelve patients (29.3%) developed stable mixed-chimerism with complete resolution of bone marrow failure (BMF); none of them had acute nor chronic GVHD. Significantly higher GVHD rates were observed in transplants from peripheral blood stem cell grafts as compared to other stem cell sources (p = .002 for acute and p = .004 for chronic GVHD). Outcome parameters were comparable between HSCT from matched-sibling (n = 20) to other donors (n = 21), including survival rates (p = .1), time to engraftment (p = .69 and p = .14 for neutrophil and platelet engraftment time, respectively), chimerism status (p = .36 and p = .83 for full-donor and mixed chimerism, respectively), and GVHD prevalence (p = 1). Our results demonstrate the vast improvements in HSCT outcomes of patients with FA, narrowing the gap between matched-sibling versus alternative donor transplantations. Our data identifies factors that may significantly affect transplant outcomes such as graft source and chimerism status.     

Clostridium difficile‐associated disease in allogeneic hematopoietic stem‐cell transplant recipients: risk associations,protective associations,and outcomes

Dubberke ER, Reske KA, Srivastava A, Sadhu J, Gatti R, Young RM, Rakes LC, Dieckgraefe B, DiPersio J, Fraser VJ. Clostridium difficile‐associated disease in allogeneic hematopoietic stem‐cell transplant recipients: risk associations, protective associations, and outcomes.
Clin Transplant 2009. DOI: 10.1111/j.1399‐0012.2009.01035.x
© 2009 John Wiley & Sons A/S. Abstract:  The purpose of this study was to evaluate risk factors, protective factors, and outcomes associated with Clostridium difficile‐associated disease (CDAD) in allogeneic hematopoietic stem‐cell transplant (HSCT) recipients. A case–control study was performed with 37 CDAD cases and 67 controls. In the multivariable logistic regression analysis, receipt of a third or fourth generation cephalosporin was associated with increased risk of CDAD (OR = 4.6, 95% CI 1.6–13.1). Receipt of growth factors was associated with decreased risk of CDAD (OR=0.1, 95% CI 0.02–0.3). Cases were more likely to develop a blood stream infection after CDAD than were controls at any point before discharge (p < 0.001). CDAD cases were more likely than controls to develop new onset graft‐vs.‐host disease (GVHD) (p < 0.001), new onset severe GVHD (p < 0.001), or new onset gut GVHD (p = 0.007) after CDAD/discharge. Severe CDAD was a risk factor for death at 180 d in multivariable Cox proportional hazards regression (HR=2.6, 95% CI 1.1–6.2). CDAD is a significant cause of morbidity and mortality in allogeneic HSCT patients, but modifiable risk factors exist. Further study is needed to determine the best methods of decreasing patients’ risk of CDAD.     

A high antithymocyte globulin dose increases the risk of relapse after reduced intensity conditioning HSCT with unrelated donors

The study included 110 consecutive patients with hematological malignancies receiving fludarabine‐based reduced intensity conditioning (RIC) and hematopoietic stem cell transplantation (HSCT) from matched unrelated donors. The median age was 55 yr (range 11–68) and all but 15 patients received peripheral blood stem cell grafts. Antithymocyte globulin (ATG) (Thymoglobulin, Genzyme) at a total dose of 6 mg/kg (n = 66) or 8 mg/kg (n = 44) was given to all patients according to protocol. The ATG dose did not affect time‐to‐neutrophil or platelet engraftment. The incidences of acute GVHD grades II–IV were 34% and 18% (p = 0.11) and of chronic GVHD were 40% and 26% (p = 0.46) in patients receiving 6 and 8 mg/kg of ATG, respectively. The five‐yr relapse‐free survival (RFS) was 61% and 36% (p = 0.14) in patients, given low and high ATG dose, respectively. In patients given low‐dose ATG, the incidence of relapse was lower compared to those given high‐dose ATG, 19% vs. 41% (p = 0.04). In multivariate analysis, age >50 yr (p < 0.001), absence of acute (p < 0.001) and chronic GVHD (p = 0.001) were correlated to relapse, and low‐dose ATG was associated with improved RFS (p < 0.05). A high dose (8 mg/kg) of ATG in RIC HSCT with unrelated donors increased the risk for relapse and reduced the RFS.     

Ultrasonographic evaluation of gastrointestinal graft‐versus‐host disease after hematopoietic stem cell transplantation

Gastrointestinal graft‐versus‐host disease (GI‐GVHD) is a major and life‐threatening complication of hematopoietic stem cell transplantation (HSCT). This study evaluated the efficacy of ultrasonography (US) for assessing and monitoring GI‐GVHD. GI tract was evaluated by US in 81 patients. US findings were positive in 43 patients, including 11 false positive, and negative in 38 patients. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of US for the diagnosis of GI‐GVHD were 100%, 78%, 74%, 100%, and 86%, respectively. Diffuse wall thickening of the ileum was the most frequent finding in patients with GI‐GVHD. Severity of GI‐GVHD was correlated with the thickness of internal low echoic layer of the wall, the echogenicity of mesenteric fat tissue, and the intensity of Doppler signaling. We classified US findings of GI‐GVHD into four US grades. There was a significant correlation between clinical stage of GI‐GVHD and the US grade. These ultrasonographic abnormalities were improved with clinical improvement of GI‐GVHD upon treatment. Thus, US is an effective and efficient non‐invasive means of identifying the extent and severity of GI‐GVHD and monitoring response to treatment.     

High readmission rates are associated with a significant economic burden and poor outcome in patients with grade III/IV acute GvHD

Graft‐versus‐host disease (GvHD) is a common complication following haematopoietic stem cell transplant but little is published about the impact of this condition on hospital readmission rates. We report a retrospective analysis of readmission rates and associated costs in 187 consecutive allogeneic transplant patients to assess the impact of GvHD. The overall readmission rate was higher in patients with GvHD (86% (101/118) vs. 59% (41/69), p < 0.001). The readmission rate was higher both in the first 100 d from transplant (p = 0.02) and in the first year following transplant (p < 0.001). 151/455 (33%) of all readmission episodes occurred within 100 d of transplant. The mean number of inpatient days was significantly higher in patients with grade III/IV acute GvHD (101 d) compared with those with grade I/II GvHD (70 d; p = 0.003). The mean cost of readmission was higher in patients with GvHD (£28 860) than in non‐GvHD patients (£13 405; p = 0.002) and in patients with grade III/IV GvHD (£40 012) compared with those patients with grade I/II GvHD (£24 560; p = 0.038). Survival was higher in those with grade I/II GvHD (55%) compared to grade III/IV GvHD (14%; p < 0.001). This study shows the high economic burden and poor overall survival associated with grade III/IV GvHD.