Search

Donor derived regulatory T lymphocytes and the JAK1/2 kinase inhibitor ruxolitinib are currently being evaluated as therapeutic options in the treatment of chronic graft versus host disease (cGvHD). In this work, we aimed to determine if the combined use of both agents can exert a synergistic effect in the treatment of GvHD. For this purpose, we studied the effect of this combination both in vitro and in a GvHD mouse model. Our results show that ruxolitinib favors the ratio of thymic regulatory T cells to conventional T cells in culture, without affecting the suppressive capacity of these Treg. The combination of ruxolitinib with Treg showed a higher efficacy as compared to each single treatment alone in our GvHD mouse model in terms of GvHD incidence, severity and survival without hampering graft versus leukemia effect. This beneficial effect correlated with the detection in the bone marrow of recipient mice of the infused donor allogeneic Treg after the adoptive transfer., This work was supported by grants from Novartis and the Andalusian Regional Government (P18-RT-4047, PI-0052-2018). A.R.G. and J.A.P.S. are members of CIBERONC (CB16/12/00480) and TerCel (16/0011/0035). J.V. is member of CIBERNED (CB06/05/0027). A.R.G. is funded by a Grant of the University of Seville (US-1380874) co-funded by the European Regional Development Fund (ERDF). This study is partially funded by Novartis.

This multicenter phase I trial was designed to evaluate the safety and efficacy of bortezomib (Bz) as part of both the conditioning regimen and the graft-versus-host disease (GvHD) prophylaxis. Patients received fludarabine, melphalan and Bz (days −9 and −2). GVHD prophylaxis consisted of Bz (days +1, +4, and +7), sirolimus (Siro) from day −5 and tacrolimus (Tk) from −3 (except the first five patients that did not receive Tk). Twenty-five patients with poor prognostic multiple myeloma were included. Eleven out of the 19 patients had high-risk features. Out of the 21 patients evaluable at day +100, 14 were in CR (67%) and 7 (33%) in PR. Cumulative incidence (CI) of nonrelapse mortality at 1 year was 24%. CI of grades 2–4 and 3–4 acute GvHD was 35% and 10%, respectively; CI of chronic GvHD was 35% and 55% at 1 and 2 years, respectively. Overall and event free survival at 2 years were 64% and 31%, respectively. Bz as part of the conditioning regimen and in the combination with Siro/tacrolimus for GvHD prophylaxis is safe and effective allowing an optimal disease control early after transplant and reducing the risk of GvHD., This trial was supported by Janssen and Celgene and the Ministerio de Sanidad y Política Social, convocatoria de concesión de ayudas para el fomento de la investigación clínica independiente 2010 (EC10–289); this study was partially supported by two grants from the Ministry of Health CIBER ONC, code CB16/12/00480. TCV was supported by a grant from Ministerio de Sanidad y Política Social (CM10/00161).

On behalf of the Grupo Español de Trasplante Hematopoyético (GETH): et al., Graft-versus-host disease is the main cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. First-line treatment is based on the use of high doses of corticosteroids. Unfortunately, second-line treatment for both acute and chronic graft-versus-host disease, remains a challenge. Ruxolitinib has been shown as an effective and safe treatment option for these patients. Seventy-nine patients received ruxolitinib and were evaluated in this retrospective and multicenter study. Twenty-three patients received ruxolitinib for refractory acute graft-versus-host disease after a median of 3 (range 1–5) previous lines of therapy. Overall response rate was 69.5% (16/23) which was obtained after a median of 2 weeks of treatment, and 21.7% (5/23) reached complete remission. Fifty-six patients were evaluated for refractory chronic graft-versus-host disease. The median number of previous lines of therapy was 3 (range 1–10). Overall response rate was 57.1% (32/56) with 3.5% (2/56) obtaining complete remission after a median of 4 weeks. Tapering of corticosteroids was possible in both acute (17/23, 73%) and chronic graft-versus-host disease (32/56, 57.1%) groups. Overall survival was 47% (CI: 23–67%) at 6 months for patients with aGVHD (62 vs 28% in responders vs non-responders) and 81% (CI: 63–89%) at 1 year for patients with cGVHD (83 vs 76% in responders vs non-responders). Ruxolitinib in the real life setting is an effective and safe treatment option for GVHD, with an ORR of 69.5% and 57.1% for refractory acute and chronic graft-versus-host disease, respectively, in heavily pretreated patients., This study has been performed in collaboration with the Spanish Group of Hematopoietic Transplant and Cell Therapy (GETH). To the CIBERONC (CB16/12/00480).

Previous studies have shown the potential of microRNAs (miRNA) in the pathological process of stroke and functional recovery. Bone marrow mononuclear cell (BM-MNC) transplantation improves recovery in experimental models of ischemic stroke that might be related with miRNA modifications. However, its effect on circulating miRNA has not been described in patients with stroke. We aimed to evaluate the circulating levels of miRNAs after autologous BM-MNC transplantation in patients with stroke. We investigate the pattern of miRNA-133b and miRNA-34a expression in patients with ischemic stroke included in a multicenter randomized controlled phase IIb trial (http://www.clinicaltrials.gov; unique identifier: NCT02178657). Patients were randomized to 2 different doses of autologous intra-arterial BM-MNC injection (2×106/kg or 5×106/kg) or control group within the first 7 days after stroke onset. We evaluate plasma concentration of miRNA-113b and miRNA-34a at inclusion and 4, 7, and 90 days after treatment. Thirteen cases (8 with 2×106/kg BM-MNC dose and 5 with 5×106/kg dose) and 11 controls (BM-MNC non-treated) were consecutively included. Mean age was 64.1±12.3 with a mean National Institutes of Health Stroke Scale score at inclusion of 14.5. Basal levels of miRNA were similar in both groups. miR-34a-5p and miR-133b showed different expression patterns. There was a significant dose-dependent increase of miRNA-34a levels 4 days after BM-MNC injection (fold change 3.7, p, This work has been supported by the grants PI15/01197, PI18/01414 and RD16/0019/0015 (INVICTUS+) from the Spanish Ministry of Economy and Competitiveness, cofunded by ISCIII and FEDER funds; Mutua Madrileña grant. FMa is supported by a Rio Hortega contract (CM16/00015). Andalusian Initiative for Advanced Therapies (IATA) is the sponsor of the trial.

[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.

Chronic medical diseases, evaluated by several comorbidities indexes have been reported to influence on overall survival in patients with myelodysplastic syndrome (MDS). However, these studies included patients with lower and higher-risk disease by IPSS. This study retrospectively evaluates the role of comorbidities (evaluated by the MDS comorbidity index; MDS-CI) together with clinical parameters in a series of 232 patients with LR-MDS (defined as either an IPSS score of low/intermediate-1 and favorable cytogenetic categories by IPSS-R). In multivariate analysis, together with age >75 years, diabetes requiring therapy and hemoglobin

Somatic mutations in patients with myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (HSTC) are associated with adverse outcome, but the role of chronic graft-versus-host disease (cGVHD) in this subset of patients remains unknown. We analyzed bone marrow samples from 115 patients with MDS collected prior to HSCT using next-generation sequencing. Seventy-one patients (61%) had at least one mutated gene. We found that patients with a higher number of mutated genes (more than 2) had a worse outcome (2 years overall survival [OS] 54.8% vs. 31.1%, p = 0.035). The only two significant variables in the multivariate analysis for OS were TET2 mutations (p = 0.046) and the development of cGVHD, considered as a time-dependent variable (p, This work has been supported by Gerencia Regional de Salud de Castilla y León (GRS 1033/A/14), Instituto de Salud Carlos III - Fondo de investigación sanitaria (FIS PI17/01741), Instituto de Salud Carlos III - Contratos Río Hortega (CM17/0017), Instituto de Salud Carlos III & FEDER funds (PI16/01302), and CIBERONC Centro de Investigación Biomédica en Red Cáncer (CB16/12/00284).

The prognosis of patients with lower-risk myelodysplastic syndrome (LR-MDS) is very heterogeneous. In addition to survival estimates, identification of factors related to the probability of leukemic progression might help prognosis assessment.The present study is a retrospective analysis of 409 patients with primary LR-MDS. The probability of leukemic progression was estimated in the competing risk framework by the cumulative incidence method considering death without acute myeloid leukemia (AML) as a competing event.Sixty-six patients (16.1%) progressed to AML. The following covariates influenced the probability of leukemic progression in a multivariate competing risk regression model: intermediate karyotype versus diploid or chromosome 5 deletion, 5% to 9% bone marrow blast percentage, platelet count 50 × 10eAccording to these, a predictive model is proposed, which categorizes patients with different probability of leukemic progression (P .001). Validation of these results might help prognostic refinement of patients with LR-MDS.

Summary Background Continuation of empirical antimicrobial therapy (EAT) for febrile neutropenia in patients with haematological malignancies until neutrophil recovery could prolong the therapy unnecessarily. We aimed to establish whether EAT discontinuation driven by a clinical approach regardless of neutrophil recovery would optimise the duration of therapy. Methods We did an investigator-driven, superiority, open-label, randomised, controlled phase 4 clinical trial in six academic hospitals in Spain. Eligible patients were adults with haematological malignancies or haemopoietic stem-cell transplantation recipients, with high-risk febrile neutropenia without aetiological diagnosis. An independent, computer-generated randomisation sequence was used to randomly enrol patients (1:1) to the experimental or control group. Investigators were masked to assignment only before randomisation. EAT based on an antipseudomonal β-lactam drug as monotherapy (ceftazidime or cefepime, meropenem or imipenem, or piperacillin-tazobactam) or as combination therapy (with an aminoglycoside, fluoroquinolone, or glycopeptide) was started according to local protocols and following international guidelines and recommendations. For the experimental group, EAT was withdrawn after 72 h or more of apyrexia plus clinical recovery; for the control group, treatment was withdrawn when the neutrophil count was also 0·5 × 10 9 cells per L or higher. The primary efficacy endpoint was the number of EAT-free days. Primary analyses were done in the intention-to-treat population. Efficacy and safety analyses were done in the intention-to-treat population and the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01581333. Findings Between April 10, 2012, and May 31, 2016, 157 episodes among 709 patients assessed for eligibility were included in analyses. 78 patients were randomly assigned to the experimental group and 79 to the control group. The mean number of EAT-free days was significantly higher in the experimental group than in the control group (16·1 [SD 6·3] vs 13·6 [7·2], absolute difference −2·4 [95% CI −4·6 to −0·3]; p=0·026). 636 adverse events were reported (341 in the experimental group vs 295 in the control group; p=0·057) and most (580 [91%]; 323 in the experimental group vs 257 in the control group) were considered mild or moderate (grade 1–2). The most common adverse events in the experimental versus the control group were mucositis (28 [36%] of 78 patients vs 20 [25%] of 79 patients), diarrhoea (23 [29%] of 78 vs 24 [30%] of 79), and nausea and vomiting (20 [26%] of 78 vs 22 [28%] of 79). 56 severe adverse events were reported, 18 in the experimental group and 38 in the control group. One patient died in the experimental group (from hepatic veno-occlusive disease after an allogeneic haemopoietic stem-cell transplantation) and three died in the control group (one from multiorgan failure, one from invasive pulmonary aspergillosis, and one from a post-chemotherapy intestinal perforation). Interpretation In high-risk patients with haematological malignancies and febrile neutropenia, EAT can be discontinued after 72 h of apyrexia and clinical recovery irrespective of their neutrophil count. This clinical approach reduces unnecessary exposure to antimicrobials and it is safe. Funding Instituto de Salud Carlos III, Spanish Ministry of Economy (PI11/02674).

The use of PET in patients with marginal zone B cell lymphoma (MZL) is controversial because of variability of fluorodeoxyglucose (FDG) avidity. We analyzed 40 PET/CT in 25 consecutive patients to compare its performance with CT at staging and as a first-line response assessment. Sensitivity of PET/CT and CT was 96 and 76%. Mean standard uptake value was 6.1, 6.9 and 3.4 (p = 0.3) in nodal, extranodal and splenic subtypes, respectively. Of 17 patients (extranodal: n = 9; nodal: n = 6; splenic subtype: n = 2) with both imaging tests available at diagnosis, 8 (47%) had more involved areas with PET/CT than with CT, 75% of which were extranodal lesions. PET/CT resulted in upstaging of five patients although treatment of only two of them was changed. Responses of 15 patients with post-treatment PET/CT were the following: 9 negative and 6 positive of which 3 were isolated residual lesions. Progression was documented in two of these three patients. Response was also assessed by CT in 11 patients. Discrepancies were found in three: Two were in complete remission by CT while PET/CT detected localized residual disease; another patient was in partial remission by CT, whereas PET/CT showed only one positive lesion. Two of these three patients relapsed. Patients with negative post-treatment PET/CT did not relapse. With a median follow-up of 50 months (10–152 months), 3-year overall survival was 100 and 80% for patients with negative and positive post-treatment PET/CT (p = 0.2). Three-year disease-free survival was 86%; the negative predictive value (NPV) was 100%, and the positive predictive value (PPV) was 83.3%. Although a larger number of patients will be required to further confirm these data, we can conclude that PET/CT is a useful imaging tool for both staging and response assessment in patients with nodal and extranodal MZL as a result of its high sensitivity, NPV and PPV. Copyright © 2014 John Wiley & Sons, Ltd.

Background High-dose chemotherapy supported by autologous stem cell transplantation (ASCT) is an effective treatment for patients with lymphomas. However, failure to reach the minimum threshold of hematopoietic stem cells to proceed to ASCT may occur, even with the most effective strategies currently available. Study Design and Methods We report on 33 patients diagnosed with lymphoma who had at least one prior mobilization failure and received cytarabine at a dose of 400 mg/m2/day intravenously × 3 days plus granulocyte–colony-stimulating factor (G-CSF) 10 to 12 μg/kg/day as mobilization regimen. The median number of previous lines of chemotherapy was three. Results Thirty-two of 33 patients (96.8%) reached the target CD34+ cell dose (>2 × 106/kg). The mean (range) number of apheresis procedures was 1.8 (1-3) with 4.69 × 106 (1.5 × 106-6.8 × 106)/kg CD34+ cells obtained. All but one patient received chemomobilization in the outpatient department. Severe infections or treatment-related mortality were not observed. All patients that received ASCT (31/33) engrafted without requiring G-CSF during the posttransplant period. Conclusion This study shows that cytarabine at intermediate doses plus G-CSF in patients diagnosed with lymphoma who had a prior mobilization failure is a feasible and effective mobilization regimen.

Rationale No neuroprotective or neurorestorative therapies have been approved for ischemic stroke. Bone marrow mononuclear cell intra-arterial transplantation improves recovery in experimental models of ischemic stroke. Aims This trial aims to test safety and efficacy of intra-arterial injection of autologous bone marrow mononuclear cell in ischemic stroke patients. Design Multicenter, prospective, phase II, randomized, controlled (non-treated group as control), assessor-blinded clinical trial. Seventy-six stroke patients will be enrolled. Patients fulfilling clinical and radiological criteria (e.g. age between 18 and 80 years, middle cerebral artery ischemic stroke with a National Institutes of Health Stroke Scale score of 6–20 within one- to seven-days from stroke onset and no lacunar stroke) will be randomized to intervention or control group (1 : 1). Bone marrow harvest and intra-arterial injection of autologous bone marrow mononuclear cell will be done in the intervention group with two different doses (2 × 106/kg or 5 × 106/kg in 1 : 1 proportion). Patients will be stratified at randomization by National Institutes of Health Stroke Scale score. Patients will be followed up for two-years. Study outcomes The primary outcome is the proportion of patients with modified Rankin Scale scores of 0–2 at 180 days. Secondary outcomes include National Institutes of Health Stroke Scale and Barthel scores at six-months, infarct volume, mortality, and seizures. Discussion This is the first trial to explore efficacy of different doses of intra-arterial bone marrow mononuclear cell in moderate-to-severe acute ischemic stroke patients. The trial is registered as NCT02178657.

The role of hemopoietic stem cell transplantation (HSCT) is not well established in certain types of lymphoma, such as those with a high relapse risk or relapsing after initial therapy. New chemotherapeutic schemes and immunotherapy have improved survival of these patients. Nevertheless, there is not enough evidence regarding whether transplantation is the best therapeutic approach. Moreover, published data on long-term follow-up of high-risk lymphoma patients treated with HSCT are scarce. We analyzed 177 consecutive patients diagnosed with a high risk of relapse or with relapsed lymphoma who underwent HSCT after induction with standard chemotherapy in a tertiary academic center from 1989 to 2013. The median age was 40 years. Diagnoses were Hodgkin disease (n = 56), diffuse large B-cell lymphoma (n = 44), follicular lymphoma (n = 29), mantle cell lymphoma (n = 15), T-cell lymphoma (n = 18), and others (n = 15). Patients received either an autologous graft (n = 154) in first complete remission (1CR; n = 59) or more advanced stages (AS; n = 95), or an allogeneic graft (n = 23) in 1CR (n = 4) or AS (n = 19). In the autologous group, overall survival (OS) at 5 years was 57% and 75% in the periods 1989-2001 and 2002-2013, respectively (P = .05). Patients receiving an allogeneic graft presented an OS of 25% and 43% in the 2 periods. With a mean follow-up of 5 years (95% confidence interval 3.5-6.6), for patients receiving a transplant in 1CR, OS at 5 years was 80%, and for those receiving a transplant in AS it was 59% (P = .003). Nonrelapse mortality (NRM) at 5 years was 3.1% in the autologous group and 27.9% in the allogeneic group (P < .001). The main cause of NRM was infection (44%) in the whole cohort. All this leads to the conclusion that transplantation, as a therapeutic strategy, has shown a high long-term OS in this subgroup of patients with such a poor prognosis. OS improved over the years and reaching 1CR was a good prognostic feature. Infections were the main cause of NRM.

The use of PET in patients with marginal zone B cell lymphoma (MZL) is controversial because of variability of fluorodeoxyglucose (FDG) avidity. We analyzed 40 PET/CT in 25 consecutive patients to compare its performance with CT at staging and as a first-line response assessment. Sensitivity of PET/CT and CT was 96 and 76%. Mean standard uptake value was 6.1, 6.9 and 3.4 (p = 0.3) in nodal, extranodal and splenic subtypes, respectively. Of 17 patients (extranodal: n = 9; nodal: n = 6; splenic subtype: n = 2) with both imaging tests available at diagnosis, 8 (47%) had more involved areas with PET/CT than with CT, 75% of which were extranodal lesions. PET/CT resulted in upstaging of five patients although treatment of only two of them was changed. Responses of 15 patients with post-treatment PET/CT were the following: 9 negative and 6 positive of which 3 were isolated residual lesions. Progression was documented in two of these three patients. Response was also assessed by CT in 11 patients. Discrepancies were found in three: Two were in complete remission by CT while PET/CT detected localized residual disease; another patient was in partial remission by CT, whereas PET/CT showed only one positive lesion. Two of these three patients relapsed. Patients with negative post-treatment PET/CT did not relapse. With a median follow-up of 50 months (10-152 months), 3-year overall survival was 100 and 80% for patients with negative and positive post-treatment PET/CT (p = 0.2). Three-year disease-free survival was 86%; the negative predictive value (NPV) was 100%, and the positive predictive value (PPV) was 83.3%. Although a larger number of patients will be required to further confirm these data, we can conclude that PET/CT is a useful imaging tool for both staging and response assessment in patients with nodal and extranodal MZL as a result of its high sensitivity, NPV and PPV.

High-dose chemotherapy supported by autologous stem cell transplantation (ASCT) is an effective treatment for patients with lymphomas. However, failure to reach the minimum threshold of hematopoietic stem cells to proceed to ASCT may occur, even with the most effective strategies currently available.We report on 33 patients diagnosed with lymphoma who had at least one prior mobilization failure and received cytarabine at a dose of 400 mg/m(2) /day intravenously × 3 days plus granulocyte-colony-stimulating factor (G-CSF) 10 to 12 μg/kg/day as mobilization regimen. The median number of previous lines of chemotherapy was three.Thirty-two of 33 patients (96.8%) reached the target CD34+ cell dose (2 × 10(6) /kg). The mean (range) number of apheresis procedures was 1.8 (1-3) with 4.69 × 10(6) (1.5 × 10(6) -6.8 × 10(6) )/kg CD34+ cells obtained. All but one patient received chemomobilization in the outpatient department. Severe infections or treatment-related mortality were not observed. All patients that received ASCT (31/33) engrafted without requiring G-CSF during the posttransplant period.This study shows that cytarabine at intermediate doses plus G-CSF in patients diagnosed with lymphoma who had a prior mobilization failure is a feasible and effective mobilization regimen.

Introduction Mobilization regimens for hematopoietic stem cell transplantation have not undergone major changes except for the introduction of new drugs such as plerixafor. However, in patients receiving multiple lines of treatment, to obtain a suitable amount of hematopoietic progenitors (PH) is often difficult even with the addition of new drugs. We present our experience with a protocol of mobilization for poor mobilizer patients based on the use of cytarabine. Material and Methods From a total of 111 patients diagnosed with lymphoma who underwent autologous hematopoietic progenitors in our center from January 2005 to March 2013, 32 patients (35% of total) with previous mobilization failure, received cytarabine 400 mg/m2 /day x3 days + G-CSF (filgrastim or lenograstim) 10-16 mg /kg/day from day 7 to the end of collection. Cell blood cound and CD34 assays in peripheral blood were performed from day +11 postchemotherapy, and apheresis was started when CD34 > 10 x10e6/L. Results 30 patients had non-Hodgkin lymphoma (NHL) (13 diffuse large B-cell lymphoma, 7 mantle cell lymphoma, 5 follicular lymphoma, 2 MALT lymphoma, 1 angioimmunoblastic lymphoma, 2 cutaneous lymphomas) and 2 Hodgkin's lymphoma (HL). Median age was 49 years (range 27-67). Median number of treatment lines prior to mobilization was 3 (1-5). In all 30 patients with NHL, an adequate amount of CD34 + cells was obtained. Only one patient with HL, who had previously received 5 lines of chemotherapy, did not mobilize. The average time from the end of chemotherapy to start of apheresis was 13.7 days (12-20). The average number of CD34 + cells circulating the starting day of apheresis was 41/μL (11-109). The mean of apheresis performed was 1.8 (1-3) with an average amount of CD34 obtained of 4.69 x10e6/kg (1.5-6.8). All patients received outpatient treatment and only 2 required hospitalization: one for short-term neutropenic fever and another due to a limited cutaneous hemorrhage during the neutropenia phase. All patients were transplanted without incidence and successfully engrafted. None required G-CSF early postransplant. Conclusions Mobilization with intermediate-dose cytarabine has proven to be a cost-effective regimen in lymphoma patients with prior mobilization failure. Disclosures: No relevant conflicts of interest to declare.

Introduction Intensive chemotherapy (IC) followed by allogeneic stem cell transplantation (AlloSCT) is standard of care for intermediate and high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). However, morbidity and lack of response are common with IC. Retrospective data have shown similar outcomes with azacitidine (AZA) when compared to IC. Moreover, the combination of AZA with other epigenetic modifiers such as HDAC inhibitors seems to improve quality of responses. Aim Evaluate response, toxicity and feasibility of AlloSCT after AZA alone or the combination with valproic acid (VPA) as a bridge strategy in MDS and AML. Patients Nineteen consecutive patients (pts) receiving azacitidine alone (n=11) or in combination with valproic acid (VPA) (n=8) were analyzed. Median age of the cohort was 57 years (18-67). Diagnosis by WHO classification included: RAEB-2 (n=10/19; 52.6%), RAEB-1 (n=2; 10.5%), RCMD (n=2; 10.5%) and AML (n=5; 26.3%). Four out of 5 AML pts had bone marrow blast count >30% at diagnosis. In MDS patients, according to International Prognostic Scoring System (IPSS): 1 intermediate-1 (7%), 3 intermediate-2 (21.5%) and 10 high-risk (71.5%) and by IPSS-revised (IPSS-R): 1 intermediate (7%), 4 high (29%) and 9 very high (64%). Regarding karyotype, in MDS: 5 good (35.7%), 2 intermediate (14.3%), 6 poor (43%) and 1 insufficient metaphases (7%) whereas in AML Patients 1 intermediate (20%) and 4 adverse (80%). Eleven out of 19 pts (58%) received AZA as frontline therapy. The remaining 8 pts experienced disease relapse after intensive chemotherapy (IC) or had primary refractory AML, and subsequently received AZA plus VPA as salvage therapy. Median courses of previous IC were 2 (1-4). For pts receiving AZA/VPA, median bone marrow blast % and leukocyte were 31% (2-60) and 1.9x10e9/L (0.3-4.2) when therapy started. Most of these pts had refractory or relapsed disease (n=6/8; 75%) with 4 pts displaying poor karyotype. Treatment schema was AZA (75 mg/m2, 7d/4w) and VPA (20-25 mg/kg/d, 10 days). Results At analysis, 17/19 pts are evaluable for response. Median courses of AZA: 5 (2-53). Overall response (ORR) at 4 courses: 59% (CR=4/17; 23.5%, CRm=5/17; 29.5% and PR=1/17; 6%). For pts receiving AZA/VPA (Table 1, n=8), ORR: 83% (CR=1/6; 17% and CRm=4/6, 66%) in 6 evaluable pts. Median courses to response were 2. Among pts achieving CR/CRm/PR/SD at 4 courses (n=12), 2 pts lost response prior to AlloSCT. Most frequent toxicity was hematological (58% grade 3-4) with no treatment related mortality attributable to AZA/VPA. Eleven out of 19 pts (58%) received AlloSCT (matched related=5, matched unrelated=5, haploidentical=1). Causes for not proceeding to AlloSCT: Disease progression (n=4; 50%), infection (n=1; 12.5%), pending evaluation after 2 courses (n=2; 25%) and 1 pt (12.5%) scheduled for matched unrelated AlloSCT. Conditioning regimen: Reduced intensity (9/11) and myeloablative (2/11). Tacrolimus/sirolimus (50%) and cyclosporine/MMF (40%) as GVHD prophylaxis. With a median follow-up of 4 months after AlloSCT (1-26), only 1 pt developed acute GVHD, 1 had early relapse postransplant and 9 patients continue in CR at last follow up. Conclusions AZA alone and particularly the combination AZA/VPA prior to AlloSCT is a well-tolerated and highly effective schema even in pts with poor prognostic features and refractory to prior IC. Adequate selection of pts (leukocyte AML; Acute myeloid leukemia, RAEB-2; Refractory anemia with excess blasts type 2, RAEB-1; Refractory anemia with excess blasts type 1, IM; Insufficient metaphases, IC; Intensive chemotherapy, CR; Complete response, CRm; marrow CR, NA; Not assessable (pending bone marrow evaluation). 1Refractory to IC. 2Relapsed after IC. aBone marrow evaluation after 2 and 4 courses of therapy Disclosures: No relevant conflicts of interest to declare.

Introduction Factor XIII deficiency (FXIII) is an uncommon coagulation disorder. Congenital FXIII deficiency, generally due to mutations in F13A1 gene, presents with early life- threating hemorrhages in homozygotes. Acquired deficiency, a more rare state, has been associated with certain drugs and inhibitors against FXIII. Materials and methods We retrospectively analyzed 47 patients (male:female 1:1.3). Study criteria were unexplained hemorrhage, mainly after surgery, or spontaneous intracranial bleeding at perinatal period and no relevant findings in conventional haemostasia assays, from 01/01/2010 to 15/07/2013. FXIII measure was performed by a functional method. Results 20 out of 47 patients (42.5%) other abnormalities that might contribute to bleeding were detected: 13 had primary haemostasis disorders and 7 had low levels of a coagulation factor different from FXIII. In 10 patients, FXIII deficiency was observed: 4 congenital and 6 acquired. In all acquired deficiencies, the presence of an inhibitor was discarded. Patients with congenital FXIII deficiency, had mucocutaneous bleeding in 75% of cases and hemorrhage after surgery in 50%. However, there was no intracranial hemorrhage. In acquired deficiency (median FXIII 44.5 U/dl at first diagnostic work up), mucocutaneous bleeding appeared in 40% patients and postoperative and intracranial hemorrhage in 100%. In 8/ 10 patients FXIII concentrate was administered, achieving bleeding control in 7. In 3 cases of congenital deficiency, prophylactic substitutive therapy was started enabling a cessation of new bleeding episodes, except for a posttraumatic muscle hematoma; median FXIII levels reached 6.8 U/ dL. 2 patients with acquired deficiency died of non-hemorrhagic complications, 3 patients developed spontaneous remission of the deficiency in a median time of 2 months and 1 is still receiving substitutive therapy. Conclusions In congenital deficiency, maintenance of FXIII through levels in the range of 5-10% is enough to avoid bleeding manifestations. The acquired deficiencies have at least the same frequency as congenital, develop hemorrhage episodes at higher levels of factor and respond to therapy in a thrifty way. For those reasons, tests for FXIII are essential for diagnosis in high index clinical suspicious cases, such as unexplained bleeding. Disclosures: No relevant conflicts of interest to declare.

Several drug-metabolizing enzymes, preferentially expressed in the liver, have the potential to act as minor histocompatibility antigens. In the present study, we analyzed the impact of glutathione S-transferase T1 (GSTT1), glutathione S-transferase M1, glutathione S-transferase P1, and UDP glucuronosyl transferase 2B17 (UGT2B17) disparities on the outcome of 125 patients undergoing allogeneic hematopoietic stem cell transplantation. Grades 2 to 4 acute graft-versus-host disease (aGVHD) developed in 56.2% versus 73.3% of GSTT1-matched versus mismatched patients (P = .048). Remarkably, 8.6% GSTT1-matched patients developed grades 2 to 4 liver aGVHD, compared with 36.8% among GSTT1-mismatched recipients (P

Frequency of additional chromosomal abnormalities in chronic myeloid leukemia (CML) is estimated to be 7% in chronic phase and increases to 40–70% in advanced disease. Progression of CML from chronic phase to accelerated phase or blast crisis is often associated with secondary chromosomal aberrations. We report an exceptional case of CML as debut in lymphoblastic blast crisis and a subsequent progression in myeloblastic blast crisis with rare cytogenetic abnormalities.