Modified donor lymphocyte infusion‐associated acute graft‐versus‐host disease after haploidentical T‐cell‐replete hematopoietic stem cell transplantation: incidence and risk factors

We performed a study to investigate the profile of donor lymphocyte infusion (DLI)‐associated acute graft‐versus‐host disease (GVHD) in haploidentical T‐cell‐replete hematopoietic stem cell transplantation (HSCT). A total of 124 patients receiving modified DLI after haploidentical T‐cell‐replete HSCT were enrolled. The cumulative incidence of DLI‐associated acute GVHD was 53.2% for grades II–IV and 28.4% for grades III–IV. The duration of GVHD prophylaxis after DLI was the only risk factor for DLI‐associated grades III–IV acute GVHD (p < 0.05). The cumulative incidence of grades III–IV acute GVHD in patients with prophylaxis more than six, four to six, two to four, and <2 wk were 9.3%, 14.4%, 31.6%, and 49.5%, respectively (p = 0.018). Furthermore, DLI‐associated grades III–IV acute GVHD was the only risk factor for overall survival (p = 0.038, OR   = 2.869) and transplant‐related mortality (p = 0.018, OR = 3.296) but not a risk factor for relapse after DLI (p = 0.840). This study confirms for the first time that the duration of GVHD prophylaxis after DLI is the only risk factor for the development of grades III–IV acute GVHD. Donor lymphocyte infusion with prophylaxis more than six wk was associated with a lower incidence of grades III–IV acute GVHD.     

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.     

Extended Mycophenolate Mofetil Administration Beyond Day 30 in Allogeneic Hematopoietic Stem Cell Transplantation as Preemptive Therapy for Severe Graft-Versus-Host Disease

To prevent acute graft-versus-host disease (GVHD), mycophenolate mofetil (MMF) combined with calcineurin inhibitors have been used in allogeneic hematopoietic stem cell transplantation (allo-SCT). Previous studies commonly utilize MMF treatment until day 30 after allo-SCT. However, the feasibility of continuous administration after day 30 has not been well evaluated. We retrospectively assessed the safety and efficacy of extended drug administration. Twenty-five patients ceased MMF at day 30 (group A); whereas, 16 patients (group B) received extended regimens depending on individual risk factors for GVHD. No severe adverse events were observed in either group. Although the cumulative incidence (CI) of grade I to IV GVHD at day 100 was comparable between the 2 groups, the CI of grade II to IV GVHD was less among group B (12.5%) compared with group A (42.3%). Extended MMF administration may be safe and beneficial as preemptive therapy to reduce the development of moderate-to-severe acute GVHD.     

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.     

A prospective observational study of immune reconstitution following transplantation with post‐transplant reduced‐dose cyclophosphamide from HLA‐haploidentical donors

Allogeneic hematopoietic cell transplantation (HCT) from HLA‐haploidentical donors with post‐transplantation high‐dose cyclophosphamide (PT/Cy‐haplo) now predominates worldwide. However, to our knowledge, no prospective study has compared immune reconstitution after PT/Cy‐haplo with that after conventional HCT. The mechanism by which chronic graft‐versus‐host disease (GVHD) is inhibited by PT/Cy‐haplo also remains unknown. We prospectively compared immune recovery patterns of lymphocyte subsets among four groups of adult patients with hematological disease who received HCT from either HLA‐matched related or HLA‐matched unrelated donors, cord blood transplantation, or reduced‐dose PT/Cy‐haplo. Counts of CD4+ T‐cell subsets, CD8+ T‐cell subsets, and NK cells on days 30 and 60 were often lower in PT/Cy‐haplo than those in HLA‐matched related HCT. The immune recovery pace in PT/Cy‐haplo subsequently caught up with that of the other grafts. The regulatory T cells (Tregs) to conventional CD4+ T‐cell (Tcon) ratio was significantly higher until day 90 in PT/Cy‐haplo. In multivariate analysis, a higher Tregs‐to‐Tcon ratio on day 60 was significantly associated with a lower incidence of chronic GVHD (P < 0.01). The preservation of Tregs by PT/Cy in the early phase might have resulted in a lower incidence of chronic GVHD.     

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.     

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.     

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.     

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.     

Serum microRNA155 is increased in patients with acute graft‐versus‐host disease

To explore the clinical relevance of three lymphocyte‐related serum microRNAs (miR‐155, miR‐214, and miR‐326) to the pathogenesis of graft‐versus‐host disease (GVHD), 64 subjects who received allogeneic peripheral blood stem cell transplantation (allo‐PBSCT) were recruited in this study, of whom 19 subjects did not develop GVHD, 25 subjects were diagnosed with acute GVHD (aGVHD), and 20 subjects were diagnosed with chronic GVHD (cGVHD). Serum miRNAs were determined by real‐time RT‐PCR. Expression level of miRNAs and the expression signatures of miRNAs as a panel were analyzed among the three groups. The expression level of miR‐214 and miR‐326 showed no significant difference between GVHD and non‐GVHD groups. However, miR‐155 was significantly up‐regulated in GVHD patients. There was a correlation between the level of miR‐155 and the severity of aGVHD. Moreover, serum IFN‐gamma, IL‐17, and IL‐9 levels were higher in aGVHD patients with high miR‐155. In conclusion, the expression level of lymphocyte‐related miR‐155 in serum was significantly increased in aGVHD patients. The miR‐155 may be considered as a potential targeted therapy for aGVHD patients.     

No effect of HLA‐C mismatch after allogeneic hematopoietic stem cell transplantation with unrelated donors and T‐cell depletion in patients with hematological malignancies

HLA‐C mismatch in unrelated donor's hematopoietic stem cell transplantation (HSCT) has been associated with poor patient outcome. However, the impact of HLA‐C mismatch in the context of HSCT combined with in vivo T‐cell depletion remains unclear. We therefore performed a single‐center, retrospective analysis of the clinical outcome on patients with hematological malignancies treated with allo‐HSCT, who underwent T‐cell depletion. The majority of the patients (n=276) received a HLA‐A, HLA‐B, HLA‐DRB1‐matched graft that were either also HLA‐C matched (n=260), or patients with the permissive HLA‐C*03:03/03:04 mismatch (n=16), while the remaining patients (n=95) received a HLA‐C‐mismatched graft (excluding HLA‐C*03:03/03:04 mismatches). We did not observe any significant differences between the HLA‐C‐matched patients (including the permissive HLA‐C*03:03/03:04 mismatch) and the HLA‐C‐mismatched patients regarding cumulative proportion surviving, graft failure, relapse‐free survival, relapse, or acute graft‐versus‐host disease. Our data suggest that in the context of high dose T lymphocyte‐depleting agents, HLA‐C matching is not essential for patients with hematological malignancies.     

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.     

Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease

There is no consistently effective therapy for patients with steroid-refractory acute graft-versus-host disease (GVHD). Various alternative approaches have been tested, including antithymocyte globulin, mycophenolate mofetil (MMF), pentostatin, and monoclonal antibodies; however, they have only been modestly successful. The purpose of our study was to evaluate the efficacy of human adipose-tissue-derived mesenchymal stem cells (AMSC) as salvage therapy for steroid-refractory acute GVHD. Six patients with steroid-refractory grades III-IV acute GVHD received IV infusions of AMSC. The AMSC dose was 1.0x10(6)/kg. No side effects were noted after the AMSC infusions. Five patients were treated once and one patient twice. Two patients received AMSC from haplo-identical family donors and four from unrelated mismatched donors. Acute GVHD disappeared completely in five of six patients, four of whom are alive after a median follow-up of 40 months (range, 18-90 months) after the initiation of AMSC therapy. All four surviving patients are in good clinical condition and in remission of their hematological malignancy. Two patients died-one with no obvious response to AMSC died of multiorgan failure and one a relapse of leukemia. These results suggested that AMSC is a promising treatment for severe steroid-resistant acute GVHD.     

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.     

ADHERE: randomized controlled trial comparing renal function in de novo kidney transplant recipients receiving prolonged‐release tacrolimus plus mycophenolate mofetil or sirolimus

ADHERE was a randomized, open‐label, Phase IV study comparing renal function at Week 52 postkidney transplant, in patients who received prolonged‐release tacrolimus‐based immunosuppressive regimens. On Days 0–27, patients received prolonged‐release tacrolimus (initially 0.2 mg/kg/day), corticosteroids, and mycophenolate mofetil (MMF). Patients were randomized on Day 28 to receive either prolonged‐release tacrolimus plus MMF (Arm 1) or prolonged‐release tacrolimus (≥25% dose reduction on Day 42) plus sirolimus (Arm 2). The primary endpoint was glomerular filtration rate by iohexol clearance (mGFR) at Week 52. Secondary endpoints included eGFR, creatinine clearance (CrCl), efficacy failure (patient withdrawal or graft loss), and patient/graft survival. Tolerability was analyzed. The full‐analysis set comprised 569 patients (Arm 1: 287; Arm 2: 282). Week 52 mean mGFR was similar in Arm 1 versus Arm 2 (40.73 vs. 41.75 ml/min/1.73 m²; P = 0.405), as were the secondary endpoints, except composite efficacy failure, which was higher in Arm 2 versus 1 (18.2% vs. 11.5%; P = 0.002) owing to a higher postrandomization withdrawal rate due to adverse events (AEs) (14.4% vs. 5.2%). Results from this study show comparable renal function between arms at Week 52, with fewer AEs leading to study discontinuation with prolonged‐release tacrolimus plus MMF (Arm 1) versus lower dose prolonged‐release tacrolimus plus sirolimus (Arm 2).     

Combination of tacrolimus,methotrexate, and methylprednisolone prevents acute but not chronic graft-versus-host disease in unrelated bone marrow transplantation

BACKGROUND: Graft-versus-host disease (GVHD) is still a major problem in allogeneic bone marrow transplantation (BMT). Prophylactic regimens used against GVHD in unrelated BMT, including cyclosporine (CsA)-plus-methotrexate (MTX), CsA-plus-MTX-plus-prednisone, and tacrolimus (FK506)-plus-MTX, are still unsatisfactory (34-70% occurrence of grades II-IV GVHD). To address this problem, we examined the efficacy of FK506-plus-MTX-plus-methylprednisolone (mPSL) in 20 patients who underwent BMT from unrelated donors. METHODS: All patients received FK506 beginning the day before transplantation at a dose of 0.03 mg/kg per day by continuous intravenous (IV) infusion. MTX was administered at a dose of 10 mg/m(2) IV on day 1, and 7 mg/m(2) on days 3, 6, and 11. Intravenous administration of mPSL was started at a dose of 2 mg/kg per day on day 1. In the absence of acute GVHD, mPSL was gradually tapered from day 29. RESULTS: Development of acute GVHD was almost completely suppressed (one patient with grade I, none with grades II-IV). However, the incidence and severity of chronic GVHD did not decrease. Eight of 12 patients with extensive chronic GVHD died of thrombotic microangiopathy or infection. A vigorous fluctuation (>100 U/mL per 10 days) of the soluble interleukin 2 receptor level in the serum after engraftment was highly related to the occurrence of chronic GVHD. CONCLUSIONS: An FK506-plus(+)-MTX-plus(+)-mPSL prophylactic regimen could almost completely suppress acute GVHD but not chronic GVHD in unrelated BMT. In this GVHD prophylactic system, the extent of the change of soluble interleukin 2 receptor level may be a good predictor of development of chronic GVHD.     

Female‐Versus‐Male Alloreactivity as a Model for Minor Histocompatibility Antigens in Hematopoietic Stem Cell Transplantation

H‐Y encoded gene products were the first to be recognized as clinically relevant minor histocompatibility antigens. Compared to other gender combinations, female donor/male recipient (FDMR) transplants are associated with increased graft‐versus‐host disease (GvHD), increased transplant‐related mortality (TRM) and reduced risk of relapse. Still, their relative impact on transplant outcome remains controversial. We analyzed donor/recipient sex combination in 53 988 patients treated with allogeneic hematopoietic stem cell transplantation (HSCT) between 1980 and 2005. We found a strong increase in chronic GvHD and late TRM and decreased survival in FDMR transplants irrespective of underlying disease. Conversely, FDMR patients had lower relapse rates. The negative effect on survival decreased with advancing disease stage as relapse protection became more important. Effects of H‐Y alloreactivity were most pronounced in patients transplanted from HLA‐matched donors and in those receiving transplants from an adult donor. Adjustment for acute and chronic GvHD only partially corrected the effects of H‐Y alloreactivity. Analysis of the FDMR proportion over time indicated that the frequency of this gender combination has declined in unrelated transplants over the last 10 years. These data define the role of H‐Y mismatching in allogeneic HSCT and support the current practice of avoiding female donors for male patients, if possible.     

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.     

The association between the incidence of intestinal graft‐vs‐host disease and antibiotic use after allogeneic hematopoietic stem cell transplantation

Intestinal microbiota plays an important role in the regulation of allogeneic immune reaction after allogeneic hematopoietic stem cell transplantation (allo‐SCT). Intestinal graft‐vs‐host disease (GVHD) is one of the major causes of mortality after allo‐SCT and often complicated with intestinal dysbiosis. Recent studies suggest that antibiotic‐induced dysbiosis is a risk factor for intestinal GVHD. We retrospectively evaluated the impacts of antibiotic use on the incidence of intestinal GVHD occurring before day 100 after allo‐SCT. Among 213 patients who underwent allo‐SCT, 200 patients achieving engraftment were analyzed. Antibiotics were classified into carbapenem, quinolone, penicillin, cephem, and glycopeptide. Among 128 patients who developed acute GVHD, intestinal GVHD developed in 36 patients. Patients with intestinal GVHD received significantly longer administration of carbapenem and glycopeptide compared to those without it in periengraftment period. In multivariate analysis, use of carbapenem for greater than 7 days was associated with an increased risk of intestinal GVHD. However, use of antibiotics for greater than 7 days was not associated with poor overall survival and high nonrelapse mortality. Long use of carbapenem in periengraftment period may be a risk for intestinal GVHD. Prospective studies are required to validate our findings.     

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.