ALBERT

Description: Objectives Fever during neutropenia occurs in 〉 90% and 80% of allogeneic and autologous hematopoietic stem cell transplantation (HSCT) recipients, respectively. Current guidelines recommend the prophylaxis with fluoroquinolones (FQs) in HSCT patients. Although there is evidence that antibiotic prophylaxis improve clinical outcome in patients with chemotherapy-induced neutropenia, prophylactic antibiotic therapy has not been thoroughly evaluated in HSCT recipients. Therefore, we performed a meta-analysis to evaluate the impact of systemic antibiotic prophylaxis in HSCT recipients on mortality, incidence of infection and related adverse events. Data sources We identified reports that were not restricted to those in English and not restricted to published trials through PubMed, the Cochrane Library, and references of identified studies. Review Methods We included prospective, randomized studies on systemic antibiotic prophylaxis in HSCT recipients. The outcome measures included the all-cause mortality, infection-related mortality, febrile episodes, incidence of clinically or microbiologically documented infection, bacteremia, or related adverse events. The summarized odds ratios (ORs) were calculated using the Mantel–Haenszel method and the DerSimonian–Laird method. Results Seventeen trials with 1453 patients (842 autologous and 407 allogeneic HSCT recipients) were included. The percentage of autologous and allogeneic HSCT recipients was not specified in 2 trials. Systemic antibiotic prophylaxis was compared with placebo or no prophylaxis in 10 trials and with non-absorbable antibiotic in 2 trials, respectively. Systemic antibiotics other than FQs were evaluated in five out of these 12 trials. Four trials evaluated the effect of addition of antibiotics for gram positive bacteria to FQs. Remaining 1 trial compared the two different systemic antibiotic regimens, FQs versus trimethoprim sulfamethoxazole. As a result, systemic antibiotic prophylaxis reduced the incidence of febrile episodes (OR 0.16; 95 percent confidence interval [CI], 0.09-0.30), clinically or microbiologically documented infection (OR 0.41; 95% CI 0.30-0.57) and bacteremia (OR 0.37; 95% CI 0.26-0.53) without the significant effect on all-cause mortality or infection-related mortality (OR 0.89; 95% CI 0.48-1.66, OR 1.37; 95% CI 0.50-3.76, respectively). Impact of prophylaxis with FQs on mortality was inconclusive because of small number of clinical trials evaluated. Adverse events increased in patients with systemic antibiotic prophylaxis compared to controls (OR 3.32; 95% CI 1.45-7.63). In meta-regression, percentage of allogeneic HSCT recipients was not associated with each outcome measure. With regard to the comparison between different prophylactic regimens, addition of antibiotics for gram positive bacteria to FQs decreased the incidence of bacteremia (OR 0.44; 0.24-0.80) without significant effects on all-cause mortality, infection related death and febrile episodes. There was not significant, but consistent decrease in clinically or microbiologically documented infection (OR 0.55; 95% CI 0.30-1.01). There was significant increase of adverse events in patients receiving addition of antibiotics for gram positive bacteria to FQs (OR 6.65; 95% CI 2.15-20.54). Conclusions Systemic antibiotic prophylaxis successfully reduced the incidence of infection in HSCT recipients. However, there was no significant impact on mortality. Impact of prophylaxis with FQs on mortality in HSCT recipients was inconclusive because of small number of trials evaluated. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4048 Introduction: Chemotherapy + GCSF mobilization and GCSF alone are the most common mobilization regimens for autologous stem cell transplant (ASCT). We examined the benefits and limitations of both regimens in terms of mobilization success, predictability and costs. Methods: A retrospective, multi-center chart review was conducted of multiple myeloma (MM) and lymphoma patients mobilized between January 1, 2006 and December 31, 2007 for ASCT. Patients were excluded if they were mobilized with plerixafor (Mozobil®) or enrolled in a clinical trial of mobilization regimens. Data collected included demographics, disease and treatment history, mobilization regimen, blood counts, aphaeresis, remobilization, cells transplanted, time to engraftment and resource use. Stem cell collection practices and related clinical outcomes were analyzed separately for patients that were mobilized with chemotherapy + GCSF vs. GCSF alone. Resource use was evaluated using US unit cost data. Results: Data were collected for 227 consecutive patients from 11 centers (143 patients that received a chemotherapy + GCSF mobilization regimen and 84 patients who received GCSF alone). Total cells collected were significantly higher in the chemotherapy + GCSF mobilization group compared to GSF alone (18.6 × 106/kg vs.7.0 × 106/kg, p

Description: Background: Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm developing in a minority of individuals infected with human T-cell leukemia virus type I (HTLV-I). Although the results of conventional chemotherapy remain unsatisfactory for the management of ATL, allogeneic hematopoietic stem-cell transplantation (allo-SCT) is emerging as a promising alternative which can provide long-term remission in selected patients. Methods: To evaluate the efficacy of allo-SCT for the treatment of ATL, data on 397 patients (pts) with ATL who had received allo-SCT between 01/1996 and 12/2005 were collected through JSHCT, JMDP and JCBBN. We analyzed pts who did not have a history of previous stem-cell transplantation; who received a T-cell-replete graft; who had data on age at transplantation, sex, donor type, stem-cell source, conditioning regimen, and graft-versus-host disease (GVHD) prophylaxis. A total of 363 pts, with a median age of 51 yrs (range, 18–79), 201 males and 162 females, fulfilled these criteria: 175 received bone marrow and/or peripheral blood from a related donor; 188 received marrow or cord blood from an unrelated donor. At the time of transplantation, 91 pts were in complete remission (CR) and 226 were not in CR. Risk factors which potentially affect the survival outcomes were analyzed using proportional-hazards models. Results: The median follow-up was 21.6 months (range, 1.5–102). The unadjusted 3-year overall survival, disease-associated mortality, and treatment-related mortality (95% confidence interval [CI]) for pts in CR at transplantation were 48% (35–59%), 16% (8–27%), and 35% (24–45%), respectively, while those for pts not in CR were 22% (16–29%), 35% (28–42%), and 41% (34–48%), respectively. Multivariable analyses revealed four significant factors which adversely affected survival: older recipient age (〉50 yrs)(adjusted hazard ratio [HR] 1.71; 95% CI, 1.24–2.38; P=0.001), male recipient (HR 1.46; 95% CI, 1.10–1.93; P=0.009), disease status other than CR (HR 2.21; 95% CI, 1.57–3.12; P

Description: To clarify which is preferable, a related donor with an HLA-1 Ag mismatch at the HLA-A, HLA-B, or HLA-DR loci in the graft-versus-host (GVH) direction (RD/1AG-MM-GVH) or an HLA 8/8-allele (HLA-A, HLA-B, HLA-C, and HLA-DRB1)–matched unrelated donor (8/8-MUD), we evaluated 779 patients with acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome who received a T cell–replete graft from an RD/1AG-MM-GVH or 8/8-MUD. The use of an RD/1AG-MM-GVH donor was significantly associated with a higher overall mortality rate than the use of an 8/8-MUD in a multivariate analysis (hazard ratio, 1.49; P 〈 .001), and this impact was statistically significant only in patients with standard-risk diseases (P = .001). Among patients with standard-risk diseases who received transplantation from an RD/1AG-MM-GVH donor, the presence of an HLA-B Ag mismatch was significantly associated with a lower overall survival rate than an HLA-DR Ag mismatch because of an increased risk of treatment-related mortality. The HLA-C Ag mismatch or multiple allelic mismatches were frequently observed in the HLA-B Ag-mismatched group, and were possibly associated with the poor outcome. In conclusion, an 8/8-MUD should be prioritized over an RD/1AG-MM-GVH donor during donor selection. In particular, an HLA-B Ag mismatch in the GVH direction has an adverse effect on overall survival and treatment-related mortality in patients with standard-risk diseases.

Description: Background: Iron overload has been suggested to be associated with various treatment-related complications of allogeneic stem cell transplantation. Since hepcidin, a peptide-hormone produced by the liver, plays a central role in the regulation of iron homeostasis, we analyzed the association between pre-transplant serum hepcidin-25 levels and early treatment-related complications within 100 days after transplantation. Patients and methods: We studied 49 consecutive patients with a median age of 47 years (range, 23–64 years) who underwent allogeneic transplantations for hematologic malignancies at Kyoto University Hospital from 07/2006 to 08/2008. We excluded patients who had undergone any prior transplantation within one year or who had an active bacterial infection before transplantation. A total of 31 patients (63%) had myeloid malignancies; the remaining 18 (37%) had lymphoid malignancies. Twenty-seven patients (55%) received reduced-intensity conditioning regimens. The sources of stem cells were the bone marrow (n = 33), peripheral blood (n = 1), and cord blood (n = 15). Patients received fungal (fluconazole 400 mg/day) and viral (acyclovir 1000 mg/day) prophylaxes with a few exceptions. No bacterial prophylaxis was prescribed. Serum hepcidin-25 levels prior to the administration of conditioning regimen were measured by use of a liquid chromatography-tandem mass spectrometry-based assay system. The cumulative incidences of bacterial and fungal infections, hepatic veno-occlusive disease (VOD), and treatment-related mortality at day 100 were analyzed. The proportional-hazard model of sub-distribution functions in competing risks was used. The probability of overall survival at day 100 was also analyzed. Results: The median pre-transplant serum hepcidin level among the patients was 18.7 ng/ml (range, 1.4–371 ng/ml), which was comparable to that among healthy volunteers (median, 19.1 ng/ml; range, 2.3–37 ng/ml, n = 17). The correlation between pre-transplant hepcidin and ferritin levels was weak among the patients (R2 = 0.2914). These patients were divided into two groups: the low hepcidin group (

Description: Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disorder with systemic manifestations such as lymphadenopathy, fever and microcytic anemia. Over-production of interleukin-6 (IL-6) has been speculated to be a key event in the pathogenesis of this disorder. IL-6 is known to stimulate hepatic expression of hepcidin, a central regulator of body iron homeostasis. We developed a SELDI-TOF mass spectrometry-based semi-quantitative method for serum hepcidin-25 (Tomosugi N, et al. Blood108, 1381–7, 2006). Utilizing this method, we previously reported a rapid decrease in serum hepcidin-25 in two MCD patients after administration of tocilizumab, an anti-IL-6 receptor antibody (Kawabata H, et al. Haematologica92, 857–8, 2007). Recently, by introducing liquid chromatography tandem mass-spectrometry and an isotopic hepcidin as an internal standard, we developed another serum hepcidin quantification system with very small intra- and inter-assay CVs. Utilizing this new method in this study, we further evaluated the clinical relevance of monitoring serum hepcidin in MCD patients treated with tocilizumab. Serum hepcidin-25 was monitored in 5 MCD cases including two previously reported cases (Cases 1 and 2). Tocilizumab (8 mg/kg body weight) was administered intravenously at 2-week intervals. This study was approved by the Ethics Committee of Kyoto University Graduate School and the Faculty of Medicine. Written informed consent was obtained from each patient. The initial levels of serum hepcidin-25 before tocilizumab treatment varied widely, between 14 and 256 ng/ml (normal range, 22 ± 12 ng/ml). In all cases, rapid reduction of serum hepcidin-25 was observed after the initial dose of tocilizumab, followed by decreases of C-reactive protein and gradual improvement of anemia (Table 1). In Case 5, the initial hepcidin level was extremely high (256 ng/ml) and it decreased only slightly after tocilizumab administration. In this case, the serum hepcidin level on day 35 remained considerably elevated (90.5 ng/ml) even after 3 doses of tocilizumab. On the same day, an anti-tocilizumab antibody was detected in the serum, and this medication was discontinued. In the other 4 cases, serum hepcidin levels decreased below the upper normal limit within 2 weeks. After 16 weeks treatment with tocilizumab, Hb increased from 5.7 to 11.2 g/dl in Case 1, from 10.2 to 11.9 g/dl in Case 2, from 6.3 to 11.0 g/dl in Case 3 and from 8.2 to 13.7 g/dl in Case 4. There were no apparent side effects in these 4 cases. These findings imply that inadequate levels of serum hepcidin caused by overproduction of IL-6 are associated with the pathogenesis of microcytic anemia observed in MCD patients. Monitoring of serum hepcidin may be useful to evaluate the efficacy of tocilizumab in MCD cases. Table 1 Case 1 Case 2 Case 3 Case 4 Case 5 Pre/Day14 Pre/Day14 Pre/Day14 Pre/Day14 Pre/Day14 Hepcidin-25 (ng/ml) 44.8/2.2 55.5/24.6 14/0.8 43.5/1.5 256/166 CRP (mg/dl) 24.3/5.4 11.7/4.1 16.9/3.6 7.6/0.2 11.9/6.8 Hb (g/dl) 5.7/9.2 10.2/11.2 6.3/7.9 8.2/9.4 6.5/7.4

Description: Abstract 3523 A high graft failure rate and treatment-related mortality (TRM) have historically been major pitfalls of myeloablative adult umbilical cord blood (UCB) transplantation. The goal of this prospective clinical trial was to identify an approach that addresses both of these problems. There is compelling evidence that increasing cell dose with the use of two partially matched UCB grafts reduces the graft failure rate. While non-myeloablative preparative regimens reduce TRM, this comes at the cost of an increased risk of disease relapse. Therefore, there is continued clinical need for myeloablative conditioning regimens that exert potent antitumor activity and provide sufficient immunosuppression to facilitate engraftment of mismatched unrelated UCB grafts. The combination of total body irradiation (TBI) (1320cGy)/fludarabine (Flu)/cyclophosphamide (Cy) has been studied extensively by other groups. In this trial, we hypothesized that elimination of Cy would improve tolerability yet maintain comparable anti-tumor effects and engraftment potential. Methods: The conditioning regimen consisted of TBI 1350cGy and Flu 40mg/m2 × 4 days. Two cord blood units at least HLA 4/6 matched with the recipient (low resolution class I and high resolution class II), with a minimum cryopreserved cell dose of 1.5 × 106/kg were selected for transplantation. Tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis and G-CSF was administered until the neutrophil count exceeded 1000/mm3. Disease-free and overall survival was estimated using the Kaplan-Meier method. In the analysis of cumulative incidence of neutrophil and platelet engraftment, a competing event was defined as relapse or death without an event of interest, whereas in the analysis of relapse and acute and chronic GVHD, a competing event was defined as death without an event of interest. Relapse was defined as a competing risk in the analysis of TRM. The Wilcoxon signed rank test was used to evaluate the effect of cell dose on the sustained engraftment of a single cord unit. Results: 27 patients from 2 centers (Duke-24, UBC-3) with a median age of 33 (range, 20–58) years with hematologic malignancies were enrolled on the trial. Fifteen had AML (CR1-1 and CR2-14), five had ALL (CR1-2 and 2CR–3), three had MDS, one had CML, and three had NHL. The median combined total nucleated cell dose was 4.3 (range, 3.2–7.7) × 107/kg. The cumulative incidence of neutrophil engraftment (≥500/μl) was 80% (95% confidence interval (CI), 58–91%), with a median of 24 (range, 13–45) days. The cumulative incidences of platelet engraftment ≥20,000 and ≥50,000/μl was 76% (95% CI, 54–88%) and 68% (95% CI, 46–83%), respectively, and a median day of platelet engraftment ≥50,000/μl was 52 (range, 33–78). A single cord blood unit represented ≥79% of hematopoiesis by day 100. Higher cryopreserved and infused total nucleated cell dose and infused CD3+ cell dose were significant factors associated with the predominant UCB unit (P = 0.032, 0.020, and 0.042, respectively). Three patients experienced graft failure, and hematopoiesis was restored in two patients with either autologous or haploidentical hematopoietic stem cells. The cumulative incidences of grades II–IV and grades III–IV acute GVHD were 37% (95%CI, 20–55%) and 11% (95% CI, 3–26%), respectively and that of chronic GVHD was 31% (95% CI, 15–49%). With a median follow-up period of 23 months, the overall and disease-free survival rates at 2 years were 58% (95% CI, 34–75%) and 52% (95% CI, 29–70%), respectively. The 180 day and 2-year incidence of TRM was 19% (95% CI, 7–35%) and 28% (95% CI, 12–47%), respectively. The relapse rate at 2 years was 20% (95% CI, 7–37%). As an indicator of tolerability of this modified myeloablative regimen, we observed a cumulative incidence of total parental nutrition usage of just 56%. In conclusion, we find that the modified myeloablative regimen of TBI (1350cGy)/fludarabine provides dual cord blood engraftment rates comparable to more conventional myeloablative regimens. In contrast to other reports, we found that graft size predicts for the predominant UCB unit. This study supports the use of TBI 1350cGy/fludarabine as an alternative to conventional myeloablative conditioning for dual UCB transplantation and provides justification for larger studies. Disclosures: Off Label Use: Fludarabine; used as part of the stem cell transplant conditioning regimen. Chao:Genzyme: Research Funding. Horwitz:Genzyme: Honoraria, Research Funding.

Description: Abstract 3541 We have previously shown that SCT from HLA-haploidentical related donors (HAPLO) after nonmyeloablative conditioning is feasible with a low incidence of grade III-IV acute GVHD or treatment-related mortality (TRM) (Rizzieri et al. JCO 2007). We now report our comparative study in patients who received SCT from a 6/6 HLA-matched related (MRD), 8–10/8 HLA-matched unrelated (MUD), or HAPLO donor, after nonmyeloablative conditioning. Methods: Patients with chemosensitive relapse or high risk disease with minimal residual disease at study entry were eligible. The conditioning regimen consisted of fludarabine, 40 mg/m2 for 4 days; melphalan, 140 mg/m2 for 1 day; and alemtuzumab, 20 mg for 4 days for patients with lymphoid or myelomatous diseases. Fludarabine and alemtuzumab at the same doses with busulfan, 130 mg/m2 for 2 days was used for patients with myeloid diseases. Mycophenolate mofetil was used for GVHD prophylaxis. Donor lymphocyte infusions were performed in 15 MRD patients and 4 HAPLO patients. Disease-free survival (DFS) and overall survival (OS) rates after SCT were estimated using the Kaplan–Meier method, and univariate comparisons were performed using the log-rank test. Cox proportional-hazards regression was used to evaluate variables that potentially affected the survival rates. Results: The lymphoid cohort included 52 patients with ALL (n = 6), lymphoma (n = 42), or myeloma (n = 4), whereas the myeloid cohort included 46 patients with AML/MDS (n = 40), and myeloproliferative disorder (MPD) (n = 6). The median subject age was 56.5 (range, 20–73) years with a median follow-up of 15 months among survivors. A total of 29, 40, and 29 patients received transplants from MRD, MUD, and HAPLO, respectively. All 29 patients engrafted after HCT from MRD. One of 40 patients who received SCT from MUD had a primary graft failure (GF), with 2 secondary GF and 1 early relapse. Two of them were rescued by subsequent nonmyeloablative SCT from the same MUD or new HAPLO donor. Among 28 HAPLO patients evaluable for engraftment, 8 had a primary GF, 6 of these had myeloid disease; 2 additional patients had donor cell recovery but without full recovery of normal blood counts. Three of the 8 were rescued with subsequent nonmyeloablative SCT from the same donor. The transplant regimen resulted in 11% TRM at day 100. Grade III-IV acute GVHD rates were 0/29 (0%), 4/40 (10%), and 5/29 (17%) in patients who received a transplant from a MRD, MUD, or HAPLO, respectively. CMV reactivation occurred in 57% of patients and 6% developed CMV disease. Other infectious complications included polyomavirus in 24% of patients, bacteria in 23%, respiratory viruses in 13%, and fungal infections in 7%. The common causes of death were progressive disease (30% for all cause of death) and infections (32%). The 1-year DFS rate after SCT from MRD, MUD, and HAPLO was 55% (95% CI, 33–73%), 39% (22–56%), and 34% (16–53%), respectively (Log-rank test, P = 0.094) (Figure 1); the corresponding 1-year OS rate was 66% (43–82%), 39% (21–55%), and 34% (16–53%), respectively (Log-rank test, P = 0.012) (Figure 2). Multivariate analysis revealed that SCT from MUD/HAPLO, compared with that from MRD, was the only adverse factor that affected the OS rate (HR for MUD, 2.62 (95% CI, 1.15–5.96), P = 0.022; HR for HAPLO, 3.17 (1.36–7.37), P = 0.007), but the OS rate after SCT from HAPLO did not significantly differ from that after SCT from MUD (P = 0.560). Other variables (recipient age, conditioning regimen, and disease status at transplant) were not significantly associated with the outcome. Conclusions: The results show the feasibility of this approach with this regimen and the clinical outcomes in patients who received transplants from HAPLO are comparable to patients who received transplants from MUD. Development of strategies to improve immune recovery remains a current challenge. Disclosures: Off Label Use: Alemtuzumab for conditioning in allogeneic stem cell transplantation. Horwitz:Genzyme: Honoraria, Research Funding. Chao:Genzyme: Research Funding. Rizzieri:Genzyme: Speakers Bureau.

Description: Background: Donor selection is one of key factors for better outcomes after hematopoietic stem cell transplantation (HSCT). It is shown that increased donor age is associated with high mortality. In the era of high-resolution typing of HLA and various methodological options in HSCT (e.g. conditioning regimens or cell source), however, the significance of donor age in the selection of donor or cell source is unclear. Here we examined the impact of donor age on clinical outcome after unrelated bone marrow transplantation (UBMT) and compared to the outcome after unrelated cord blood transplantation (UCBT). Patients and methods: For this retrospective cohort study, clinical data of donors and recipients were obtained from the registry data of the Japan Society of Hematopoietic Cell Transplantation (JSHCT). This study included 6035 adult patients 16 years of age or older with AML, MDS, ALL, or CML who received the first HSCT between 2000 and 2010. Among them, 3304 recipients received UBMT from 8/8 HLA-matched or 7/8 HLA-matched for HLA-A, -B, -C, and -DRB1 allele-level donor and 2731 recipients received single-unit UCBT from maximum 2-antigen (HLA-A, -B, -DR antigen-level) mismatched donor. Risk factors for overall mortality and other endpoints were analyzed using Cox proportional hazards models and Fine and Gray's proportional hazards models, respectively. Results: The median ages of UBMT and UCBT recipients were 42 years (range, 16-77) and 50 years (range, 16-82), respectively. The median age of UBMT donor was 34 years (range, 20-55). Among 3304 UBMT recipients, older donor age (≥40 years) was a significant risk factor for overall mortality (adjusted HR, 1.14; 95% CI, 1.03-1.27, p=0.015) and grades II-IV acute graft-versus-host disease (aGVHD) (adjusted HR, 1.27; 95% CI, 1.13-1.43, p

Description: Introduction: HLA 1-locus mismatched unrelated donor (1MMUD) has been used in allogeneic hematopoietic stem cell transplantation (HCT) for patients who lack an HLA-matched related or unrelated donor, although its outcome has been shown to be inferior to that of HLA-matched HCT. The use of anti-thymocyte globulin such as thymoglobulin (Thymo) as GVHD prophylaxis may overcome this drawback. The aims of this study were to compare the transplant outcomes between 1MMUD and matched unrelated donor (MUD) and to evaluate the effectiveness of Thymo in unrelated HCT from 1MMUD using the recent cohort. Methods: We retrospectively analyzed 3313 adult patients with acute myeloid leukemia (n=1835), acute lymphoblastic leukemia (n=830), or myelodysplastic syndrome (n=648) who underwent a first bone marrow transplantation from HLA -8/8 allele MUD or 1MMUD between 2009 and 2014. The patients who underwent allo-HCT from MUD with Thymo were excluded in this study. Clinical data for these patients were obtained from the Transplant Registry Unified Management Program (TRUMP), which includes clinical data of HCT performed in Japan. We compared the outcomes of MUD (n=2089) and 1MMUD with Thymo (n=109) with those of 1MMUD without Thymo (n=1115). Results: The median total dose of Thymo was 2.5 mg/kg (range 1.0-11.0 mg/kg) in the 1MMUD with Thymo group. The incidence of grade II-IV and III-IV acute GVHD were 44.5% (95% confidence interval (CI), 41.5- 47.4%) and 13.1% (95% CI, 11.2-15.2%), 33.4% (95% CI, 24.5-42.5%) and 5.8% (95% CI 2.4-11.6%), and 36.1% (95% CI, 34.1-38.2%) and 10.5% (95% CI, 9.2-11.9%) in the 1MMUD without Thymo group, the 1MMUD with Thymo group, and the MUD group, respectively (p