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We conducted a multicenter interventional study to assess the efficacy of Therakos ECP to treat steroid-resistant graft-vs-host disease (SRes-GVHD) after allogeneic HSCT and to identify biomarkers of GVHD response. A total of 62 patients were treated for acute SRes-GVHD (n = 37) or chronic SRes-GVHD (n = 25). Median time to best response was 35 days (range, 28-85) and 90 days (range, 27-240) in acute and chronic SRes-GVHD, respectively. Overall, 27 patients (72.9%) with SRes-aGVHD responded to treatment (40.5% CR and 32.4% PR). The response rate was significantly higher in grade I-II than in grade III-IV aGVHD (100% vs 50.0%, respectively, P-value = .001). In chronic SRes-GVHD, 22 patients (88%) achieved a clinical response (24.0% CR and 64% PR). Response was higher in moderate than in severe SRes-cGVHD (100% vs 75%, P = .096). In both acute and chronic SRes-GVHD patients, the percentage of peripheral blood CD3+ CD4+ was higher and CD3+ CD8+ lower in responding than nonresponding patients. Acute SRes-GVHD responding patients presented a higher number of Treg cells (CD4+ CD25+ CD127low/- ) at day 0 (P = .028) than nonresponding patients, differences that were maintained over the observation period. Phenotypic analysis of T-cell maturation showed a trend toward reduction in TCD8 naive cells, along with an increased percentage of TCD8 Mem Efect T cells after starting ECP in responding patients. None of the studied serum cytokines displayed statistically significant changes in either acute or chronic SRes-GVHD. ECP is an effective treatment for patients with SRes-GVHD. Biomarkers could help guide decision-making on ECP treatment initiation and duration.

The potential role of active CMV infection in promoting acute Graft-versus-Host Disease (aGvHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a matter of debate. We further addressed this issue conducting a retrospective, observational, multicenter study of 632 patients subjected to allogeneic peripheral blood HSCT at 20 Spanish centers. Monitoring of CMV DNA load in plasma or whole blood was performed by real-time PCR assays. Cumulative incidence of CMV DNAemia was 48.9% (95% CI, 45%-52.9%), of any grade aGvHD, 45.6; 95% (CI, 41.3%-50.1%), and of grade II-IV aGvHD, 30.7 (95% CI, 24.9%-36.4%). Overall, development of CMV DNAemia at any level resulted in an increased risk of subsequent all grade (HR, 1.38; 95% CI, 1.08 - 1.76; P = .009) or grade II-IV (HR, 1.58; 95% CI, 1.22 - 2.06; P = .001) aGvHD. The increased risk of aGvHD linked to prior occurrence of CMV DNAemia was similar to the above when only clinically significant episodes were considered for the analyses (HR for all grade aGvHD, 1.48; 95% CI, 1.13 - 1.91; P = .041, and HR for grade II-IV aGvHD, 1.53; 95% CI. 1.13-1.81; P = .04). The CMV DNA doubling time in blood was comparable overall in episodes of CMV DNAemia whether followed by aGvHD or not. Whether CMV replication is a surrogate risk marker of aGvHD or it is causally involved is an important question to be addressed in future experimental research.

The net impact of cytomegalovirus (CMV) DNAemia on overall mortality (OM) and nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a matter of debate. This was a retrospective, multicenter, noninterventional study finally including 749 patients. CMV DNA monitoring was conducted by real-time polymerase chain reaction (PCR) assays. Clinical outcomes of interest were OM and NRM through day 365 after allo-HSCT. The cumulative incidence of CMV DNAemia in this cohort was 52.6%. A total of 306 out of 382 patients with CMV DNAemia received preemptive antiviral therapy (PET). PET use for CMV DNAemia, but not the occurrence of CMV DNAemia, taken as a qualitative variable, was associated with increased OM and NRM in univariate but not in adjusted models. A subcohort analysis including patients monitored by the COBAS Ampliprep/COBAS Taqman CMV Test showed that OM and NRM were comparable in patients in whom either low or high plasma CMV DNA threshold (= 500 IU/mL) was used for PET initiation. In conclusion, CMV DNAemia was not associated with increased OM and NRM in allo-HSCT recipients. The potential impact of PET use on mortality was not proven but merits further research.

Background Little is known about characteristics of seasonal human coronaviruses (HCoVs) (NL63, 229E, OC43, and HKU1) after allogeneic stem cell transplantation (allo-HSCT). Methods This was a collaborative Spanish and European bone marrow transplantation retrospective multicenter study, which included allo-HSCT recipients (adults and children) with upper respiratory tract disease (URTD) and/or lower respiratory tract disease (LRTD) caused by seasonal HCoV diagnosed through multiplex polymerase chain reaction assays from January 2012 to January 2019. Results We included 402 allo-HSCT recipients who developed 449 HCoV URTD/LRTD episodes. Median age of recipients was 46 years (range, 0.3–73.8 years). HCoV episodes were diagnosed at a median of 222 days after transplantation. The most common HCoV subtype was OC43 (n = 170 [38%]). LRTD involvement occurred in 121 episodes (27%). HCoV infection frequently required hospitalization (18%), oxygen administration (13%), and intensive care unit (ICU) admission (3%). Three-month overall mortality after HCoV detection was 7% in the whole cohort and 16% in those with LRTD. We identified 3 conditions associated with higher mortality in recipients with LRTD: absolute lymphocyte count Conclusions Seasonal HCoV after allo-HSCT may involve LRTD in many instances, leading to a significant morbidity.

There is limited information on the impact of CMV DNAemia episodes developing prior to engraftment (pre-CMV DNAemia) on clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). This issue was addressed in the current retrospective multicenter study including 878 patients. All participant centers used preemptive antiviral therapy strategies for prevention of CMV disease. CMV DNA load in blood was monitored by real-time PCR assays. A total of 144 patients (cumulative incidence 16.5%, 95% CI, 14%-19%) had an episode of pre-CMV DNAemia at a median of 10 days after allo-HSCT. Patients who developed pre-CMV DNAemia had a significantly higher (P = < 0.001) probability of recurrent episodes (50%) than those who experienced post-CMV DNAemia (32.9%); Nevertheless, the incidence of CMV disease was comparable (P = 0.52). Cumulative incidences of overall mortality (OM) and non-relapse mortality (NRM) at 1-year after allo-HSCT were 32% (95% CI, 29-35%) and 23% (95% CI 20-26%), respectively. The risk of OM and NRM in adjusted models appeared comparable in patients developing a single episode of CMV DNAemia, regardless of whether it occurred before or after engraftment, in patients with pre- and post-engraftment CMV DNAemia episodes or in those without CMV DNAemia.

Grupo Español de Trasplante Hematopoyético (GETH) and Grupo Español de Linfoma y Trasplante Autólogo (GELTAMO)., We performed a retrospective multicenter study including 140 patients with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) from March 1995 to November 2018. Our objective was to analyze long term outcomes. Seventy-four percent had received a previous auto-SCT (ASCT) and the median number of lines pre-allo-SCT was 3 (range 1–9). Three year-event free survival (EFS) and overall survival (OS) were 38% and 44%, respectively. Non-relapse mortality (NRM) at day 100 was 19%. Cumulative incidence of grade III–IV acute graft versus host disease (GVHD) at day 100 was 16% and moderate/severe chronic GVHD at 3 years 34%. Active disease at allo-SCT (HR 1.95, p = 0.039) (HR 2.19, p = 0.019), HCT-CI ≥ 2 (2.45, p = 0.002) (HR 2.33, p = 0.006) and donor age >37 years (HR 2.75, p = 0.014) (HR 1.98, p = 0.043) were the only independent variables both for PFS and OS, respectively. NRM was significantly modified by HCT-CI ≥ 2 (HR 4.8, p = 0.008), previous ASCT (HR 4.4, p = 0.048) and grade III–IV acute GVHD on day 100 (HR 6.13, p = 0.016). Our data confirmed that allo-SCT is a curative option for patients with R/R DLBCL, displaying adequate results for fit patients with chemosensitive disease receiving an allo-SCT from a young donor.

Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD.We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56.A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]).Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy. (Funded by Novartis; REACH2 ClinicalTrials.gov number, NCT02913261.).

OBJECTIVES Whole blood-derived platelet concentrates can be obtained by the platelet-rich plasma (PRP-PCs) or the buffy-coat (BC-PCs) method. Few studies have shown that BC-PCs display lower in vitro platelet activation, but scarce information exists regarding transfusion efficacy. We have performed a retrospective study assessing platelet transfusion in patients undergoing allogeneic hematopoietic cell transplantation (AHCT) in our clinic, before and after the implementation of BC-PCs. METHODS We reviewed clinical records corresponding to 70 PRP-PCs and 86 BC-PCs prophylactic transfusions, which were performed to 55 AHCT patients. Transfusion efficacy was assessed by the 24-h post-transfusion corrected count increment (24-h CCI) and bleeding events. Clinical factors affecting transfusion outcome were also investigated. RESULTS Clinical characteristics and the total number of platelet transfusions were similar among groups. Mean donor exposure was 5.8 and 5.0 in each single PRP-PCs and BC-PCs transfusion, respectively (p

Introduction: High-dose post transplant cyclophosphamide (PTCY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplant (HSCT) and offer low rates of GVHD in the setting of HLA identical transplant. The objective of our study was to compare the outcomes of haplo vs HLA identical HSCT in patients undergoing HSCT for acute myeloid leukemia (AML) using PTCY. Patients and methods: We conducted a retrospective study of 229 patients undergoing a first HSCT for AML using PTCY, 130 from an haploidentical donor between 2013 and 2018 (median follow up 62.5 months) and 99 from a matched sibling (MSD) (n=38) or unrelated donor (MUD) (n=61) (median follow up 27 months) between 2013 and 2019, in 20 centers in Spain. Last update of the cohort was performed in March 2021. Results: Baseline characteristics are summarized in Table 1. There were more patients with active disease at transplant (5% MSD/MUD vs. 20% haplo, p=0.001), high/very high DRI (32% vs. 67%, p=0.000) and prior autologous HSCT (2% vs. 11%, p=0.010) in the haplo group. Mobilized peripheral blood stem cells was the most frequent stem cell source in both groups. Most patients received myeloablative conditioning (55% vs. 64%, p=0.170). All Patients in the haplo group received PTCY days +3+4 followed by a calcineurin inhibitor (CNI) and MMF from +5. In the MSD/MUD group, 37% received both CNI+MMF, 33% only CNI and 30% PTCY with sirolimus+MMF (this group included only MUD donors). None of the patients received ATG. Cumulative incidence of neutrophil recovery at day 28 was 97% in both groups, with a median of 16 and 17 days respectively (p=0.948). Both 2-year overall survival (OS) (72% vs. 62%, p=0.07) and event-free survival (EFS) (70% vs. 54%, p=0.055) were higher in the MSD/MUD group, but the difference was not statistically significant (Figure 1). Multivariate analysis only identified age and pre-transplant status as independent risk factors for OS, and pre-transplant status for EFS. No differences were found in the cumulative incidence of relapse at 2 years (19% vs. 25%, p=0.13) and non-relapse mortality (14% vs. 19%, p=0.145). Cumulative incidence of grade II-IV acute GVHD was lower in MSD/MUD (14% vs. 47%, p=0.000, Figure 2), while III-IV aGVHD was similar (4% vs. 9%, p=0.14). Cumulative incidence of chronic GVHD and moderate-severe cGVHD at 2 years was similar for both groups (42% vs. 33% (p=0.051); 22% vs. 19% (p=0.28)). No differences were found in GRFS (48% vs. 46% (p=0.506)). Most frequent cause of death in the early post-transplant period was non-GVHD related infection in both groups. Conclusions: in our experience, PTCY as GVHD prophylaxis in both MSD/MUD and Haplo transplant in AML using mostly PBSC effectively prevents GVHD and offers similar NRM, relapse and survival rates. Poor control of the disease before transplant was the only factor affecting OS and EFS in this setting. Prospective studies are needed to confirm our results. Figure 1 Figure 1. Disclosures Bailen: Pfizer, Kite-Gilead, Gilead: Honoraria. Guerreiro: Novartis, Gilead: Consultancy, Honoraria. Oarbeascoa: Gilead: Honoraria, Speakers Bureau. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria.

[Aims] To estimate the frequency and management of PTLD in Spain and to identify prognostic factors influencing outcomes., [Methods] Multicenter, retrospective analysis of allo‐SCT performed in 14 transplant units over a 15‐year period., [Results] 102 PTLD were diagnosed among 12 641 allo‐SCT, leading to an estimated frequency of 0.8%. PTLD was diagnosed at a median of 106 days after SCT. Eighty‐seven cases (85%) were diagnosed between 2007 and 2013. At diagnosis, 22% and 17% of the patients had gastrointestinal tract and CNS involvement. Eighty‐seven (85%) received rituximab treatment, alone or in combination with immunosuppression reduction, with an ORR of 50.6%. With a median follow‐up for survivors of 58 months, the 2‐year overall survival (OS) was 33% and the PTLD‐related mortality 45%. Age ≥ 40 years, malignant underlying disease, non‐response to rituximab, and severe thrombocytopenia or lymphocytopenia at PTLD diagnosis were associated with worse overall survival., [Conclusions] Only a small proportion of allografted patients were diagnosed a PTLD. Its clinical course was highly aggressive, and prognosis poor, especially in those failing rituximab. The prognostic impact found of the platelet, and lymphocyte count at diagnosis requires further confirmation.

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (alloSCT) is the only curative strategy for relapsed/refractory T cell lymphoma (T-NHL). In the past ten years, there have been several improvements in conditioning regimens and graft versus host disease prophylaxis (GVHD), which have contributed to lower transplant-related mortality (TRM). Also, selective and low toxicity therapies, might improve response quality in some T-NHL Recently, haploidentical stem cell transplantation (Haplo) with post-transplant cyclophosphamide is a new option for those patients who do not have an HLA-identical sibling or a suitable unrelated donor, but also it has shortened the time for urgent cases. METHODS: This study analyzes overall outcomes of 211 consecutive patients diagnosed with T-NHL who received an alloSCT from 1995 to 2018 in GELTAMO/GETH centers. Previous therapies (chemotherapies and autologous stem cell transplantation) and baseline diagnostic parameters were recorded. RESULTS The median age at alloSCT was 47 years (range, 17-69). (see table 1). Forty-nine (23%) had primary extranodal disease. Disease status pre alloSCT was available in 202 patientes: 54% were in complete response (CR), 30% in partial response (PR) and 16% with stable/progressive disease (PD). Since 2013 BV was used as a bridge therapy in ≥ 3rd line in 25 patients with CD30+ tumor expression, it was effective in 20 (CR 68% (n=17), PR 12% (n=3) PD 16% (n=4), not assessed in 1 case). The use of BV was not associated with a better response probability pre alloSCT compared with other regimens used after third line and it did not impact on post alloSCT outcomes. Reduced intensity conditioning (RIC) was the most frequent (76%, n=156). (see table 2) GVHD prophylaxis were Methotrexate + CsaA or Tacrolimus (n=72, 35,8%), sirolimus-tacrolimus (n=37; 18,4%), Cy-post based (n=44, 21,9%; used in Haplo setting n= 29). The median follow-up of all cohort was 22.5 months (range, 0-280). The two year overall survival (OS) and disease free survival (DFS) were 60% (CI95%, 53-67%) and 76.7% (CI95%, 69.3-82.5%) (Figure 1A) We observed a significant improvement in alloSCT outcomes since 2011 (OS Disease status was the only pre alloSCT variable that impacts 2 years - OS: CR 72.8% (CI95%, 63-80.4%), PR 52%(38.7-63.7%), PD 43.8 (26.5-59.8%) (p=0.002) (Figure 1C). Forty-three (21%) cases relapsed after alloSCT. To analyze the impact of GVHD on OS and DFS we selected landmark time point at day +100 and +1 year after alloSCT for acute (aGVHD) and chronic GVHD (cGVHD) respectively, which allowed us to capture the majority of events that could interfere with the analysis. A landmark analysis (day +100) showed a 2 year OS for grade 3-4 aGVHD was 18% and for 1-2 aGVHD 54,6% (p Cumulative incidence of acute GVHD at 90 days was 51.6% (CI95%, 43.9-58.2%) being 27% grade 3-4. Chronic GVHD at 6 months was 53.9% (46.1-60.5), 54% of cases were grade 3-4). The 2 years non relapse mortality (NRM) was 30.2% (CI95%, 23.3-36.5%); the main causes contributing to NRM were GVHD (40%) and infections (44%) Haploidentical (Haplo) alloSCT was introduced in 2012 (29 of 128). With a median follow up of 13 months (range, 0-60) we found that outcomes in terms of 1 year OS (Haplo 60.7% vs. others 67,5%), 1 year DFS (Haplo 74.8% vs. others 83.8%) and 1 year NRM (Haplo 29.7% vs. 26%) are similar to other alloSCT modalities (Figure 1D). Not additional analysis could be estimated due to the low number of population at risk for each category. CONCLUSION Overall outcomes of alloSCT for T-NHL have improved over time. Complete response pre alloSCT is the only determinant for OS. Haploidentical alloSCT is not significantly different from other approaches and should be considered as an alternative. Disclosures Sierra: Novartis: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria; Pfizer: Honoraria; Daiichi-Sankyo: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria.

BackgroundHigh-risk acute leukemia (AL) and myelodysplastic syndrome (MDS) remain a therapeutic challenge. Unmanipulated haploidentical-related donor transplantation based on a myeloablative conditioning regimen (HAPLO-MAC) and post-transplant cyclophosphamide (PT-Cy) as prophylaxis against graft vs host disease (GvHD) is now a promising rescue strategy that could become universally available. ObjectiveTo evaluate the results of HAPLO-MAC with PT-Cy in patients with AL and MDS reported to the Haploidentical Transplantation Subcommittee of the Spanish Group for Hematopoietic Transplantation (GETH). Patients and methodsWe report our multicenter experience using an IV busulfan-based HAPLO-MAC regimen and PT-Cy for treatment of 65 adults with high-risk AL and MDS. ResultsEngraftment was recorded in 64 patients (98.5%), with a median time to neutrophil and platelet recovery of 16 and 27days, respectively. The cumulative incidence of grade II-IV acute GvHD and chronic GvHD was 28.6% and 27.5%, respectively. After a median follow-up of 31months for survivors, the cumulative incidence of non-relapse mortality and relapse at 2years was 18.8% and 25%, respectively. Estimated 30-month event-free survival and overall survival were 56% and 54.5%, respectively. ConclusionHAPLO-MAC comprising an IV busulfan-based conditioning regimen enabled long-term disease control with acceptable toxicity in high-risk AL and MDS.

For patients with AML, the best alternative donor remains to be defined. We analyze outcomes of patients who underwent myeloablative umbilical cord blood or haploidentical hemopoietic stem cell transplantation (HSCT) in Spain. Fifty-one patients underwent single umbilical cord blood transplantation supported by a third party donor (Haplo-Cord) between 1999 and 2012, and 36 patients received an haploidentical HSCT with post-transplant cyclophosphamide (PTCY-haplo) between 2012 and 2014 in GETH centers. The Haplo-Cord cohort included a higher proportion of patients with high disease risk index and use of TBI in the conditioning regimen, and hematopoietic cell transplantation-age Comorbidity Age Index was higher in PTCY-haplo patients. Cumulative incidence of neutrophil engraftment was 97% in the Haplo-Cord and 100% in the PTCY-haplo group, achieved in a median of 12 and 17 days, respectively (P = 0.01). Grade II-IV acute GvHD rate was significantly higher in the PTCY-haplo group (9.8% vs 29%, P = 0.02) as well as chronic GvHD rates (20% vs 38%, P = 0.03). With a median follow-up of 61 months for the Haplo-Cord group and 26 months for the PTCY-haplo cohort, overall survival at 2 years was 55% and 59% (P = 0.66), event-free survival was 45% vs 56% (P = 0.46), relapse rate was 27% vs 21% (P = 0.79), and non-relapse mortality was 17% vs 23% (P = 0.54), respectively. In this multicenter experience, Haplo-Cord and PTCY-haplo HSCT offer valid alternatives for patients with AML. Neutrophil engraftment was faster in the Haplo-Cord cohort, with similar survival rates, with higher GvHD rates after haploidentical HSCT.

We designed a phase II clinical trial including Y-90 ibritumomab-tiuxetan as part of a reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (AlloSCT) in high-risk non-Hodgkin lymphoma (Clinical Trials Identifier: NCT00644371). Eligible patients had high-risk relapsed refractory aggressive lymphoma. The conditioning regimen consisted of rituximab 250 mg (days-21 and -14), Y-90 ibritumomab IV (.4 m Ci/kg, day -14), fludarabine 30 mg/m(2) i.v. (days-3 and -2) plus melphalan 70 mg/m2 i.v. (days-3 and -2) or 1 dose of melphalan and thiotepa 5 mg/kg (day-8). Donors were related. Eighteen patients were evaluable. At the time of transplantation, responses were complete remission (CR) (n = 7, 39%), partial remission (n = 6, 33%) or refractory disease (n = 4, 28%). Y-90-ibritumomab infusions were well tolerated, with no adverse reactions. Nonrelapse mortality at 1 year was 28%. Median follow-up was 46 (range, 39 to 55) months. Estimated 1-year progression-free survival (PFS) was 50%, and 4-year overall survival (OS) and PFS were both 44.4%. CR at the moment of AlloSCT had significant impact on PFS (71% versus 27%, P =.046) and OS (71% versus 27%, P=.047). Our results show that Y-90-ibritumomab-tiuxetan as a component of RIC for AlloSCT is feasible in patients with high-risk B cell lymphoma. Development of phase III clinical trials is needed to clarify the contribution of radioimmunotherapy to RIC AlloSCT. (C) 2017 American Society for Blood and Marrow Transplantation.

Umbilical cord blood (CB) is increasingly used as an alternative source of stem cells in adult unrelated transplantation. Although registry studies report similar overall outcomes in comparison with BM/PB, comparative studies focusing on severe infections and infection-RM (IRM) with a long follow-up are scarce. A total of 434 consecutive unrelated transplants (1997-2009) were retrospectively analyzed to compare overall outcomes, incidence and risk factors of severe viral and invasive fungal infections in CB (n = 65) vs BM/PB recipients (n = 369). The 5-year OS was 38 vs 43%, respectively (P = 0.2). CB transplantation (CBT) was associated with a higher risk of invasive aspergillosis (100-days-cumulative incidence 16 vs 6%, P = 0.04) and CMV infection without differences in RM. No statistically significant differences were found regarding NRM (NRM of 38% in CB vs 37% in BM/PB at 1 year) nor IRM (30% in CB vs 27% in BM/PB at 1 year). In the overall population, NRM and IRM improved in more recent years. In adults who receive a single CBT, the risk of severe infections is increased when compared with unrelated BM/PB recipients, but mortality from infections is similar, leading to similar NRM and survival.

INTRODUCTION: Extracorporeal photoapheresis (ECP) is an immunomodulatory therapy for patients with acute or chronic graft-versus-host disease (aGVHD/cGVHD). So far, few studies have explored the molecular regulation of GVHD, and to date no studies have addressed how specific is miRNA expression change during ECP, and whether selected miRNA profiles might be predictive of clinical responses to ECP. OBJECTIVE: The aim of the study was to analyze the expression profile of miRNAs in plasma of patients with GVHD candidates for ECP, and their changes in responding and non-responding patients to this therapy. PATIENTS AND METHODS: Patients with GVHD underwent ECP therapy by off-line methods according to internal protocols. Peripheral blood samples were drawn pre-ECP and after 6 months of treatment. Data on patient characteristics, medical therapies and responses were obtained from medical records. We included the following study cohorts: 1) Initial cohort of 10 GVHD patients (7 cGVHD, 3 aGVHD) and 3 controls; 2) Internal validation cohort with 21 GVHD patients (14 cGVHD, 7 aGVHD) and 10 controls; and 3) External validation cohort (Policlinico S. Matteo, Pavia) composed of 24 GVHD patients (17 cGVHD, 7 aGVHD) and 12 controls. Additionally, samples from 12 patients undergoing ECP due to lung transplantation were also included. Plasma miRNAs were purified with NucleoSpin miRNA Plasma (Macherey-Nagel). In the initial cohort, we analyzed 178 miRNAs, using the Plasma focus miRNAs PCR array (Exiqon). In the validation cohorts we quantified, by qRT-PCR, candidate miRNAs using miRcury LNA RT miRNA PCR (Exiqon) and specific Exiqon primers. RESULTS: In the initial cohort, 4 miRNAs (miR-22-5p, miR-34a-5p, miR-148a-3p, and miR-505-3p) showed higher expression in patients with GVHD compared to controls (p CONCLUSION: This study identifies miR-34a-5p and miR-148a-3p as potential biomarkers to predict responses to ECP in patients with GVHD. The combinatorial function of these miRNAs can provide a more informative outlook on the pathophysiology of the disease by identifying potential target genes being inhibited and the pathways involved, both in the development of GVHD and following responses to ECP. Overall, this information would enable the implementation of more personalized patient treatment strategies, and likely lead to significant advances in the management of GVHD patients. Disclosures Lozano: Amgen: Consultancy; Terumo S.A.: Consultancy; Grifols S.A.: Consultancy; Novartis: Consultancy; Macopharma: Consultancy.

Highly infectious diseases (HIDs) are defined as being transmissible from person to person, causing life-threatening illnesses and presenting a serious public health hazard. In most European Union member states specialized isolation facilities are responsible for the management of such cases. Ground ambulances are often affiliated with those facilities because rapid relocation of patients is most desirable. To date, no pooled data on the accessibility, technical specifications and operational procedures for such transport capacities are available. During 2009, the ‘European Network for HIDs’ conducted a cross-sectional analysis of hospitals responsible for HID patients in Europe including an assessment of (a) legal aspects; (b) technical and infrastructure aspects; and (c) operational procedures for ground ambulances used for HID transport. Overall, 48 isolation facilities in 16 European countries were evaluated and feedback rates ranged from 78% to 100% (n = 37 to n = 48 centres). Only 46.8% (22/47) of all centres have both national and local guidelines regulating HID patient transport. If recommended, specific equipment is found in 90% of centres (9/10), but standard ambulances in only 6/13 centres (46%). Exclusive entrances (32/45; 71%) and pathways (30/44; 68.2%) for patient admission, as well as protocols for disinfection of ambulances (34/47; 72.3%) and equipment (30/43; 69.8%) exist in most centres. In conclusion, the availability and technical specifications of ambulances broadly differ, reflecting different preparedness levels within the European Union. Hence, regulations for technical specifications and operational procedures should be harmonized to promote patient and healthcare worker safety.

Background: Nivolumab, an immune checkpoint inhibitor, has been tested in patients with classical Hodgkin lymphoma (cHL) who failed standard treatment options and has demonstrated remarkable activity with acceptable safety profile in clinical trials. After the impressive results of nivolumab phase I study, a significant number of patients were granted early access to nivolumab through a Name Patient Program (NPP) or compassionate use in Spain. Demonstrating that results of nivolumab use in real-life are similar to those in clinical trials is of major clinical relevance. Objective: The aim of this retrospective study was to analyze the efficacy and safety profile of nivolumab for the treatment of relapsed/refractory (RR) cHL in a real-life context. Methods: We retrospectively collected data from 34 GELTAMO centers. Eligible patients included RR cHL patients treated with at least one cycle of nivolumab. The primary end-point was to describe the overall response rate (ORR). Secondary objectives were to assess the complete response rate (CR), safety of nivolumab, and clinical outcomes (overall survival [OS], and progression free survival [PFS]). Results: Between September 2015 and May 2018, 74 patients with RR cHL received nivolumab monotherapy dosed at 3mg/kg once every 2 weeks (97%). The median age was 38 years (range 17-78). Patients have received a median of 4 (1-15) prior therapy lines; all but 2 were previously treated with brentuximab vedotin (97%), and 38 (51%) of them underwent a hematopoietic stem cell transplantation (HSCT) (n=33 autologous, autoHSCT, and n=5 allogeneic, alloHCST). Median number of nivolumab cycles was 8 (1-65). Ten (14%) patients are still on treatment. Reasons for nivolumab discontinuation were disease progression in 23/64 (36%), referral to HSCT in 27/64 (42%), adverse events (AE) in 8/64 (13%), patient or physician's decision in 5/64 (8%), and unknown in 1/64 (1%). Treatment related AE were reported in 42/69 (61%). Half of them (21, 30%) were probably immune related AE: grade 1-2, 67% (cutaneous n=5, hepatitis n=3, hypothyroidism n=3, gastrointestinal n=3, suprarenal insufficiency n=1); grade 3-4, 24% (pneumonitis n=2, hepatitis n=1, encephalitis n=1, hypothyroidism n=1); grade 5, 3% (pneumonitis n=1, Stevens-Johnson syndrome + hepatitis + nephritis n=1). ORR was 58% (CR 21/72 patients, partial response [PR] 21/72). Stable disease (SD) was achieved in 9 patients (13%). After an initial response (4 PR and 3 SD), 7 patients developed lymphoma progression. A total of 40 (54%) patients finally underwent HSCT, 4 autoHSCT and 36 alloHCST. AlloHSCT was performed after a median of 63 days (41-115) and 8 patients received prior salvage therapy. Complications after alloHSCT consisted of non-infectious fever requiring steroid treatment in 13 (36%), acute graft-versus-host disease in 19 (53%) (2 of them grade 3-4, 1 death), hepatic venocclusive disease in 2 (6%, 1 death), and non-infectious pulmonary complications in 2 (6%). Five (14%) patients died due to transplant complications. At the last follow-up, all autoHSCT patients and 23/36 alloHSCT were in CR. The 2-year OS for the whole series (n=74) was 54% (median not reached). After a median follow-up of survivors patients of 12.5 months (1-31), 29 (39%) were alive in CR. Conclusions: Our real-life experience confirms the efficacy of nivolumab in very heavily pretreated cHL patients with an ORR of 58%. The safety profile of our cohort is comparable with that previously reported in clinical trials with manageable side effects and low treatment related mortality. In our study the percentage of patients who bridged to transplantation was significantly higher to that previously reported indicating this preference for Spanish physicians. AlloHSCT post-nivolumab showed encouraging results and toxicity seemed comparable to that previously described with other treatment regimens. Authors thank Bristol Myers Squibb for its support in this study. Disclosures Martinez: BMS: Research Funding; Takeda: Consultancy. García-Sanz:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Hospira: Research Funding; Pharmacyclics: Research Funding; Spanish Government: Research Funding; Gilead: Research Funding; Amgen Inc.: Research Funding; Incyte: Consultancy.

Background Herpes zoster (HZ) and its complications can have a substantial impact on patients’ quality of life (QoL), particularly in immunocompromised patients. The vaccine efficacy (VE) of an adjuvanted recombinant zoster vaccine (RZV) was studied in a randomized, placebo-controlled, phase 3 study in adult hematopoietic stem cell transplant (HSCT) recipients (NCT01610414). The VE in preventing HZ cases was 68.2% (95% CI: 55.6%–77.5%). Herein we report the impact of the vaccine on patients’ quality of life (QoL) associated with HZ episodes. Methods HSCT recipients were randomized 1:1 to receive 2 doses of RZV or placebo, given 1–2 months apart and followed for the occurrence of HZ. QoL parameters were measured by the Short-Form health survey (SF-36) and Euro-Quality of Life-5 Dimension (EQ-5D) at baseline, 1 month and 1 year post-dose 2, as well as during suspected HZ episodes in conjunction with the Zoster Brief Pain Inventory (ZBPI). For confirmed HZ cases, QoL scores were compared between the vaccine and placebo groups. The RZV impact in reducing the ZBPI Burden of Illness and Burden of Interference scores was estimated in patients in the modified total vaccinated cohort (mTVC). The 2 scores were calculated from the area under the curve (Days 0 to 182) of the ZBPI Worst Pain and ZBPI Activities of Daily Living scores, respectively, assuming a score of 0 for patients who did not have a confirmed HZ episode. Results Both the ZBPI maximum Worst Pain and Average Pain scores were significantly lower in the vaccine than placebo group (Table 1), suggesting less burden in breakthrough HZ cases following RZV. Consequently, the HZ Burden of Illness and Burden of Interference VE estimates were higher than the HZ VE estimate. RZV showed statistically significantly better QoL scores than placebo one week following rash-onset among patients with confirmed HZ, i.e., SF-36 bodily pain, social functioning, role emotional, mental health and mental component scores, and the EQ-5D Utility Score. Conclusion In addition to reducing the risk of HZ and HZ complications, RZV significantly reduces the impact of HZ on patient’s QoL in those who develop breakthrough disease. Funding: GlaxoSmithKline Biologicals SA. Disclosures D. Curran, GlaxoSmithKline: Employee, GSK Shares and Salary. A. Bastidas, GSK: Employee, Salary. M. El Idrissi, GSK: Employee and Shareholder, Salary. S. Matthews, GSK group of companies: Consultant, Consulting fee. L. Oostvogels, GSK group of companies: Employee, Salary and stock and stock option. J. A. Young, GSK: Investigator, The University of Minnesota is reimbursed for contract costs associated with conducting clinical trials of vaccine. I receive no personal financial benefit.

s / Biol Blood Marrow Transplant 21 (2015) S266eS321 S284 percentage of hCD68+ cells (linear regression; r21⁄40.70, p

Acute myeloid leukemia (AML) is a heterogeneous disease whose prognosis is mainly related to the biological risk conferred by cytogenetics and molecular profiling. In elderly patients (>= 60 years) with normal karyotype AML miR-3151 have been identified as a prognostic factor. However, miR-3151 prognostic value has not been examined in younger AML patients. In the present work, we have studied miR-3151 alone and in combination with BAALC, its host gene, in a cohort of 181 younger intermediate-risk AML (IR-AML) patients. Patients with higher expression of miR-3151 had shorter overall survival (P = 0.0025), shorter leukemia-free survival (P = 0.026) and higher cumulative incidence of relapse (P = 0.082). Moreover, in the multivariate analysis miR-3151 emerged as independent prognostic marker in both the overall series and within the unfavorable molecular prognostic category. Interestingly, the combined determination of both miR-3151 and BAALC improved this prognostic stratification, with patients with low levels of both parameters showing a better outcome compared with those patients harboring increased levels of one or both markers (P = 0.003). In addition, we studied the microRNA expression profile associated with miR-3151 identifying a six-microRNA signature. In conclusion, the analysis of miR-3151 and BAALC expression may well contribute to an improved prognostic stratification of younger patients with IR-AML., Marina Diaz-Beya is supported by ISCIII (Rio Hortega CM13/00205). This research was in part supported by Fundacion Espanola de Hematologia y Hemoterapia (beca de investigacion MDB). This research is also supported by grants from Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III PI13/00999 (PI: JE), RETICS RD12/0036/0010 (JE; MDB) and SDCSD from School of Medicine, University of Barcelona, AECC-Catalunya 2013 (AN) (sponsored by Mat Holding), and grants AGAUR 2014SGR-1281, ISCIII RD12/0036/0071 and PI014/00450 (JS). Anna Cordeiro is an APIF fellow of the University of Barcelona.

Background Umbilical cord blood transplantation (CBT) is an established alternative source of stem cells in the setting of unrelated transplantation. When compared with other sources, single-unit CBT (sCBT) is associated with a delayed hematologic recovery, which may lead to a higher infection-related mortality (IRM). Co-infusion with the sCBT of CD34+ peripheral blood stem cells from a third-party donor (TPD) (sCBT + TPDCD34+) has been shown to markedly accelerate leukocyte recovery, potentially reducing the IRM. However, to our knowledge, no comparative studies have focused on severe infections and IRM with these 2 sCBT strategies. Methods A total of 148 consecutive sCBT (2000–2010, median follow-up 4.5 years) were included in a multicenter retrospective study to analyze the incidence and risk factors of IRM and severe viral and invasive fungal infections (IFIs). Neutrophil engraftment occurred in 90% of sCBT (n = 77) and 94% sCBT + TPDCD34+ (n = 71) recipients at a median of 23 and 12 days post transplantation, respectively (P

Serpinopathies, a group of diseases caused by mutations that disrupt the structurally sensitive serpins, have no known acquired cause. Interestingly, l-asparaginase treatment of acute lymphoblastic leukemia patients causes severe deficiency in the serpin antithrombin. We studied the consequences of this drug on antithrombin levels, activity, conformation, and immunohistological and ultrastructural features in plasma from acute lymphoblastic leukemia patients, HepG2 cells, and plasma and livers from mice treated with this drug. Additionally, we evaluated intracellular deposition of α1-antitrypsin. l-Asparaginase did not affect functional or conformational parameters of mature antithrombin; however, patients and mice displayed severe type I deficiency with no abnormal conformations of circulating antithrombin. Moreover, l-asparaginase impaired secretion of antithrombin by HepG2 cells. These effects were explained by the intracellular retention of antithrombin, forming aggregates within dilated endoplasmic reticulum cisterns. Similar effects were observed for α1-antitrypsin in plasma, cells, and livers, and intracellular aggregates of additional proteins were observed in frontal cortex and pancreas. This is the first report of a conformational drug-associated effect on serpins without genetic factors involved. l-Asparaginase treatment induces severe, acquired, and transient type I deficiency of antithrombin (and α1-antitrypsin) with intracellular accumulation of the nascent molecule, increasing the risk of thrombosis.

Acute graft-versus-host disease (aGVHD) after autologous progenitor cell transplantation has been associated with blood transfusion or cyclosporine. Mild aGVHD grades I-II, identified as autoaggression or engraftment syndrome, has recently been described in autologous progenitor transplantation. Here, we report the first case of pathologically documented grade IV aGVHD after autologous peripheral blood progenitor cell transplantation in a patient with breast cancer. The allogeneic origin was excluded by molecular techniques, and no cyclosporine or cytokines were administered.

Acute myeloid leukemia (AML) is a heterogeneous disease, and optimal treatment varies according to cytogenetic risk factors and molecular markers. Several studies have demonstrated the prognostic importance of microRNAs (miRNAs) in AML. Here we report a potential association between miRNA expression and clinical outcome in 238 intermediate-risk cytogenetic AML (IR-AML) patients from 16 institutions in the CETLAM cooperative group. We first profiled 670 miRNAs in a subset of 85 IR-AML patients from a single institution and identified 10 outcome-related miRNAs. We then validated these 10 miRNAs by individual assays in the total cohort and confirmed the prognostic impact of 4 miRNAs. High levels of miR-196b and miR-644 were independently associated with shorter overall survival, and low levels of miR-135a and miR-409-3p with a higher risk of relapse. Interestingly, miR-135a and miR-409-3p maintained their independent prognostic value within the unfavorable molecular subcategory (wild-type NPM1 and CEBPA and/or FLT3-ITD), and miR-644 retained its value within the favorable molecular subcategory. miR-409-3p, miR-135a, miR-196b and mir-644 arose as prognostic markers for IR-AML, both overall and within specific molecular subgroups.

Background: We herein report the long-term results of an allogeneic reduced-intensity conditioning (allo-RIC) protocol used in 21 consecutive patients (16 males, median age 56 years, 71% in complete remission) diagnosed with mantle cell lymphoma (MCL). Methods: The allo-RIC consisted of fludarabine plus melphalan and peripheral blood hematopoietic stem cells (PBSCs) from human leukocyte antigen (HLA)-identical siblings were used in all cases. Median CD34+ infused cells was 5.8 × 106/kg. All patients engrafted promptly. Results: Early toxicity included mild/moderate mucositis (43%), febrile neutropenia (33%) and bacterial infections (19%). With a median follow up of 48 months, four deaths were reported, all due to infections and/or graft- versus-host disease (GVHD), yielding a 3-year cumulative incidence of nonrelapse mortality of 19.5%. Grade III–IV acute GVHD occurred in 15% and chronic GVHD in 78%, being extensive in 39%. The 5-year progression-free survival (PFS) and overall survival (OS) were both 80% (95% CI: 63–97%). Age was the only possible prognostic factor for OS, which was 43% for those aged more than 60 years and 100% for those younger ( p Conclusions: Our data confirm that allo-RIC offers a low toxicity profile and a chance for prolonged long-term disease-free survival in MCL, particularly in younger patients.

We retrospectively assessed whether normalized bone marrow WT1 levels could be used for risk stratification in a consecutive series of 584 acute myeloid leukemia (AML) patients. A cutoff value of 5065 copies at diagnosis identified two prognostic groups (overall survival (OS): 44 ± 3 vs 36 ± 3%, P=0.023; leukemia-free survival (LFS): 47 ± 3 vs 36 ± 4%, P=0.038; and cumulative incidence of relapse (CIR): 37 ± 3 vs 47 ± 4%, P=:0.043). Three groups were identified on the basis of WT1 levels post-induction: Group 0 (WT1 between 0 and 17.5 copies, 134 patients, OS: 59 ± 4%, LFS:59 ± 4% and CIR: 26 ± 4%); Group 1 (WT1 between 17.6 and 170.5 copies, 160 patients, OS: 48 ± 5%, LFS:41 ± 4% and CIR: 45 ± 4%); and Group 2 (WT1170.5 copies, 71 patients, OS: 23 ± 6%, LFS: 19 ± 7% and CIR: 68 ± 8%) (P0.001). Post-intensification samples distinguished three groups: patients with WT1100 copies (47 patients, 16%); an intermediate group of patients with WT1 between 10 and 100 copies (148 patients, 52%); and a third group with WT110 copies (92 patients, 32%). Outcomes differed significantly in terms of OS (30 ± 7%, 59 ± 4%, 72 ± 5%), LFS (24 ± 7%, 46 ± 4%, 65 ± 5%) and relapse probability (CIR 72 ± 7%, 45 ± 4%, 25 ± 5%), all P0.001. WT1 levels in bone marrow assayed using the standardized ELN method provide relevant prognostic information in de novo AML.

The current study was designed to assess the safety and efficacy of bortezomib in combination with fludarabine and melphalan as reduced intensity conditioning before allogeneic stem cell transplantation in patients with high risk multiple myeloma. Sixteen patients were evaluable. The median number of previous line of treatment was 3; all patients had relapsed following a prior autograft and 13 had previously received bortezomib. Fifteen of them either remained stable or improved disease status at day +100 post-transplant, including 11 patients with active disease. More specifically, nine patients (56%) and five patients (31%) reached complete remission and partial response, respectively. 25% developed grade III acute graft-versus-host disease. The cumulative incidence of non-relapse mortality, relapse and overall survival were 25%, 54% and 41%, respectively, at 3 years. Regarding the non-haematological toxicity (grade>2), two patients developed peripheral neuropathy, two patients liver toxicity and 1 pulmonary toxicity early post-transplant. The haematological toxicity was only observed during the first three cycles mostly related to low haemoglobin and platelet levels. The current trial is the first one evaluating the safety and efficacy of bortezomib as part of a reduced intensity conditioning regimen among patients with high risk multiple myeloma., This study was partially supported by a grant from the Ministery of Health (EC10-289); Teresa Caballero was supported by a grant Rio Hortega (code: CM10/00161) from the Instituto de Salud Carlos III. The study was supported by Jassen-Cilaj providing bortezomib free of charge as well as financial support.

Introduction: Allogeneic haematopoietic stem cell transplantation (alloHCT) is a potentially curative approach for patients (pts) with multiple myeloma (MM). The high transplant related mortality (TRM) rate with myeloablative conditioning has resulted in a shift to reduced intensity conditioning regimens (RIC). However, most MM pts who receive an alloRIC ultimately relapse and their treatment remains a challenge. Since alloHCT can modify the biology of the disease, including the immune environment, responses after alloHCT to rescue therapies previously used before alloHCT could be improved. Our main objective was to evaluate the efficacy of regimens including new drugs in MM pts relapsing after alloHCT comparing the efficacy achieved before and after alloHCT. Material and Methods: We report a retrospective multicenter analysis of 126 consecutive pts that underwent alloHCT for MM from 2010 to 2013 at 8 Spanish centers. Results: Baseline pts and transplant characteristics are shown in Table I. The median of prior therapies prior to alloHCT was 3 (1-9), 83% had received previous autologous HCT and 26% had high risk cytogenetic. 71 (56%) and 48 pts (38%) had been treated with regimens containing proteasome inhibitors (PI) and immunomodulatory drugs (IMIDs) before transplantation, respectively. Disease status at transplant was complete remission (CR) in 16 (13%) pts, partial response (PR) or very good PR in 86 (68%) and 24 (18.5%) had relapsed/progressive disease. 35 pts (28%) had active extramedullary disease at transplant. The majority of pts received peripheral blood HCT (90%), RIC (90%) with fludarabine plus melphalan based conditioning regimen (61%) and calcineurin inhibitor plus MTX as GVHD prophylaxis (68%). 19% receiving allo-HCT from an unrelated donor (91% 10/10 HLA matched). All pts engrafted. Grade II-IV acute GVHD occurred in 54% pts (grade IV 8%) and chronic GVHD in 45% (moderate 15%, severe 12%). TRM within the first 100 days after transplant was 6% (overall TRM 28%). 60% pts improved their pre-transplant response, with an overall response rate of 74% (56% CR). After a median follow-up of 92 months for pts alive (22-197), the OS was 51 and 43% at 2 and 5 years respectively. 75 pts (59.5%) relapsed after alloHCT, 57 of them with extramedullary involvement. Median time to relapse was 8 months post-transplant (1-141). The cumulative incidence of relapse was 79% at 3 years. Median OS after relapse was 22 months (8-33). Seventeen out of 75 pts who relapsed received IP both in the pre-transplant and in the post-transplant period. Sixteen pts out of 17 who received IP achieved at least PR pre-transplant while 10 out of these 16 pts responded again to PI post-HCT. Moreover, 1 patient reached a deeper response (CR) post as compared to pre alloHCT (PR) and 1 patient who was refractory pre-alloHCT did respond post-alloHCT. In addition, 6 out of 7 pts who did not respond to IP post-transplant reached stable disease with time to progression (TTP) lasting 4 to 12 months. Twelve out of 75 pts who relapsed received IMIDs both pre and post-alloHCT. Ten pts out of 12 who received IMID pre-alloHCT achieved at least PR, and 8 out of these 10 pts responded again to IMIDs post-alloHCT. Moreover, 1 patient who had been refractory to IMIDs in the pre-transplant period reached CR after alloHCT. In addition, 2 out of 4 pts who were refractory to IMIDs in the post-transplant period reached stable disease with TTP of 8 to 13 months. Remarkably, among pts who respond both in the pre and the post-transplant period to IP or IMIDs, the time to response (TTR) and time to progression (TTP) was similar despite the regimens used in the pre-transplant setting were more aggressive (TTR 3 vs 3.5 and TTP 9 vs 7 months before and after alloHCT for IP, and TTR 4 both before and after alloHCT and TTP 10 vs 9.5 months before and after alloHCT for IMIDs). All but 2 pts received first generation IP pre and post-alloHCT (two pts received carfilzomib) and all but 5 received first generation IMIDs (5 pts were treated with pomalidomide). Conclusions: MM pts relapsing after alloHCT should be considered candidates to receive new drugs, as they can achieve response rates at least in a similar proportion and durability to those observed in the pre-transplant setting. This finding is in contrast to the usual course of the disease outside the alloHCT setting, where response rates and TTP decreases with consecutive lines of treatment. Disclosures Mateos: Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria.

Introduction: Allogeneic transplantation is the only curative option for patients with high risk leukemias or MDS. Only one third of them have an HLA identical sibling donor and around 60-70% will find an unrelated donor, that´s why haploidentical stem cell transplantation (HAPLO-HSCT) offers a therapeutic option to most of these patients. Myeloablative conditioning (MAC) produce better disease control than reduced intensity conditioning regimens (RIC), but with higher toxicity, rendering long term similar results. Patients and methods: We retrospectively evaluated the results of our MAC-HAPLO regimens in patients diagnosed with high risk leukemias or MDS (Fludarabine 30 mg/m2 x5 days, Cyclophosphamide14,5 mg/kg x2 days, IV Busulfan 3,2 mg/kg x 3 days (BUX3), or Fludarabine 40 mg/m2 x4 days and IV Busulfan 3,2 mg/kg x 4 days (BUX4)) with GVHD prophylaxis based on PT-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5, performed in GETH centers (Spanish Group for Hematopoietic Transplantation). Results: From Feb-2012, 65 MAC-HAPLO HSCT have been reported by 14 centers. Median age was 41 years (15-67), 66% were males and all were in advanced disease phase or presented high risk features (AML 47/ALL 8/MDS 5/ Others 5). Previous HSCT had been employed in 12% (autologous in 5, allogeneic in 3), and in 88% the HAPLO-HSCT was their first transplant. Disease status at HAPLO-HSCT was morphologic CR in 80%, but disease persisted in 52% (MRD+ by flow or molecular markers 32%, morphologic disease 20%). Their disease risk index (DRI) was high or very high in 65%, and the comorbidity index (HCT-CI) was higher than 2 in 18%. PBSC was the graft source in 56 (86%), non T-cell depleted in all cases. The haploidentical donor was the patient´s mother (21.5%), father (12%), siblings (43%) or offspring (23%). MAC regimen was BUX3 in 25 (38.5%) and BUX4 in 40 patients (61.5%). Median infused CD34+ cells were 5.31 x10e6/kg (2.75-11.42). There were no graft failures. Median neutrophils engraftment was reached at day +17 (12-29) and platelets >20K at day +26 (11-150). Complete chimerism was obtained at a median of 28 days (13-135) in 60 evaluated patients. Cumulative incidence (CI) of non-relapse mortality (NRM) was 12.5% at day +100 and 19% at 1 year. CI of grade II-IV acute GVHD was 28.5% at day +100, and grade III-IV was 6.5%. CI of chronic GVHD at 2 years was 28%, being extensive in 8% . No differences in acute or chronic GvHD CI were seen when comparing BUX3 against BUX4. After a median follow-up of 17 months (5-50), estimated 24-months event-free survival (EFS) and overall survival (OS) were 58,5% and 60% respectively. CI of relapse or progression was 21%. No significant differences in NRM, EFS, OS and relapse incidence were detected between BUX3 and BUX4. The impact of CR prior to MAC-HAPLO, the DRI or chronic GvHD in the disease control have not been apropiately demostrated probably due to the limited number of events in our series. Conclusions: IV Busulfan based MAC-HAPLO with PT-CY in the treatment of high risk leukemias and MDS offers good disease control with manageable toxicity, with either BUX3 or BUX4. These efective MAC regimens combined with peripheral blood HAPLO donors could control high risk hematologic diseases in the long term. Severe acute or chronic GvHD are low frecuency events, but relapses persist as the main problem in this patients population. Disclosures No relevant conflicts of interest to declare.

We describe a transient bone marrow heterogeneous B-cell lymphoproliferation with a complex spectrum of cytological, phenotypic, molecular, and immune features in the setting of adult patients with acute myeloid leukemia following umbilical cord blood transplantation procedure. In our view, the lymphoproliferation described herein could add another element to the differential diagnosis of post-transplant lymphoproliferative disorders.

Comparative Study; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't; BACKGROUND About one half of adults with acute lymphoblastic leukemia are not cured of the disease and ultimately die. The objective of this study was to explore the factors influencing the outcome of adult patients with relapsed acute lymphoblastic leukemia. DESIGN AND METHODS. We analyzed the characteristics, the outcome and the prognostic factors for survival after first relapse in a series of 263 adult patients with acute lymphoblastic leukemia (excluding those with mature B-cell acute lymphoblastic leukemia) prospectively enrolled in four consecutive risk-adapted PETHEMA trials. RESULTS. The median overall survival after relapse was 4.5 months (95% CI, 4-5 months) with a 5-year overall survival of 10% (95% CI, 8%-12%); 45% of patients receiving intensive second-line treatment achieved a second complete remission and 22% (95% CI, 14%-30%) of them remained disease free at 5 years. Factors predicting a good outcome after rescue therapy were age less than 30 years (2-year overall survival of 21% versus 10% for those over 30 years old; P

Background: We have investigated if rituximab-based salvage regimens improve response rates and survival of patients with diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous stem-cell transplantation (ASCT). Patients and methods: We have retrospectively analyzed 82 patients with DLBCL who received salvage therapy for relapse or progression after ASCT. Patients were divided into two groups, according to whether rituximab-based salvage regimens were given (n = 42, ‘R2’ group) or not (n = 40, ‘R+’ group) after ASCT. Results: Patients in the R+ group had better complete remission (CR) (55% versus 21.4%, P = 0.006) and overall response (OR) (75% versus 40.4%, P = 0.001) rates, and better 3-year event-free survival (EFS) (37% versus 9%, P = 0.002) and overall survival (OS) (50% versus 20%, P = 0.005) than patients in the R2 group. Patients retreated with rituximab had better CR (42.9% versus 21.4%, P = 0.032) and OR (66.7% versus 40.4%, P = 0.019) rates, and better OS (36.2% versus 20% at 3 years, P = 0.05) and EFS (36.2% versus 9% at 3 years, P = 0.05) than patients who received chemotherapy alone at relapse after ASCT. Conclusions: The addition of rituximab to salvage chemotherapy improves response rates and EFS in patients with relapsed DLBCL after ASCT. These patients may benefit from rituximab retreatment, although larger prospective studies are needed to confirm these results.

Adults with high-risk acute lymphoblastic leukemia (HR-ALL) have a poor outcome with standard chemotherapy and usually undergo unrelated stem cell transplantation (SCT) if a matched sibling donor is not available. We analyzed the outcome of adult patients with unrelated SCT for HR-ALL and studied the possible effect of the hematopoietic stem cell source of the transplant. A total of 149 adult patients (median age, 29 years, range, 15-59 years) with HR-ALL underwent unrelated SCT in 13 Spanish institutions between 2000 and 2007. Patients in first complete remission (CR1) at transplantation had at least one adverse prognostic factor (advanced age, adverse cytogenetics, hyperleukocytosis, or slow response to induction therapy). ALL was in CRI in 81 patients (54%), in second CR (CR2) in 37 patients (25%), in third CR (CR3) in II patients (7%), and with overt disease in 20 patients (13%). The hematopoietic source was unrelated cord blood (UCB) in 62 patients and an unrelated donor (UD) in 87 patients. The patients undergoing UCB-SCT and UD-SCT were comparable in terms of the main clinical and biological features of ALL, except for a higher frequency of patients with more overt disease in the UCB-SCT group. There was no statistically significant difference in overall survival (OS) or disease-free survival (DFS) at 5 years between the 2 groups. Treatment-related mortality (TRM) was significantly lower in the UCB-SCT group (P = .021). The probability of relapse at 1 year was 17% (95% confidence interval [CI], 7%-27%) for the UD-SCT group and 27% (95% CI, 14%-40%) for the UCB-SCT group (P = .088), respectively. Only disease status at transplantation (CR1, 41% [95% CI, 18%-64%] vs CR2, 51% [95% CI, 17%-85%] vs advanced disease, 66% [95% CI, 46%-86%]; P = .001) and the absence of chronic graft-versus-host disease (74% [95% CI, 46%-100%] vs 33% [95% CI, 17%-49%]; P = .034) were significant factors for relapse. All unrelated transplantation modalities were associated with high treatment-related mortality for adult HR-ALL patients without a sibling donor. UCB-SCT and UD-SCT were found to be equivalent options. Disease status at transplantation and chronic GVHD were the main factors influencing relapse in both transplantation modalities. Biol Blood Marrow Transplant 16: 957-966 (2010) (C) 2010 American Society for Blood and Marrow Transplantation

Introduction: CD34+ and CD3+ cell dose in peripheral blood stem cell (PBSC) graft have been related with increased incidence of graft versus host disease (GVHD) in some transplant settings. Our aim in this study was to evaluate the impact of CD34+ and CD3+ cells graft composition on GVHD incidence in the setting of haploidentical transplant (haplo-HSCT) with post-transplant cyclophosphamide (PT-Cy), in a multicenter analysis. Materials (or patients) and methods: We retrospectively evaluated 175 patients with hematologic malignancies who were treated with a haplo-HSCT from 2011 to 2014 with PBSC in GETH centers. All patients received Busulfan-Fludarabine as conditioning regimen and GVHD prophylaxis was performed with PT-Cy (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5. We analyzed the impact of CD34+ and CD3+ cell doses (low vs. high with cut-off at the median value, and the 25-75 percentiles) on the development of acute and chronic graft versus receptor disease. Death before GVHD development was considered as a competitive event. The analysis was adjusted for conditioning intensity. STATA software was used for data analysis Results: We analyzed 175 patients. Patient characteristics are resumed in table 1. Median CD34+ and CD3+ cell dose was 5.31x10e6/kg (p 25-75: 4.31-6.1) and 2.07x10e8/kg (p25-75: 1.19-2.94), respectively. Cumulative incidences of grade II-IV acute GVHD and all grades chronic GVHD was 32.6% and 30% respectively. The median follow-up was 12.3 months (r:6-46). No difference in terms of GVHD (acute and chronic), was found between low and high CD34+ cell doses. However, if we focus on T cells, high doses of CD3+, for values above the median, have been has been associated with increased incidence of acute GVHD II-IV (day 150: 47% vs 26% p=0.01, figure 2), as well as cGVHD (30 month: 39% vs 16%, p= 0.01 figure 1). If we focus the analyses regarding the intensity of conditioning regimen, the influence of CD3+ doses remains for the group of reduced-intensity conditioning (RIC) (aGVHD, day 150: 54% vs 24%, p=0.003; cGVHD, 30 month: 47% vs 16%, p=0.006 figure 2), but lost for patients who receive myeloablative intensity (aGVHD, day 150: 33% vs 33% p=0-8; cGVHD, 30 month: 21% vs 16%, p=0.81) Conclusion: In our series, in the setting of haplo-HSCT with Pt-Cy, the highest dose of lymphocytes was associated with a higher incidence of aGHVD II-IV and cGV HD, especially for the RIC procedures. Disclosures No relevant conflicts of interest to declare.

In the present paper, we evaluate tolerability, outcome and prognostic factors in patients with poor prognosis non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) when uniformly treated with BCNU, etoposide, cytarabine and melphalan (BEAM) and autologous stem cell transplant (ASCT). On hundred and forty-eight patients with NHL (n = 112) or HD (n = 36) received BEAM followed by infusion of bone marrow (n = 55), peripheral blood stem cells (n = 79) or both (n = 14). Twenty-eight patients had low-grade lymphoma (LGL), 68 intermediate- and 16 high-grade lymphoma (IGL). Within the NHL group, 21 patients were in 2nd or subsequent complete remission (CR) at transplant, 34 had sensitive disease and 11 resistant disease; 46 patients were transplanted in 1st CR due to the presence of > or = 2 adverse prognostic features at diagnosis or to a slow CR. Of the HD patients at transplant 17 had active disease, 16 were in > or = 2 CR and three in 1st CR. The overall percentage of toxic deaths was 5.4%, while in the group of patients transplanted with PBSC it was only 1.3%. NHL patients: 78% were in CR following ASCT, including 25 out of 45 patients (56%) who were transplanted with active disease. Only two of the 11 patients transplanted with resistant disease achieved CR. Incidence of overall survival (OS) and disease-free survival (DFS) at 3 years was 65 and 75%, respectively. As far as histology was concerned, OS was significantly better for patients with LGL in comparison with IGL (88 vs 56%) (P = 0.002). DFS was significantly higher for patients transplanted in first CR or first partial remission (PR) than it was for those transplanted in a later CR or PR (86 vs 53%) (P = 0.02). Multivariate analysis for OS showed that histology, bulky disease, poor performance status at transplant and achievement of CR were independent prognostic factors. In addition, a high number of infused MNC was associated with poor DFS. HD patients: 30 (83%) were in CR after transplantation, with 25 maintaining CR at the end of the study. Only one of the four patients transplanted with resistant disease reached CR. Incidence of OS and DFS at 3 years was 78 and 81%. DFS was similar for patients transplanted with early or late relapse (95 and 93%). With multivariate analysis, the only independent variable for OS was CR after transplant. In conclusion, the present results demonstrate the efficacy and low toxicity of the BEAM regimen in high-risk lymphoma patients with sensitive disease. Other strategies should be investigated for patients with refractory lymphoma.

Introduction Allogeneic transplantation is the only curative option for patients with high risk hematologic malignancies. Only one third of them have an HLA identical sibling donor and around 60-70% will find an unrelated donor, that´s why HAPLO-HSCT offers a therapeutic option to most of these patients with the advantages of quick availability, easy programation and logistics, and a committed donor. Patients and methods We retrospectively evaluate the results of HAPLO-HSCT with reduced conditioning or myeloablative regimens and GVHD prophylaxis based on HD-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5 performed in GETH centers. Results From Dec-2007, 80 HAPLO-HSCT have been done in 14 centers. Median age was 37 years (16-66), 67.5% were males and all were in advanced phases of their disease or presented high risk features (29 Hodgkin´s, 22 AML, 9 ALL, 8 MDS, 5 NHL, 4 myeloma and 2 myelofibrosis). Previous HSCT has been employed in 65%, autologous in 38 and allogeneic in 15 (5 siblings, 3 unrelated and 7 cord blood transplants), and in 35% the HAPLO-HSCT was their first transplant. Disease status at HAPLO-HSCT was CR in 45%, with persistent disease in 55%. Bone marrow was the graft source for 51% and peripheral blood for 49%, non T-cell depleted in all cases. The haploidentical donor was the patient´s mother (21), father (7), brother/sister (35) or offspring (17). Non-myeloablative conditioning was employed in 77.5% and myeloblative in 22.5%. Median neutrophils engraftment was reached at day +18 (13-45) and platelets >50K at day +27 (11-150). Main toxic complications were grade II-III muchositis in 36%, febrile neutropenia in 75% and CMV reactivations in 62%, with a transplant related mortality rate of 12.5% at day +100 and 19% at 6 months post-transplant. Acute GVHD grade II-IV affected to 24/73 patients at risk (33%), with grade III-IV in 10/73 (14%). Chronic GVHD was present in 12/51 (24%), being extensive in 6/51 (12%). After a median follow-up of 9 months (0.3-49), 26/80 patiens have died due to relapse in 13, infections in 10 and GVHD in 3 cases. Event-free survival and overall survival at 1 year were 48% and 60% respectively. Immune reconstitution was fast and complete in those evaluated. Conclusions HAPLO-HSCT with HD-CY is a useful tool in the treatment of high risk hematologic malignancies, rendering long-lasting remissions with limited toxicity, low GVHD incidence and early immune reconstitution. Disclosures: No relevant conflicts of interest to declare.

Introduction Allogeneic transplantation is the only curative option for patients with high risk hematologic malignancies. HAPLO-HSCT offers a therapeutic option to most of these patients with the advantages of quick availability, easy programation and logistics, and a committed donor. This procedure has shown promissing results in patients diagnosed with relapsed or refractory Hodgkin´s disease (Burroughs LM et al. Biol Blood Marrow Transplant 2008; 14:1279-1287). Patients and Methods We retrospectively evaluate the results of HAPLO-HSCT with RIC regimens (Fludarabine 30 mg/m2 x5 days (-6 to -2), Cyclophosphamide14,5 mg/kg x2 days (-6 to -5), Busulfan IV 3,2 mg/kg x 1-2 days (BUX, days -3 to -2) or 200 cGy TBI on day -1) and GVHD prophylaxis based on HD-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5 performed in GETH centers to patients diagnosed with relapsed or refractory Hodgkin´s disease. Results From March-2009, 29 HAPLO-HSCT have been performed in patients diagnosed with relapsed or refractory Hodgkin´s disease in 11 GETH centers. Median age was 31 years (18-53), 19 were males and all were in advanced phases of their disease. Autologous HSCT was previously employed in 90% of them, and allogeneic HSCT in 10%. Disease status at HAPLO-HSCT evaluated by PET was complete remission in 8 (28%) and persistent disease in 21 (72%). Bone marrow was the stem cell source in 15 (52%) and peripheral blood in 14 (48%), without T-cell depletion in all cases. The haploidentical donor was the patient´s mother (13), father (2), brother (8), sister (5) or daughter (1). The RIC regimens employed included 1 dose BUX (11), 2 doses BUX (14) or 200cGy TBI (4). Median neutrophils engraftment was day +17 (11-44) and platelets >20K was day +26 (11-150). Main toxic complications were grade II-III muchositis in 50%, febrile neutropenia in 75% and CMV reactivations in 58% with a transplant related mortality rate of 7% (2/29) at day +100 and 17% (5/29) at 6 months post-transplant. Acute GVHD grade II-IV affected to 7/28 patients at risk (25%), with grade III-IV in 3/28 (11%). Chronic GVHD was present in 3/19 (16%), being extensive in 1/19 (5%). After a median follow-up of 9 months (0.3-49), 13/22 (59%) remain alive and in complete remission. Relapse or progression occured in 6/28 (21%). Immune reconstitution was fast and complete in those evaluated. Conclusions HAPLO-HSCT with HD-CY is a useful tool in the treatment of patients with relapsed or refractory Hodgkin´s disease, rendering long-lasting remissions with limited toxicity, low GVHD incidence and early immune reconstitution. Disclosures: No relevant conflicts of interest to declare.