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Background The incorporation of genetic variables into risk scores for predicting venous thromboembolic events (VTE) could improve their capacity to identify those patients for whom thromboprophylaxis would be most beneficial. Proof‐of‐concept of this is provided by the TiC‐ONCO score for predicting the risk of VTE in patients with solid tumours. Our aim was to develop a similarly improved tool—the TiC‐LYMPHO score—for predicting VTE in patients with lymphoma. Methods In a retrospective observational study of 208 patients with lymphoma, 31 (14.9%) were found to have experienced an episode of VTE either at the time of diagnosis or over the next 6 months. Clinical variables associated with VTE, determined via logistic regression analysis, plus the same genetic variables included in the TiC‐ONCO score, were used to build the TiC‐LYMPHO score algorithm. The sensitivity, specificity, predictive values and AUC of the TiC‐LYMPHO, the Khorana and ThroLy scores were compared in the same population. Results The TiC‐LYMPHO score showed a significantly higher AUC, sensitivity and NPV (0.783, 95.35% and 97.98% respectively) than the other scores. The ThroLy score showed a significantly higher specificity (96.43% vs. 54.49%; p, This is a single‐centre observational study that analyses the utility of combining genetic and clinical variables in a thromboembolism risk score in patients with lymphoma. The TiC‐LYMPHO score showed a significantly higher AUC, sensitivity and NPV (0.783%, 95.35% and 97.98%, respectively) than the other scores. These results show that by incorporating genetic and clinical data into VTE risk assessment, the TiC‐LYMPHO score can categorize patients with lymphoma better in terms of their risk of VTE and allow individualized thromboprophylaxis to be prescribed.

Background “Hospital-at-home” (HAH) programs have been shown to optimize resource utilization, shorten hospitalization and prevent nosocomial infection. Methods We retrospectively analysed data regarding implementation of an HAH unit for caring patients with hematological malignancies in our center, during the COVID-19 pandemic. Results Between January and November 2020, 105 patients were treated in the HAH unit for a total of 204 episodes. Nine patients with multiple myeloma (MM) received autologous HSCT (auto-HSCT). Three patients with acute myeloid leukemia (AML) received consolidation therapy, 32 patients underwent clinical and analytical monitoring, 20 were transplant recipients early discharged (5 auto-HSCT and 15 allo-HSCT) and 2 had received CART cells therapy. Azacitidine, bortezomib and carfilzomib were administered at home to 54 patients with AML, myelodysplastic syndrome (MDS) or MM. A median of 17 (IQR 13–19) days of admission per patient and a total of 239 visits to the Hematology day-care hospital were avoided. Overall, 28 patients (14% of all episodes) needed admission to the hospital, 4 of them due to COVID-19. Conclusions Implementation of a Hematology HAH unit was feasible and safe, and provided thorough advanced care to a high-risk population. Advanced care-at-home strategies can be crucial during times of COVID-19 to minimize treatment interruptions and reduce the risk of cross-infections.

Early descriptions of COVID-19 associated coagulopathy identified it as a disseminated intravascular coagulation (DIC). However, recent studies have highlighted the potential role of endothelial cell injury in its pathogenesis, and other possible underlying mechanisms are being explored. This study aimed to analyse the coagulation parameters of critically and noncritically ill patients with COVID-19 bilateral pneumonia, determine if coagulation factors consumption occurs and explore other potential mechanisms of COVID-19 coagulopathy. Critically and noncritically ill patients with a diagnosis of COVID-19 bilateral pneumonia were recruited. For each patient, we performed basic coagulation tests, quantification of coagulation factors and physiological inhibitor proteins, an evaluation of the fibrinolytic system and determination of von Willebrand Factor (vWF) and ADAMTS13. Laboratory data were compared with clinical data and outcomes. The study involved 62 patients (31 ICU, 31 non-ICU). The coagulation parameters assessment demonstrated normal median prothrombin time (PT), international normalized ratio (INR) and activated partial thromboplastin time (APTT) in our cohort and all coagulation factors were within normal range. PAI-1 median levels were elevated (median 52.6 ng/ml; IQR 37.2-85.7), as well as vWF activity (median 216%; IQR 196-439) and antigen (median 174%; IQR 153.5-174.1). A mild reduction of ADAMTS13 was observed in critically ill patients and nonsurvivors. We demonstrated an inverse correlation between ADAMTS13 levels and inflammatory markers, D-dimer and SOFA score in our cohort. Elevated vWF and PAI-1 levels, and a mild reduction of ADAMTS13 in the most severe patients, suggest that COVID-19 coagulopathy is an endotheliopathy that has shared features with thrombotic microangiopathy.

Cytokine release syndrome (CRS) is a systemic inflammatory response with aberrant immune activation and immune hyperstimulation, that leads to increased cytokine levels and inflammation. CRS has been described after antibody and cellular-based therapies. The use of posttransplant cyclophosphamide (PTCy) as graft-vs-host disease (GVHD) prophylaxis in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has led to the extension of allogeneic HSCT to patients without HLA-identical donors. Furthermore, PTCy has also been introduced in matched and unrelated donor HSCT. However, description of incidence and clinical impact of CRS on outcomes in these patients is scarce. We retrospectively analyzed 107 consecutive haplo-HSCT and 39 HLA-identical HSCT with PTCy from 2010 to 2017 in our institution. We used published CRS criteria to identify 76% and 14% of patients who developed CRS after haplo-HSCT and HLA-identical HSCT, respectively. Most patients presented CRS grades 1 and 2. Only one patient from the whole series presented grade 3 CRS and required tocilizumab therapy. The use of peripheral blood stem cells (PBSC), as well as total nucleated cells infused were associated with an increased risk of CRS. Patients who presented CRS developed grade II-IV acute GVHD more frequently than those who did not (60% vs 28.6% respectively, P = .012). The development of CRS was not significantly associated with nonrelapse mortality or overall survival. CRS is a frequent complication after PBSC haploidentical T-repleted HSCT, but significantly less frequent after HLA-identical HSCT. Most cases are mild. Prompt identification allows adequate management of severe forms.

Extracorporeal photopheresis (ECP) is an established treatment strategy in steroid-refractory graft-versus-host disease (GVHD). This study's main objective was to analyze the clinical response and impact of ECP therapy in steroid dose reduction. A retrospective observational series of 113 patients from 7 transplantation centers was analyzed. Sixty-five patients (58%) had acute GVHD (aGVHD), and 48 (42%) had chronic GVHD (cGVHD). All ECP procedures were performed with the off-line system. The median number of procedures until achievement of initial response was 3 for both patients with aGVHD and those with cGVHD. ECP was the second-line therapy in 48% of the aGVHD cases and in 50% of the cGVHD cases. 71% of the cases of aGVHD were grade III-IV, and 69% of the cases of cGVHD were severe. The overall response rate on day 28 was 53% (complete response [CR] rate, 45%) in the patients with aGVHD and 67% (CR, 23%) in those with cGVHD. Skin was the most frequently involved organ, with a response rate of 58% (CR, 49%) in the patients with aGVHD and 69% (CR 29%) in those with cGVHD. At the end of ECP treatment, 60% of patients treated for aGVHD who responded were able to stop steroid therapy, with a median dose reduction of 100%. Significant differences in overall survival were observed for patients responding to ECP with aGVHD (hazard ratio [HR], 4.3; P.001) and with cGVHD (HR, 4.8; P = .003). Our data indicate that ECP is a valid therapeutic alternative in patients with steroid-refractory aGVHD and cGVHD, permitting significant steroid dosage reductions.

Although next-generation sequencing (NGS) data on lymphomas require further validation before being implemented in daily practice, the clinical application of NGS can be considered right around the corner. The aim of our study was to validate an NGS lymphoid panel for tissue and liquid biopsy with the most common types of non-Hodgkin’s lymphoma [follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL)]. In this series, 372 somatic alterations were detected in 93.6% (44/47) of the patients through tissue biopsy. In FL, we identified 93 somatic alterations, with a median of 7.4 mutations per sample. In DLBCL, we detected 279 somatic variants with a median of 8.6 mutations (range 0–35). In 92% (24/26) of the cases, we were able to detect some variant in the circulating tumor DNA. We detected a total of 386 variants; 63.7% were detected in both types of samples, 13.2% were detected only in the circulating tumor DNA, and 23% were detected only in the tissue biopsy. We found a correlation between the number of circulating tumor DNA mutations, advanced stage, and bulky disease. The genetic alterations detected in this panel were consistent with those previously described at diagnosis. The liquid biopsy sample is therefore a complementary tool that can provide new genetic information, even in cases where a solid biopsy cannot be performed or an insufficient sample was obtained. In summary, we describe and analyze in this study the findings and difficulties encountered when incorporating liquid biopsy into clinical practice in non-Hodgkin’s lymphoma at diagnosis.

Conventional cytogenetics are the gold standard for the identification of chromosomal alterations recurrent in myeloid neoplasms. Some next-generation sequencing (NGS) panels are designed for the detection of copy number variations (CNV) or translocations, however, their use is far from being widespread. Here we report on the results of a commercial panel including frequent mutations, CNVs and translocations in myeloid neoplasms. Frequent chromosomal alterations were analyzed by NGS in 135 patients with myeloid neoplasms and three with acute lymphoblastic leukemia. NGS analysis was performed using the enrichment-capture Myeloid Neoplasm-GeneSGKit (Sistemas Genómicos, Spain) gene panel including 35 genes for mutational analysis and frequent CNVs and translocations. NGS results were validated with cytogenetics and/or MLPA when possible. A total of 66 frequent alterations included in NGS panel were detected, 48 of them detected by NGS and cytogenetics. Ten of them were observed only by cytogenetics (mainly trisomy 8), and another eight only by NGS (mainly deletion of 12p). Aside from this, 38 secondary CNVs were detected in any of the genes included mainly for mutational analysis. NGS represents a reliable complementary source of information for the analysis of CNVs and translocations. Moreover, NGS could be a useful tool for the detection of alterations not observed by conventional cytogenetics.

Posttransplant cyclophosphamide (PTCy) effectively prevents graft-versus-host disease (GVHD) after HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PTCy in HLA-identical HSCT is less explored. We conducted a retrospective study of 107 consecutive patients undergoing an HLA-identical sibling (10/10) HSCT in 2 centers in Spain, 50 with GVHD prophylaxis with methotrexate–cyclosporin A (MTX-CsA) and 57 using a PTCy-based regimen with additional immunosuppression. Graft source was unmanipulated mobilized peripheral blood stem cells (PBSC) in most patients (97 patients, 91%). Cumulative incidences of grade II to IV and III to IV acute GVHD at 100 days were lower in the PTCy group (22.6% vs 52.2%, P = .0015; 8.8% vs 24.4%, P = .016), without statistically significant differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (16.7% vs 26%, P = .306). At 2 years, no statistically significant differences were observed in OS (78% vs 56%, P = .088), EFS (62.5% vs 48%, P = .054), relapse (28% vs 27%, P = .47), and NRM (8.8% vs 24%, P = .054). The composite endpoint of GVHD and relapse-free survival (GRFS) was favorable for the PTCy group (24% vs 48%, P = .011), PTCy being the sole independent factor identified in the multivariate analysis for this endpoint. In this study, PTCy combination with additional immunosuppression using mostly PBSCs grafts showed a reduction of acute GVHD rate and an impact on GRFS, with safety results comparable with those obtained with MTX-CsA. Further prospective studies are needed to confirm these observations..

Invasive fungal infections are one of the main infectious complications in allogeneic stem cell transplantation (SCT). Triazoles (voriconazole, posaconazole) are the main prophylactic and therapeutic options for the treatment of invasive aspergillosis. However, pharmacological interactions and hepatotoxicity limit its use. Isavuconazole (ISV) is a recently approved azole with a promising interaction and safety profile. We present a case with invasive aspergillosis in the post-allogeneic SCT setting in a critically ill patient with severe multiorgan failure due to veno-occlusive disease. The patient was treated with ISV and B amphotericin during severe kidney and liver failure and multiple immunosuppressants, without significant drug-related toxicity and with favorable outcome. The interaction and safety profile of ISV is discussed along the reported experience. ISV can be an effective salvage therapy even in complex clinical situations with multiple potential interactions.

The presence of IKZF1 gene mutations is associated with poor prognosis of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The goal of this retrospective study was to evaluate outcome of allogeneic hematopoietic cell transplantation (allo-HCT) in this population. Ninety-five patients transplanted in first (n = 75) or second (n = 20) complete remission (CR) from either HLA-matched sibling (n = 32), unrelated (n = 47) or haploidentical (n = 16) donor were included in the analysis. The probabilities of the overall survival (OS) and leukemia-free survival (LFS) at 2 years were 55% and 47%, respectively. Relapse incidence (RI) was 32% while non-relapse mortality (NRM), 21%. The incidence of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD was 34% and 30%, respectively. The probability of GVHD and relapse-free survival (GRFS) was 35%. In a multivariate analysis positive minimal residual disease (MRD) status was associated with decreased chance of LFS (HR = 3.15, p = 0.004) and OS (HR = 2.37, p = 0.049) as well as increased risk of relapse (HR = 5.87, p = 0.003). Disease stage (CR2 vs. CR1) affected all, LFS, OS, GRFS, RI, and NRM. Results of allo-HCT for patients with BCP-ALL and IKZF1 mutations are generally improving, however, individuals with detectable MRD have poor prognosis and require additional intervention prior to transplantation.

Patients with cancer are poorly represented in coronavirus disease 2019 (COVID-19) series, and heterogeneous series concerning hematology patients have been published. This study aimed to analyze the impact of COVID-19 in patients with lymphoma. We present a multicenter retrospective study from 19 centers in Madrid, Spain, evaluating risk factors for mortality in adult patients with COVID-19 and lymphoma. About 177 patients (55.9% male) were included with a median follow-up of 27 days and a median age of 70 years. At the time of COVID-19 diagnosis, 49.7% of patients were on active treatment. The overall mortality rate was 34.5%. Age >70 years, confusion, urea concentration, respiratory rate, blood pressure, and age >65 score ≥2, heart disease, and chronic kidney disease were associated with higher mortality risk (P < 0.05). Active disease significantly increased the risk of death (hazard ratio, 2.43; 95% confidence interval, 1.23-4.77; P = 0.01). However, active treatment did not modify mortality risk and no differences were found between the different therapeutic regimens. The persistence of severe acute respiratory syndrome coronavirus 2-positive polymerase chain reaction after week 6 was significantly associated with mortality (54.5% versus 1.4%; P < 0.001). We confirm an increased mortality compared with the general population. In view of our results, any interruption or delay in the start of treatment should be questioned given that active treatment has not been demonstrated to increase mortality risk and that achieving disease remission could lead to better outcomes.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has shown favorable results in the treatment of hematological malignancies. Despite the use of post-transplant cyclophosphamide (PTCy), graft versus host disease (GVHD) remains as one of the main complications in this setting. Since the skin appears affected in up to 80% of cases of acute GVHD (aGVHD), its prognosis and diagnosis are essential for the correct management of these patients. Plasma concentration of elafin, an elastase inhibitor produced by keratinocytes, has been described elevated at the diagnosis of skin GVHD, correlated with the grade of GVHD, and associated with an increased risk of death. In this study we explored elafin plasma levels in the largest series reported of T cell–replete haplo-HSCT with PTCy. Plasma samples drawn from 87 patients at days +15 and +30 were analyzed (“discovery cohort”). Elafin levels at days +15 were no associated with chronic GVHD, non-relapse mortality, relapse, therapy-resistant GVHD, or overall survival. In our series, elafin levels at day +30 were not associated with post-transplant complications. On the other hand, elafin plasma levels at day +15 were higher in patients with severe skin aGVHD (21,313 vs.14,974 pg/ml; p = 0.01). Of note, patients with higher elafin plasma levels at day +15 presented a higher incidence of stage III-IV skin aGVHD (HR = 18.9; p < 0.001). These results were confirmed (HR = 20.6; p < 0.001) in an independent group of patients (n = 62), i.e. the “validation cohort.” These data suggest that measurement of elafin in patients undergoing haplo-HSCT with PTCy might be useful for an early identification of those patients who are at higher risk of suffering severe skin aGVHD and thus, improve their treatment and prognosis.

Background Patients with cancer have been shown to have a higher risk of clinical severity and mortality compared to non-cancer patients with COVID-19. Patients with hematologic malignancies typically are known to have higher levels of immunosuppression and may develop more severe respiratory viral infections than patients with solid tumors. Data on COVID-19 in patients with hematologic malignancies are limited. Here we characterize disease severity and mortality and evaluate potential prognostic factors for mortality. Methods In this population-based registry study, we collected de-identified data on clinical characteristics, treatment and outcomes in adult patients with hematologic malignancies and confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection within the Madrid region of Spain. Our case series included all patients admitted to 22 regional health service hospitals and 5 private healthcare centers between February 28 and May 25, 2020. The primary study outcome was all-cause mortality. We assessed the association between mortality and potential prognostic factors using Cox regression analyses adjusted for age, sex, comorbidities, hematologic malignancy and recent active cancer therapy. Results Of 833 patients reported, 697 were included in the analyses. Median age was 72 years (IQR 60–79), 413 (60%) patients were male and 479 (69%) and 218 (31%) had lymphoid and myeloid malignancies, respectively. Clinical severity of COVID-19 was severe/critical in 429 (62%) patients. At data cutoff, 230 (33%) patients had died. Age ≥ 60 years (hazard ratios 3.17–10.1 vs 2 comorbidities (1.41 vs ≤ 2), acute myeloid leukemia (2.22 vs non-Hodgkin lymphoma) and active antineoplastic treatment with monoclonal antibodies (2·02) were associated with increased mortality; conventional chemotherapy showed borderline significance (1.50 vs no active therapy). Conversely, Ph-negative myeloproliferative neoplasms (0.33) and active treatment with hypomethylating agents (0.47) were associated with lower mortality. Overall, 574 (82%) patients received antiviral therapy. Mortality with severe/critical COVID-19 was higher with no therapy vs any antiviral combination therapy (2.20). Conclusions In this series of patients with hematologic malignancies and COVID-19, mortality was associated with higher age, more comorbidities, type of hematological malignancy and type of antineoplastic therapy. Further studies and long-term follow-up are required to validate these criteria for risk stratification.

Introduction Methotrexate intoxication following high-dose methotrexate-induced acute kidney injury is a life-threatening complication. Glucarpidase can quickly reduce extracellular methotrexate to safe levels, but the effectiveness and safety of its use in different episodes of nephrotoxicity remain an unknown area. Case Report A 30-year-old male diagnosed with acute lymphoblastic T-cell lymphoma received methotrexate 5 g/m2 intravenous (IV) as part of the first consolidation cycle. On Consolidation 3, he restarted methotrexate at a dose of 3 g/m2 IV showing slow methotrexate elimination, associated myelosuppression, and hepatic toxicity. Glucarpidase was administered (total dose of 2000 International Units (IU)). No adverse events were observed, and his renal function returned to normal. One hundred and six days later, he was diagnosed with leptomeningeal and cerebellar relapse and treatment with methotrexate 3,5 g/m2 IV day 1 and cytosine arabinoside (Ara-C) 2 g/m2 IV twice per day days 1, 3, and 5 was started. At 36 h from methotrexate infusion, serum creatinine increased up to 1.89 mg/dL and methotrexate concentration was 100 µmol/L. Management and Outcome: Ara-C was suspended, and a second administration of glucarpidase (2000 IU) was dispensed. No adverse events were noticed, methotrexate levels decreased and renal function progressively improved, recovering completely three weeks later. Discussion The effectiveness and safety of the use of glucarpidase in different episodes of nephrotoxicity remain an unknown area, and the rate and consequences of antiglucarpidase antibody formation remain poorly understood. This case report is, to our knowledge, the first case of a second administration of glucarpidase in a different cycle of high-dose methotrexate in an adult patient.

Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT), with high mortality rates despite early medical treatment, including the use of defibrotide (DF). We retrospectively analyzed 185 unmanipulated haploidentical (haplo-) HSCT with post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis performed consecutively between 2011 and June 2019 in a single center. Seventeen patients (9.2%) were diagnosed with VOD/SOS. Based on revised European Society for Blood and Marrow Transplantation severity criteria, the VOD/SOS cases were classified as mild in 2 patients (11.7%), moderate in 2 (11.7%), severe in 2 (11.7%), and very severe in 11 (64.9%). Thirteen patients (76%) were treated with DF, including all patients with severe or very severe VOD/SOS, except 1 patient with CNS hemorrhage. Sixteen patients (94%) were alive at day +100 after HSCT. Seven patients (41%) with very severe VOD/SOS were treated with transjugular intrahepatic portosystemic shunt (TIPS) owing to rapid clinical or analytical deterioration or refractory hepatorenal syndrome despite medical treatment, including DF. TIPS insertion was performed at a median time since VOD/SOS diagnosis of 4 days (range, 1 to 28 days) without technical complications in any case. The median hepatic venous pressure gradient before and after TIPS treatment was 24 mmHg (range, 14 to 29 mmHg) and 7 mmHg (range, 2 to 11 mmHg), respectively, with a median drop of 16 mmHg (range, 9 to 19 mmHg). Following TIPS insertion, all patients showed clinical improvement with hepatomegaly, ascites, and renal failure resolution, and all showed analytical improvement with reduced alanine aminotransferase (ALT), creatinine, and international normalized ratio values, except for patient 2, whose indication for TIPS was refractory hepatorenal syndrome with a normal ALT level. The 6 patients who had initiated DF before TIPS insertion completed 21 days of treatment. All patients met the criteria for complete remission (CR) at a median of 8 days after TIPS insertion (range, 2 to 82 days). The 100-day overall survival was 100%. For patients with rapid progressive VOD/SOS, early TIPS insertion allowed completion of DF therapy. The use of TIPS together with DF resulted in CR and no associated complications with no VOD/SOS-associated mortality despite high severity. In our experience, timely and individualized use of TIPS significantly improves outcomes of very severe VOD/SOS after haplo-HSCT. Therefore, TIPS should be promptly considered in rapidly progressive cases.

Haploidentical stem cell transplantation (haploSCT) is becoming a major transplant modality for lymphoma. To assess the effects of donor characteristics, stem cell source and conditioning on outcomes, we identified 474 adults with Hodgkin (HL; 240), peripheral T-cell (PTCL; 88), diffuse large B-cell (77), mantle cell (40) or follicular lymphoma (FL; 29), who received haploSCT with post-transplant cyclophosphamide. Median follow-up of alive patients was 32 months. On multivariate analysis, acute graft-versus-host disease (GVHD) grade 2-4 was lower with offspring donors or bone marrow cells, whereas extensive chronic GVHD was higher in partial response at haploSCT or when using sisters, haploidentical donors beyond first degree, or female donors in male patients. Progression-free survival (PFS) was better for FL, HL and PTCL, whereas overall survival (OS) was better for HL and PTCL. Complete remission at haploSCT improved PFS and OS whereas these were negatively affected by cytomegalovirus donor positive/recipient positive status. No other donor characteristics (age, gender, human leucocyte antigen mismatch, ABO incompatibility) affected PFS or OS except use of haploidentical donors beyond first degree, which negatively affected OS. PFS and OS are mostly influenced by disease status and lymphoma subtype, supporting the use of any first degree haploidentical family member as a donor.

Introduction: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are the two autologous anti-CD19 chimeric antigen receptors T cells commercially approved in Europe for relapsed/refractory (R/R) DLBCL. We performed a retrospective study to evaluate patients characteristics, efficacy and safety for axi-cel and tisa-cel in a large cohort of patients within the GETH-TC (Spanish Group of Stem Transplantation and Cell Therapy)-GELTAMO (Spanish Group of Lymphoma and Autologous Stem Cell Transplantation). Methods: Ten Spanish centers contributed data. Data were collected retrospectively from consecutive patients with DLBCL in whom apheresis was performed for axi-cel or tisa-cel treatment. CRS and ICANS were graded with the ASTCT consensus criteria. Response was assessed according to the Lugano criteria. Patients included had at least 30 days of follow-up. Results: A total of 268 patients with R/R DLBCL underwent apheresis for axi-cel (n=123) and tisacel (n=145) from Nov-2018 to May-2021, of which 232 (86%) received CART-cell infusion (n=110, 89% and n=122, 84%, respectively). Reasons for not undergoing infusion were progression in 10 cases, tumor lysis syndrome in 1, infection in 1, and CR after bridging therapy in 1 for the axi-cel cohort, and progression in 21 (4 after manufacture failure), psychiatric disorder in 1, and post-apheresis cerebral hemorrhage in 1 case for the tisa-cel cohort. Time between apheresis and infusion was 41 days (IQR 40-56) and 49 days (IQR 46-62) (p=0.006), respectively. Characteristics at baseline, apheresis and at lymphodepletion are summarized in Tables 1 and 2. Median age was 60 (range 19-79), 61% of patients were male, most of them treated for DLBCL NOS (66%). There were no significant differences between patients intended to be treated with axi-cel and tisa-cel. 82% of the infused patients received bridging therapy. At apheresis and at lymphodepletion ECOG performance status score was 0-1 in 93% and 91%, and 7 and 32 patients were in response, respectively. The overall response rates (ORRs) at 1 month and 3 months were 65% and 56%, respectively, with 34% and 45% achieving a complete response (CR), respectively. In the intention-to-treat analysis, with a median follow-up of 9 months (IQR 5-15), EFS and OS at 9 months was 44% (95%CI 38-51)(Figure 1) and 59% (95%CI 53-66) with a median EFS and OS of 6 months and 11 months, respectively. At lymphodepletion, characteristics of infused patients and disease were not significantly different between axi-cel and tisa-cel cohorts. Rates of CRS, CRS grade 3-4, ICANS, ICANS grade 3-4 were 89% and 71% (p=0.001), 10% and 7% (p=0.34), 42% and 16% (p=0.001), 20% and 4% (p=0.001) for the axi-cel and tisa-cel cohorts, respectively. ICU admission was needed in 25% and 15% of patients (p=0.06), respectively. Non-relapse mortality at days 100 were 2.5% and 1.4%, and at day 180, 5.4% and 2.2% (p=0.08) for the axi-cel and tisa-cel groups, respectively. With a median follow-up of 8 months for patients who received infusion with axi-cel and 12 months for patients infused with tisa-cel, EFS and OS at 12 months were 48% and 33% (p=0.33), and 53% and 50% (p=0.27), respectively, with a median EFS of 11 and 6 months and a median OS of 13 and 12 months, respectively. In the multivariate analysis, the only factor associated with poor PFS was having ECOG-PS ≥2 at lymphodepletion (HR13, p=0.03). No factors were identified as associated independently to OS. Factors associated to CRS grade 3-4 were IPI score 4-5 at lymphodepletion (OR 1.4, p=0.03) and ECOG-PS ≥2 at apheresis (OR 1.5, p=0.03). For ICANS grade 3-4, factors associated were the use of axi-cel (OR 8, p=0.04) and diagnosis of HG double/triple hit lymphoma (OR 9, p=0.022). Conclusions:This multicentric analysis describes one of the largest real-life cohorts of patients treated with axi-cel and tisa-cel for R/R aggressive B cell lymphoma in Europe. Results are comparable to those from the pivotal studies and other large real-life experiences. Up to now, patients included for one or other product in Spain do not differ significantly in terms of baseline characteristics, and within this setting, results are comparable between both products in terms of efficacy. The use of axi-cel was associated to higher rates of CRS and especially, severe forms of ICANS. However, mortality associated to toxicity were low and not significantly different between both cohorts. Figure 1 Figure 1. Disclosures Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Reguera: Janssen, Kite/Gilead, Novartis: Speakers Bureau; BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees. Lopez Corral: Gilead, Novartis: Consultancy, Honoraria. Guerreiro: Novartis, Gilead: Consultancy, Honoraria. Caballero: Novartis, Gilead: Honoraria. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Sanchez: Janssen, Jazz Pharmaceuticals, Gilead, Novartis, Amgen: Consultancy. Sancho: Roche, Janssen, Celgene-BMS, Gilead, Novartis, Takeda: Honoraria, Speakers Bureau; Roche, Janssen, Celgene-BMS, Gilead, Novartis, Incyte, Beigene: Speakers Bureau. Bastos-Oreiro: Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS-Celgene: Honoraria, Speakers Bureau; Gilead: Honoraria; Kite: Speakers Bureau. Oarbeascoa: Gilead: Honoraria, Speakers Bureau. Mussetti: Gilead: Other: Unspecified, Research Funding; Novartis: Honoraria, Other: Unspecified; Takeda: Honoraria. Bailen: Gilead, Pfizer: Speakers Bureau. Martin Garcia-Sancho: Takeda: Honoraria; Novartis: Consultancy; Incyte: Consultancy; Celgene/BMS: Consultancy; Celgene: Honoraria, Other: travel; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Janssen: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Gilead: Consultancy, Honoraria; Morphosys: Consultancy; Kyowa Kirin: Consultancy; Clinigen: Consultancy; Eusa Pharma: Consultancy; Kern Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding.

BACKGROUND The revised genetic risk classification established by the European Leukemia Net (ELN) in 2017 stratifies patients diagnosed with acute myeloid leukemia (AML) into 3 prognostic categories (favourable, intermediate, and adverse) based on cytogenetic and molecular characteristics.The ELN classification is widely accepted in AML patients despite the fact that validation studies were performed in participants who received exclusively first-line treatment with intensive chemotherapy. For this reason, it is not well established whether the ELN risk groups are applicable to patients on non-intensive first-line treatment. OBJECTIVES - To describe and compare baseline characteristics at diagnosis between patients with AML treated with intensive and non-intensive therapy. - To assess whether the ELN prognostic classification is applicable in these subgroups of patients. METHODS We retrospectively analysed patients with newly diagnosed AML admitted to our center between 2007 and 2020. Patients with acute promyelocytic leukemia (M3), patients younger than 18 years old and/or patients who received exclusively supportive treatment were excluded. Demographic and clinical data, disease characteristics at diagnosis and first-line treatment were collected. Cytogenetic and molecular characteristics were used to classify patients in ELN risk groups. RESULTS Of the total of patients (n=218), one hundred and fifty-six (71.6%) received intensive chemotherapy treatment, while 62 (28.4%) were treated with non-intensive strategies. Idarubicin and cytarabine based schemes regimens (IA) were administered in most patients (98.6%) who received intensive treatment while the rest received fludarabine based regimens. One patient (0.6%) was treated with danurubicin and cytarabine liposome (CPX-351). Fifty-four (87%) patients treated with non-intensive regimens received hypomethylating agents, mostly azacitidine. Five patients (8%) were treated with venetoclax in combination with a hypomethylating agent. Table 1 shows the characteristics at diagnosis in both groups of patients. Patients who received intensive chemotherapy were younger and had higher leukocyte count, LDH values and a higher percentage of blasts in peripheral blood and bone marrow with a median of 40% and 62% blasts respectively. On the other hand, patients under non-intensive treatment more frequently presented a past history of hemopathy and a higher percentage of bone marrow dysplasia. Regarding ELN stratification significant differences were found between both groups. Patients who received aggressive chemotherapy vs patients who did not, were classified in low (28% vs. 7%), intermediate (36% vs. 58%) and high risk (36% vs. 35%) respectively (Figure 1). At the end of the follow-up, 41% of the patients who had received intensive therapy were alive while only 6.5% of the patients who had received non-intensive treatment were alive. Significant differences in survival were observed between both groups (p In the intensive chemotherapy group, significant differences in survival were observed according to ELN risk stratification (p However, in patients receiving non-intensive therapies, there were no significant differences in survival among different prognostic categories (p=0.06). In this group, 1-year OS was 25%, 57.6% and 40.7% and median OS was 2.1, 14.8 and 10.1 months for low, intermediate and high-risk groups respectively. See Figure 2. CONCLUSIONS: As validated in previous trials, ELN classification constitutes an adequate prognostic marker for patients with newly diagnosed AML treated with intensive chemotherapy. In our series, this classification does not appear to be a good predictor of survival for patients diagnosed with AML who initiated non-intensive treatments. Further validation in prospective studies are needed to better classify this growing subgroup of patients in clinical practice. Figure 1 Figure 1. Disclosures Martín-Rojas: Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Font Lopez: Pfizer: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees; CELGENE-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria.

Author(s): Kanate, Abraham S; DiGilio, Alyssa; Ahn, Kwang W; Al Malki, Monzr; Jacobsen, Eric; Steinberg, Amir; Hamerschlak, Nelson; Kharfan-Dabaja, Mohamed; Salit, Rachel; Ball, Edward; Bashir, Qaiser; Cashen, Amanda; Couriel, Daniel; Diez-Martin, Jose; Katsanis, Emmanuel; Linhares, Yulia; Mori, Shahram; Nash, Richard; Pawarode, Attaphol; Perales, Miguel-Angel; Phipps, Colin D; Richman, Carol; Savani, Bipin N; Shapira, Michael Y; Stiff, Patrick; Strair, Roger; Fenske, Timothy S; Smith, Sonali M; Sureda, Anna; Olteanu, Horatiu; Hamadani, Mehdi

BACKGROUND Development of de novo alloantibodies against recipient's red blood cell (RBC) antigens by engrafted donor's lymphocytes is a known phenomenon in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). This situation is usually clinically insignificant. We report a case of early clinically relevant hemolytic anemia in a blood group A1 D+ patient, due to a limited production of anti-D and anti-A1 produced by nonpreviously sensitized newly engrafted donor's immune system. CASE REPORT A 31-year-old Caucasian woman, blood group A1, D+, with Hodgkin's lymphoma, received an unmanipulated haploidentical allogeneic peripheral blood HSCT after a nonmyeloablative conditioning regimen. Donor blood group was A2B, D–. The patient had an uneventful course until Day +34, when she developed clinically significant hemolytic anemia with a positive direct antiglobulin test. Anti-D and anti-A1 produced by the donor-engrafted lymphocytes were detected both in serum and in eluate. The hemolysis produced an accelerated group change, turning the patient's ABO group into A2B 2 weeks after the detection of the alloantibodies. As the residual patient's RBCs progressively disappeared, anti-D and anti-A1 production decreased and were not detected in serum by Day +41. CONCLUSION This case illustrates that de novo alloantibody production against ABO and D antigens by the newly engrafted donor's lymphocytes can occasionally cause clinically significant anemia. To our knowledge, this is the first case reported of clinically significant hemolytic anemia due to a transient anti-D anti-A1 alloimmunization after T-cell-repleted haploidentical HSCT.

Background: Accuracy of bone marrow (BM) blast count in low-risk myelodysplastic syndromes (MDS) still remains a challenge though it is essential for prognosis. We investigated whether the enumeration of CD34+ myeloid cells by flow cytometry immunophenotyping (FCI) could be used as a consistent parameter for clinical MDS studies. Methods: Six clinical centres entered the study and information on their FCI protocols was recorded. Sixty-seven flow cytometry listmodes from BM samples of patients with low-risk MDS with

INTRODUCTION Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been established as a powerful treatment modality for patients with hematological malignancies. The graft-versus-leukemia effect, however, is strongly associated with the occurrence of graft-versus-host disease (GVHD) and subsequent transplant-related mortality (TRM). Several strategies are applied in order to prevent GVHD, the post-transplant cyclophosphamide (PT-Cy) is one of the most used in Haploidentical HSCT (Haplo-HSCT). Cyclophosphamide (CY) is an alkylating agent with antineoplastic and immunosuppressive activities. CY is metabolized by highly polymorphic enzymes to produce phosphoramide mustard which is a bifunctional DNA alkylating agent, is the therapeutically active metabolite. Thus, the aim of our study is to identity polymorphisms in the genes of the CY metabolism and correlated with complications post-HSCT (GVHD, TRM, veno-occlusive disease (VOD) or hemorrhagic cystitis (HC)). METHODS We selected 182 consecutive patients who received an Haplo-HSCT from 2007 to 2019. Eleven genes related to CY metabolism were analyzed (Table 1). The genotyping was performed in peripheral blood samples for recipient using an enrichment-capture custom gene panels (IDT probes) in a MiSeq platform (Illumina, USA). The bioinformatic analysis was carried out with BaseSpace software (Illumina, USA). Variants located in coding region and splicing sites were analyzed. We selected polymorphisms corresponding to read depth ≥30X in the canonical isoform with an allele frequency ≥0.4 and represented in at least 5% in our cohort. The collected clinical variables were age/gender recipient and donor, pathology, pretransplant status, conditioning regimen, total body irradiation, basal ferritin and CMV reactivation. Fisher test was used to compare the differences among groups. Statistical Package for the Social Sciences (SPSS, Chicago, USA) was used for statistical test. RESULTS The cumulative incidence rates for aGVHD of II-IV and III-IV grades at 100 days was 39% and 12% respectively. The cumulative incidence rates for cGVHD, moderate or severe cGVHD and TRM at 1000 days were 37%, 19% and 29%, respectively. Among the cases analyzed, 9% developed VOD and 25% HC. Patients who received ablative conditioning regimen presented a higher incidence of TRM (p=0.005). No other clinical data was associated with complications post HSCT. Forty polymorphisms were detected in 9 genes by bioinformatic analysis. The variants that presents some correlation (p Overall, polymorphisms related with decrease activity of enzymes that active cyclophosphamide (level lor active metabolite) were correlated with higher aGVHD, cGVHD, TRM and VOD (Table 1). On the other hand, polymorphisms associated with low activity in detoxification enzymes were correlated with higher toxicity (TRM). As described in bibliography, GSTM1 null allele were correlated with higher probability of developing VOD. CONCLUSIONS Genetic analysis of CY metabolism genes correlated with several post HSCT complications. The analyses of this variants before transplant could facilitate personalized risk and clinical management of patients undergoing Haplo HSCT. Results must validated in others cohorts of patients. Disclosures Kwon: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Jazz: Consultancy, Honoraria.

We report a lung-invasive fungal disease with possible cutaneous needle tract seeding in a patient with a febrile neutropenia caused by the Basidiomycetes mold Inonotus spp. Although rare, Inonotus spp. should be added to the list of microorganisms causing invasive fungal disease in neutropenic patients with hematologic malignancies.

Autologous hematopoietic stem cell transplantation (ASCT) is a well-established treatment strategy in HIV-related lymphoma patients (HIV+ Ly). Nevertheless, current evidence is mainly based on reports from specialized centers, multicentre heterogeneous studies, noncomparative analyses, or registry data-based comparisons. Likewise, the risk of infections reported so far for this population, seems to be similar to that of HIV- patients, and it does not seem to impact on mortality. We report a single-center retrospective comparative analysis of AHCT procedural results, infectious complications and survival in HIV+ Ly matched with a non-HIV comparative cohort. Thirty-three HIV+ patients and 45 matched controls, who underwent ASCT between 2000 and 2016, were included. Transplant-related toxicity, event-free survival, relapse rate, and overall survival were similar in both groups. Engraftment was delayed in HIV+ Ly (neutrophils: 15 vs 12 days (p = 0.0001), and platelets 39 vs 16 days (p = 0.00001)). Bacterial infections during the pre-engraftment period were more frequent in HIV+ Ly (RR 2.24, p = 0.017), as well as viral infections in the postengraftment period (RR 3.22, p = 0.004). CMV reactivation was more frequent in HIV+ Ly (39% vs 15% p = 0.007). In conclusion, ASCT is viable and effective in HIV+ Ly, but it is associated with a higher risk of infection.

Patient: Male, 21 Final Diagnosis: Methotrexate induced neurotoxicity Symptoms: Dysarthria • hemiparesis Medication: Methotrexate Clinical Procedure: — Specialty: Hematology Objective: Challenging differential diagnosis Background: Intraventricular administration of methotrexate (MTX) using an Ommaya reservoir is a useful therapeutic maneuver for malignant CNS involvement in patients with hematological malignancies. MTX-induced subacute neurotoxicity is a rare complication that typically progresses with involvement of the basal ganglia. Local toxicity due to misplaced catheters has been described, although the impact of normally positioned catheters on toxicity is not clear. Case Report: We report the case of a 21-year-old man diagnosed with stage IV diffuse large B-cell lymphoma who experienced a central nervous system relapse. While receiving intraventricular MTX using an Ommaya reservoir and systemic MTX, he experienced sudden left-side hemiparesis. All diagnostic tests were negative except for altered MRI findings with FLAIR hyperintensity in the basal ganglia and restricted diffusion in the same location that followed the track of the Ommaya catheter. The syndrome resolved after administration of high-dose steroids, and the patient received subsequent MTX courses without recurrence. Conclusions: MTX-induced neurotoxicity is a rare adverse event related to systemic and intrathecal administration of the drug. Many cases of Ommaya-related CNS symptoms have been described, although most were related to misplaced or malfunctioning catheters. Here we present a case of subacute MTX toxicity affecting the area around a correctly positioned catheter, suggesting that the catheter track could be more susceptible to MTX-induced toxicity.

Contains fulltext : 202803.pdf (Publisher’s version ) (Open Access) This analysis included 56 myelofibrosis (MF) patients transplanted from family mismatched donor between 2009 and 2015 enrolled in the European Society for Blood and Marrow Transplantation database. The median age was 57years (range, 38 to 72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34(+) cell dose was 4.8x10(6)/kg (range, 1.7 to 22.9; n=43). Conditioning was predominantly myeloablative in 70% and reduced intensity in the remainder. Regimens were heterogeneous with thiotepa, busulfan, fludarabine, and post-transplant cyclophosphamide used in 59%. The incidence of neutrophil engraftment by 28days was 82% (range, 70% to 93%), at a median of 21days (range, 19 to 23). At 2years the cumulative incidence of primary graft failure was 9% (95% CI 1% to 16%) and secondary graft failure was 13% (95% CI 4% to 22%). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV was 28% (95% CI 16% to 40%) and 9% (95% CI 2% to 17%) at 100days. The cumulative incidence of chronic GVHD at 1 year was 45% (95% CI 32% to 58%), but the cumulative incidence of death without chronic GVHD by 1 year was 20% (95% CI 10% to 31%). With a median follow-up of 32 months, the 1- and 2-year overall survival was 61% (95% CI 48% to 74%) and 56% (95% CI 41% to 70%), respectively. The 1- and 2- year progression-free survival was 58% (95% CI 45% to 71%) and 43% (95% CI 28% to 58%), respectively, with a 2-year cumulative incidence of relapse of 19% (95% CI 7% to 31%). The 2-year nonrelapse mortality was 38% (95% CI 24% to 51%). This retrospective study of MF allo-SCT using family mismatched donors demonstrated feasibility of the approach, timely neutrophil engraftment in over 80% of cases, and acceptable overall and progression-free survival rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimize the risk of graft failure and the relatively high nonrelapse mortality need to be used, ideally in a multicenter prospective fashion.

Mould-active prophylaxis is affecting the epidemiology of invasive mycoses in the form of a shift toward less common entities such as fusariosis. We analyze the characteristics of invasive fusariosis and its association to antifungal prophylaxis in a retrospective cohort (2004–2017) from a tertiary hospital in Madrid, Spain. Epidemiological, clinical, microbiological, and antifungal consumption data were retrieved. Isolates were identified to molecular level, and antifungal susceptibility was tested. Eight cases of invasive fusariosis were diagnosed. Three periods were identified according to incidence: 2014 (five cases). All except one case involved breakthrough fusariosis. During the earliest period, the episodes occurred while the patient was taking itraconazole (two) or fluconazole (one); more recently, while on micafungin (three) or posaconazole (one). Early cases involved acute leukemia at induction/consolidation, recent cases relapsed/refractory disease (P = .029). Main risk factor for fusariosis (62.5%) was prolonged neutropenia (median 44 days). Galactomannan and beta-D-glucan were positive in 37.5% and 100% of cases, respectively. All isolates except F. proliferatum presented high minimal inhibitory concentrations (MICs) against the azoles and lower MIC to amphotericin B. Most patients received combined therapy. Mortality at 42 days was 62.5%. Resolution of neutropenia was associated with survival (P = .048). Invasive fusariosis occurs as breakthrough infection in patients with hematologic malignancy, prolonged neutropenia, and positive fungal biomarkers. Recent cases were diagnosed in a period of predominant micafungin use in patients who had more advanced disease and protracted neutropenia and for whom mortality was extremely high. Resolution of neutropenia was a favorable prognostic factor.

We present our experience in patients with hematologic malignancy and Pseudomonas aeruginosa infection treated with ceftolozane-tazobactam. We performed a single-center case-control study comparing patients with hematologic malignancy and P. aeruginosa infection treated with ceftolozane-tazobactam (study group) with similar patients not treated with ceftolozane-tazobactam (control group) to assess safety and efficacy. Nineteen cases and 38 controls were analyzed. Cases were younger (45.6 years versus 57.6 years; P = 0.012) and less frequently had bacteremia (52.6% versus 86.8%; P = 0.008). They also had worse Multinational Association for Supportive Care in Cancer (MASCC) scores (10.2 versus 16.1; P = 0.0001), more hospital-acquired infections (78.9% versus 47.4%; P = 0.013), and more extremely drug-resistant (XDR) P. aeruginosa infections (47.4% versus 21.1%; P = 0.015). Cases received a median of 14 days (7 to 18 days) of ceftolozane-tazobactam (monotherapy in 11 cases [57.9.6%]). Ceftolozane-tazobactam was mostly used as targeted therapy (16 cases; 84.2%) because of resistance (9 cases; 47.4%), failure (4 cases; 21.1%), and toxicity (3 cases; 15.8%). Ten cases had bacteremia (52.6%). The sources were pneumonia (26.3%), catheter-related bacteremia (21.1%), primary bacteremia (21.1%), and perianal/genital (15.7%), urinary (10.5%), and skin/soft tissue (5.3%) infection. No toxicity was attributed to ceftolozane-tazobactam. More than 60% had neutropenia, and 15.8% fulfilled the criteria for sepsis. There were no significant differences in clinical cure at day 14 (89.5% versus 71.1%; P = 0.183) or recurrence (15.8% versus 10.5%; P = 0.675). Thirty-day mortality was lower among cases (5.3% versus 28.9%; P = 0.045). Ceftolozane-tazobactam was well tolerated and at least as effective as other alternatives for P. aeruginosa infection in patients with hematologic malignancy, including neutropenic patients with sepsis caused by XDR strains.

Allogeneic hematopoietic cell transplantation (allo-HCT) using siblings and matched donors has the potential for long-term disease control in a subset of high-risk patients with multiple myeloma (MM); however, the data on using haploidentical donors in this disease are limited. We conducted a retrospective analysis to examine the outcomes of patients with MM who underwent haploidentical allo-HCT within European Society for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Research centers. A total of 96 patients underwent haploidentical allo-HCT between 2008 and 2016. With a median follow-up of 24.0 months (range, 13.2 to 24.9 months), 97% (95% confidence interval [CI], 93% to 100%) of patients had neutrophil engraftment by day 28, and 75% (95% CI, 66% to 84%) achieved platelet recovery by day 60. Two-year progression -free survival (PFS) was 17% (95% CI, 8% to 26%), and overall survival (OS) was 48% (95% CI, 36% to 59%). At 2 years, the cumulative risk of relapse/progression was 56% (95% CI, 45% to 67%), and 1-year nonrelapse mortality (NRM) was 21% (95% Cl, 13% to 29%). The incidences of acute graft-versus-host-disease (GVHD) grades ll-IV by 100 days and chronic GVHD at 2 years were 39% (95% CI, 28% to 49%) and 46% (95% CI, 34% to 59%), respectively. On univariate analysis, use of post-transplantation cyclophosphamide (PT-Cy) (54% [95% CI, 41% to 68%] versus 25% [95% CI, 1% to 48%]; P=.009) and use of bone marrow as source of stem cells (72% [95% CI, 55% to 89%] versus 31% [95% CI, 17% to 46%]; P=.001) were associated with improved OS at 2 years. Disease status, patient sex, intensity of conditioning regimen, recipient/donor sex mismatch, and cytomegalovirus serostatus had no impact on OS, PFS, or NRM. Haploidentical transplantation is feasible for patients with multiply relapsed or high-risk MM, with an encouraging 2-year OS of 48% and an NRM of 21% at 1 year, supporting further investigation of haploidentical allo-HCT in suitable candidates with MM. (C) 2018 American Society for Blood and Marrow Transplantation.

Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PT-CY in HLA-identical donor is less explored. In this study, we analyzed the results of PT-CY for GVHD prophylaxis in matched unrelated donor (MUD) HSCT and compared them with those obtained after prophylaxis with anti-thymocyte globulin (ATG), methotrexate (MTX) and cyclosporine (CsA). Methods: 132 matched unrelated donor HSCT from 4 Spanish centers have been analyzed: 60 performed between 2010 and 2018 using ATG-MTX-CsA and 72 performed between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. Peripheral blood was used as graft source in 92% of the patients in the ATG group and in 78% in the PT-CY group. GVHD prophylaxis consisted in rabbit ATG either 2mg/kg days -4 to -2 (41 patients, 68%) or 0.5mg/m2 on day -3 followed by 1mg/kg days -2 and -3 (19 patients, 32%), MTX days +1, +3, +6 and +11, and CsA from day -1 in the ATG group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +4, followed by either CsA or tacrolimus plus mycophenolate mofetil (MMF) from day +5 in 30 patients (42%), or cyclophosphamide on days +3 and +5 combined with CsA or tacrolimus in 42 patients (58%; 16 out of them also received sirolimus due to 9/10 HLA-match). Cumulative incidence of grade II-IV (67% vs 46%, p=0.008) and III-IV (34% vs 3%, p=0.003) acute GVHD, were significantly higher in the ATG group (Figure 1). There were no differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (23% vs 24%, p=0.86). After a median follow-up of 78 months for the ATG group and 26 months for the PT-CY group, no differences were found in the 2-year overall survival (58% vs 60%, p=0.475), 2-year event-free survival (51% vs 50%, p=0.961) and the composite endpoint of GVHD-free and relapse-free survival (44% vs 40%, p=0.742). The 2-year cumulative incidence of relapse (22% vs 26%, p=0.67) and non-relapse mortality (NRM) (24% vs 22%, p=0.68) were also similar between both groups. However, NRM in the ATG group was due to GVHD in 9 out of 16 patients, while in the PT-CY group NRM was mostly due to infections and organ toxicity and only 3 out of 15 patients died due to GVHD. The incidence of sinusoidal obstruction syndrome was low in both groups (0% vs 4%, p=0.11). CMV reactivation rates were similar (40% vs 51%, p=0.191). However, both hemorrhagic cystitis and EBV reactivation were higher in the ATG group (56% vs 12%, p=0.00, and 5% vs 0%, p=0.05, respectively). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after MUD HSCT, using mostly peripheral blood as graft source, resulted in lower incidence of aGVHD compared to prophylaxis based on ATG-MTX-CsA. Although no impact on non-relapse mortality was observed, GVHD associated mortality was higher in the ATG group as well as cystitis and EBV reactivations. Prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI)-based versus chemotherapy (CT)-based MAC regimens in patients with acute lymphoblastic leukemia (ALL). The study included 427 patients who underwent first haplo-HCT with post-transplantation cyclophosphamide (PTCy), following TBI-based (n = 188; 44%) or CT-based (n = 239; 56%) MAC. The median patient age was 32 years. Fludarabine-TBI (72%) and thiotepa-busulfan-fludarabine (65%) were the most frequently used TBI- and CT-based regimens, respectively. In the TBI and CT cohorts, 2-year leukemia-free survival (LFS) was 45% versus 37% (P = .05), overall survival (OS) was 51% versus 47% (P = .18), relapse incidence (RI) was 34% versus 32% (P = .44), and nonrelapse mortality (NRM) was 21% versus 31% (P < .01). In the multivariate analysis, TBI was associated with lower NRM (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.33 to 0.86; P = .01), better LFS (HR, 0.71; 95% CI, 0.52 to 0.98; P =.04), and increased risk for grade II-IV acute graft-versus-host disease (GVHD) (HR, 1.59; 95% CI, 1.08 to 2.34; P = .02) compared with CT-based MAC. The type of conditioning regimen did not impact RI, chronic GVHD, OS, or GVHD-free, relapse-free survival after adjusting for transplantation-related variables. TBI-based MAC was associated with lower NRM and better LFS compared with CT-based MAC in patients with ALL after haplo-HCT/PTCy.

Acute myeloid leukemia is a clonal but heterogeneous disease differing in molecular pathogenesis, clinical features and response to chemotherapy. This latter frequently consists of a combination of cytarabine and anthracyclines, although etoposide, demethylating agents, and other drugs are also used. Unfortunately, chemoresistance is a common and serious problem. Multiple mechanisms account for impaired effectiveness of drugs and reduced levels of active agents in target cells. The latter can be due to lower drug uptake, increased export or decreased intracellular proportion of active/inactive agent due to changes in the expression/function of enzymes responsible for the activation of pro-drugs and the inactivation of active agents. Characterization of the "resistome", or profile of expressed genes accounting for multi-drug resistance (MDR) phenotype, would permit to predict the lack of response to chemotherapy and would help in the selection of the best pharmacological regime for each patient and moment, and to develop strategies of chemosensitization.

INTRODUCTION COVID-19 is associated with coagulopathy that correlates with poor prognosis. Although the underlying mechanism of COVID-19 coagulopathy remains unknown, early reports suggested that it may be a form of disseminated intravascular coagulation (DIC). However, recent studies have highlighted the potential role of endothelial cell injury in its pathogenesis. AIMS The aims of our study were to analyze the coagulation parameters of critically and non-critically ill patients with COVID-19 pneumonia admitted to our hospital, determine if coagulation factors consumption occurs, identify potential prognostic biomarkers of this new disease and explore possible underlying mechanisms of COVID-19 coagulopathy. METHODS We conducted a retrospective cohort study performed at Gregorio Marañon Hospital in Madrid, Spain. Adult patients with a diagnosis of COVID-19 hospitalized in our center were recruited, including those admitted to the ICU and to general wards. Patients were randomly selected from blood samples that arrived at our Hemostasis laboratory during April 2020. For each patient, we conducted a complete analysis of coagulation parameters, including basic coagulation tests, quantification of coagulation factors and physiological inhibitor proteins, evaluation of the fibrinolytic system and determination of von Willebrand Factor (vWF) and ADAMTS13. Laboratory data were compared with clinical data and outcomes. Data were analyzed using IBM SPSS Statistics for Mac, version 24. This study was approved by our institutional Ethics Committee and it was executed along with the international ethics recommendations for conducting research in humans following the latest revision of Declaration of Helsinki. RESULTS A total of 62 patients (31 ICU, 31 non-ICU) were analyzed. Mean age of the sample was 61.8 (SD 15.2) years and 69.4% of the patients were male. The coagulation parameters assessment demonstrated normal median PT, INR and APTT in our cohort and all coagulation factors were within normal range. Factor VIII showed an increasing trend (194.5±71.9) which could be interpreted as an acute phase reactant, and it was significantly higher in non-survivors (p=0.003). Similarly, we did not observe consumption of physiological inhibitor proteins and platelet counts were also within the normal limits, despite being slightly lower in non-survivor patients (p=0.006) (Table 1). Von Willebrand Factor (vWF) was above the normal range (median 216%, IQR 196-439, normal range 62-175%) in our cohort and higher levels of vWF-antigen (p=0.001) and vWF-activity (p=0.02) were associated with poor prognosis. Likewise, a lower ADAMTS13 activity was observed in non-survivors (p=0.008). Regarding the fibrinolytic pathway, PAI levels were above the normal range (median 52.6ng/ml, IQR 37.2-85.7, normal range 4-40ng/ml), but we found no statistically significant differences based on survival. The remaining parameters of the fibrinolytic pathway (plasminogen and alpha-2 antiplasmin) were within normal range (Table 1). ICU-patients had a poorer prognosis, with a higher rate of mortality (p=0.003). Likewise, they showed more elevated acute phase reactants (p CONCLUSIONS COVID-19 infection is associated with coagulopathy that correlates with poor prognosis. However, coagulation factors, physiological inhibitory proteins and alpha-2-antplasmin levels were preserved in our study. Similarly, we did not observe platelets or fibrinogen consumption, which leads us to assume that COVID-19 coagulopathy is not a form of DIC. Increased vWF and decreased ADAMTS13 activity in our cohort could indicate that the underlying mechanism of this coagulopathy may reside in the endothelial cells and share a similar pathogenesis with thrombotic microangiopathy (TMA), as it has been recently suggested in some scientific reports. Disclosures No relevant conflicts of interest to declare.

The present study aimed at describing the outcome of patients with HIV-associated lymphomas following autologous hematopoietic stem cell transplantation (autoHCT) in the rituximab and combined antiretroviral therapy (cART) era. Eligible for this retrospective study were HIV-positive patients with lymphoma who received autoHCT between 2007 and 2013. A total of 118 patients were included with a median age of 45 years (range 24-66). Underlying diagnoses were diffuse large B cell lymphoma in 47%, Hodgkin lymphoma in 24%, Burkitt lymphoma in 18%, and plasmablastic lymphoma in 7% of patients. Disease status at autoHCT was complete remission in 44%, partial remission (PR) in 38%, and less than PR in 18% of the patients. With a median follow-up of 4 years, 3-year non-relapse mortality, incidence of relapse, progression-free survival (PFS) and overall survival (OS) were 10%, 27%, 63% and 66%, respectively. By multivariate analysis, disease status less than PR but not CD4+ cell count at the time of autoHCT was a significant predictor of unfavorable PFS and OS. In conclusion, in the era of cART and chemoimmunotherapy, the outcome of autoHCT for HIV-related lymphoma is driven by lymphoma-dependent risk factors rather than by characteristics of the HIV infection.

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.

// Rocio I.R. Macias 1, 2 , Anabel Sanchez-Martin 1 , Gabriela Rodriguez-Macias 1, 3 , Luis I. Sanchez-Abarca 4 , Elisa Lozano 1, 2 , Elisa Herraez 1, 2 , Maria D. Odero 5 , Jose L. Diez-Martin 3, 6 , Jose J.G. Marin 1, 2, * and Oscar Briz 1, 2, * 1 Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain 2 National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Madrid, Spain 3 Department of Hematology-BMT Unit, Hospital General Universitario Gregorio Maranon, Madrid, Spain 4 Department of Hematology, University Hospital of Salamanca, IBSAL, Salamanca, Spain 5 Department of Biochemistry and Genetics and CIMA, University of Navarra, Pamplona, CIBERONC, Spain 6 Gregorio Maranon Institute for Health Research (IISGM), Madrid, Spain * These authors have contributed equally to this work Correspondence to: Rocio I.R. Macias, email: rociorm@usal.es Keywords: AML; cancer; chemoresistance; chemotherapy; tyrosine kinase inhibitor Received: December 21, 2017 Accepted: April 24, 2018 Published: June 19, 2018 ABSTRACT Background : Chemoresistance often limits the success of the pharmacological treatment in acute myeloid leukemia (AML) patients. Although positive results have been obtained with tyrosine kinase inhibitors (TKIs), such as sorafenib, especially in patients with Fms-like tyrosine kinase 3 (FLT3)-positive AML, the success of chemotherapy is very heterogeneous. Here we have investigated in vitro whether the transportome (set of expressed plasma membrane transporters) is involved in the differential response of AML to sorafenib. Methods : The sensitivity to sorafenib-induced cell death (MTT test and anexin V/7-AAD method) was evaluated in five different cell lines: MOLM-13, OCI-AML2, HL-60, HEL and K-562. The transportome was characterized by measuring mRNA using RT-qPCR. Drug uptake/efflux was determined by flow cytometry using specific substrates and inhibitors. Results : The cytostatic response to sorafenib was: MOLM-13>>OCI-AML2>HL-60>HEL≈K-562. Regarding efflux pumps, MDR1 was highly expressed in HEL>K-562≈MOLM-13, but not in OCI-AML2 and HL-60. BCRP and MPR3 expression was low in all cell lines, whereas MRP4 and MRP5 expression was from moderate to high. Flow cytometry studies demonstrated that MRP4, but not MRP5, was functional. The expression of the organic cation transporter 1 (OCT1), involved in sorafenib uptake, was MOLM-13>OCI-AML2≈HL-60 and non detectable in HEL and K-562. Transfection of HEL cells with OCT1 increased the sensitivity of these cells to sorafenib, whereas inactive genetic variants failed to induce this change. Conclusion: Together with changes in the expression/function of receptors targeted by TKIs, the expression of plasma membrane transporters involved in sorafenib uptake/efflux may affect the response of leukemia cells to this drug.

The aim of this registry-based retrospective study was to analyze the outcome of second allogeneic hematopoietic SCT (alloHSCT_2) performed in patients with lymphoma who had relapsed after a first allogeneic transplant (alloHSCT_1). Patients ⩾18 years who had received an alloHSCT_2 for lymphoma relapse between 2000 and 2011 were eligible. One hundred and forty patients were identified. The diagnosis was Hodgkin lymphoma (HL) in 31%, diffuse large B-cell lymphoma in 14%, T-cell lymphoma in 12%, indolent lymphoma in 19%, mantle cell lymphoma in 16% and other lymphomas in 8% of the patients. The median interval from alloHSCT_1 to alloHSCT_2 was 19 (range 4-116) months. Disease status at alloHSCT_2 was chemosensitive in 46%, refractory in 43% and unknown in 11% of the patients. Three-year PFS, OS, relapse incidence and nonrelapse mortality were 19%, 29%, 58% and 23%, respectively. PFS and OS were significantly affected by refractory disease at alloHSCT_2 and a short interval between alloHSCT_1 and alloHSCT_2. Long-term PFS was observed across all lymphoma subsets except for aggressive B-cell lymphoma. In conclusion, alloHSCT_2 is feasible and can result in long-term disease control in patients with lymphoma recurrence after alloHSCT_1, in particular if relapse occurs late and is chemosensitive.

We retrospectively compared the clinical outcomes of adults with acute leukemia who received single-unit umbilical cord blood (UCB) transplantation (sUCBT) (n = 135) or stem cell transplant using coinfusion of a UCB graft with CD34+ cells from a third-party donor (Haplo-Cord) (n = 72) at different institutions within the Grupo Espanol de Trasplante Hematopoyetico. In multivariable analysis, patients in the Haplo-Cord group showed more rapid neutrophil (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.5-3.3; P < .001) and platelet recovery (HR, 1.6; 95% CI, 1.2-2.3; P = .015) and lower incidence of chronic graft-versus-host disease (GVHD) (relative risk, 0.5; 95% CI, 0.3-0.8; P = .01). Nonrelapse mortality, relapse, disease-free survival (DFS), and GVHD/relapse-free survival were similar in the 2 groups. Regarding disease-specific outcomes, DFS in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients was not significantly different; however, a significantly higher relapse rate was found in patients with AML treated with Haplo-Cord (HR, 2.3; 95% CI, 1-5.4; P = .04). Our study confirms that Haplo-Cord was an effective strategy to accelerate neutrophil and platelet recovery and shows that, in the context of specific treatment platforms, sUCBT and Haplo-Cord offer similar long-term outcomes.

Background The impact of the use of anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation performed with HLA-identical sibling donors following fludarabine and 4 days intravenous busulfan myeloablative conditioning regimen has been poorly explored. Methods We retrospectively analyzed 566 patients who underwent a first HLA-identical allogeneic stem cell transplantation with this conditioning regimen for acute myeloid leukemia in first complete remission between 2006 and 2013 and compared the outcomes of 145 (25.6%) patients who received ATG (ATG group) to 421 (74.4%) who did not (no-ATG group). The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results Patients in the ATG group were older, received more frequently peripheral blood stem cell grafts from older donors, and were transplanted more recently. With a median follow-up of 19 months, patients in the ATG group had reduced 2-year cumulative incidence of chronic graft-versus-host disease (GVHD) (31 vs. 52%, p = 0.0002) and of its extensive form (8 vs. 26%, p

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.

Previous studies have shown the reproducibility of the 2008 World Health Organization (WHO) classification in myelodysplastic syndromes (MDS), especially when multilineage dysplasia or excess of blasts are present. However, there are few data regarding the reproducibility of MDS with unilineage dysplasia. The revised International Prognostic Scoring System R-IPSS described two new morphological categories, distinguishing bone marrow (BM) blast cell count between 0–2 % and >2–

Autologous stem-cell transplantation (autoSCT) is considered a standard treatment of non-frail patients with mantle cell lymphoma (MCL), but little is known about outcome of MCL patients relapsing after autoSCT. We therefore sought to analyse the outcome after autoSCT failure and the efficacy of a rescue stem-cell transplantation (SCT) in this setting. Patients with MCL were eligible if they had relapsed after autoSCT performed between 2000 and 2009. A total of 1054 patients could be identified in the EBMT registry. By contacting the transplant centres, a full dataset could be retrieved for 360 patients. Median overall survival (OS) after relapse of the whole study group was 19 months. A long (> 12 months) interval between autoSCT and relapse [P < 0.001, hazard ratio (HR) 0.62], primary refractory disease (P < 0.02, HR 1.92), prior high-dose ARA-C treatment (P = 0.04, HR 1.43), and the year of relapse (P = 0.02, HR 0.92) significantly influenced OS from relapse in multivariate analysis. Eighty patients (22%) received a rescue allogeneic SCT (alloSCT). Relapse incidence, non-relapse mortality, and OS 2 years after alloSCT was 33% [confidence interval (95% CI 21% to 45%)], 30% (95% CI 19% to 42%), and 46% (95% CI 33% to 59%), respectively. Remission duration after autoSCT was the only variable significantly affecting the outcome of salvage alloSCT. In contrast, rescue autoSCT was not associated with long-term disease control. However, individual patients survived long term even without salvage transplantation. MCL recurrence within 1 year after autoSCT has an extremely dismal outcome, while the prognosis of patients with longer remission durations after autoSCT is significantly better. AlloSCT may offer the possibility of durable survival when performed for patients with a remission duration of more than 12 months after first autoSCT, but the favourable effect of a salvage alloSCT in this setting needs further validation.

Introduction: Non-Hodgkin B lymphomas (NHL-B) are a large group of heterogeneous diseases, with well-defined, histological and clinical features. Currently, the lymph node biopsy is essential for diagnosis, often obtained from hard to reach areas. Our aims with this study was to analyze genetics variants at diagnosis trying to discriminate between different NHL-B histologic subtypes using formalin fixed paraffin embedded (FFPE) tissue sections and circulating tumor free DNA (ctDNA) samples. Material and Methods: This is a retrospective, cross-sectional, single-center study. Sixty patients were selected with a diagnosis of different NHL-B subtypes: Diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), marginal lymphoma (ML), mantle cell lymphoma (MCL) and plasmablastic lymphoma (PL). Sixty FFPE tissue samples and 23 ctDNA specimens obtained at diagnosis were selected. We performed an enrichment panel of 54 genes recurrently mutated in lymphomas (Lymphoma Solution; Sophia Genetics) by next generation sequencing (NGS; NextSeq; Illumina). The depth of 90% of the readings was greater than 2600x. Quantitative variables were expressed as median and range. Categorical variables were expressed as frequency and percentage. The Fisher exact test was used to compare the distribution of categorical variables. The Mann-Whitney test was used to compare differences between quantitative variables. Statistical significance was set at p < 0.05. Results: Our study shows that 97% (58/60) of patients presented any variant. The most frequently mutated genes were KMT2D, EP300 and SOCS1. Exclusive variants were detected in FL in the genes CCND1, PAX5, CREBBP, BCL2 and REL genes. In the same way, in DLCBL the variants detected in the BRAF, TCF3, XPO1, PIM1, CHD2, ID3 and BCL6 genes were exclusive of this subtype. Furthermore, the genes BCL2 (p=0.0021), CREBBP (p=0.0004), NOTCH2 (p=0.03), PAX5 (p=0.01) and TNFRSF14 (p=0.04) are more frequently altered in patients with FL, ATM (p=0.02) gene in MCL; NFKBIE (p=0.03), CIITA (p=0.02), MYC (p=0.009) and PIM1 (p=0.04) in DLCBL, among which it was found that high-grade lymphomas are more frequently associated with mutations in CHD2 (p=0.02), MYC (p=0.03) and MYD88 (p=0.02; data not shown). In the subgroup of 23 patients with paired samples (FFPE/ctDNA), 95% (22/23) of patients had mutations in any of the genes on the panel in FFPE tissue samples and 82% (19/23) in ctDNA specimens. The number of variants detected was different depending on the type of sample analysed, 52% of the variants were detected in both specimens, 39 only in FFPE tissue and 9% in ctDNA; Figure 1). In variants detected in both samples, the average value of the VAF was higher that when is detected only in one of the samples (FFPE: 28.1 vs 5.8 (p We did not find significant differences in the number of variants depending on the stage, classification, tumour burden or bulky mass (Table 1). Conclusion: In our study, we were able to identify genetic variables that could characterize different histological groups of NHL-B in FFPE tissue and ctDNA samples, by using a commercial gene panel of NGS. The mutational profile obtained from ctDNA and FFPE tissue is comparable in all histological subtypes, regardless tumour burden, aggressiveness or stage, throwing each one of them complemental information. These results support the hypothesis that could be possible to distinguish different histologies through non-invasive strategies, specially oriented to lesions where obtaining a tissue sample is difficult. We are working on the development of clinical-genetic algorithms that allow us to achieve our goal. Disclosures No relevant conflicts of interest to declare.

Introduction: The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. Although PTCy-Haplo has been compared with different transplant platforms, there is no information on the impact of donor types using homogeneous prophylaxis with PTCy. Methods:We retrospectively analysed outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) that received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n=215), MUD (n=235) and Haplo (n=789) donors registered in the EBMT database between 2010 and 2017. The median follow up period of the entire cohort was 2 years. Results: Median age of patients was 52 years (range, 18-76), 693 (56%) were male and 928 (78%) were CMV seropositive. AML was de novo in 1,046 (84%) patients, while 47 (6%),543 (66%) and 239 (29%) had standard, intermediate and high risk cytogenetics, respectively. Peripheral blood (PB) was used as the stem cell source in 814 (66%) patients. Regarding conditioning, 962 (78%) were chemotherapy based regimens and 500 (41%) patients received reduced intensity conditioning (RIC). Preferred conditioning regimens were thiotepa, busulfan, fludarabine for Haplo (n= 371; 47%) and busulfan, fludarabine for MSD (n= 83; 39%) and MUD (n= 102; 43%). Patients received a variety of PTCy containing immune suppressive regimens, the most frequently used being PTCy, calcineurin inhibitor and mycophenolate mofetil in Haplo (n= 684; 87%) and PTCy and calcineurin inhibitor alone in MSD (n= 52; 24%) and MUD (n= 74; 31%). In-vivo T-cell depletion (TCD) was used in 164 (13%) patients. Compared to MSD and MUD, Haplo patients were older and less frequently received RIC, TCD and PB but the distribution of cytogenetic risk group was similar between the donor types. Cumulative incidence of neutrophil recovery at 60 days was 95% (95% CI 94-96). The cumulative incidence of 100 day acute GVHD grade II-IV and III-IV, and 2-year chronic and chronic extensive GVHD were 25% (95% CI 23-28), 9% (95% CI 7-10), 31% (95% CI 28-34) and 12% (95% CI 10-14), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality (NRM) and the probability of leukemia-free survival (LFS) and overall survival (OS) were 25% (95% CI 22-28), 19% (95% CI 17-21), 56% (95% CI 53-59) and 63% (95% CI 60-66), respectively. On multivariable analysis, outcomes were not significantly different for MSD and MUD. Haplo-SCT carried a significantly increased risk of acute grade II-IV GVHD (HR 1.6; 95% CI 1.1-2.4) but the risk was not significant for chronic GVHD (HR 1.2; 95% CI 0.8-1.8). Haplo-SCT carried a higher risk of NRM (HR 2.6; 95% CI 1.5-4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9) that translated to no change in LFS (HR 1.1; 95% CI 0.8-1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8-1.3). The most frequent cause of death was relapse for MSD (n= 36, 53%) and MUD (n= 41, 48%) and infection for Haplo (n = 107, 39%). Interestingly, the use of PB was associated with an increased risk of acute (HR 1.9; 95% CI 1.4-2.6) and chronic GVHD (HR 1.7; 95% CI 1.2-2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9). Other variables that had an impact on LFS were: poor risk cytogenetics (HR 1.4; 95% CI 1.1-1.7), use of MAC-Chemo (HR 0.7; 95% CI 0.6-0.9), Karnofski performance status Conclusions:The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD and Haplo is safe and effective and rates of GVHD are low, especially chronic. HLA mismatch in Haplo has a negative impact on acute GVHD and NRM in this setting but also offers increased anti-leukemic efficacy. As seen in other transplant scenarios, PB is associated with more GVHD and less relapse. Figure Disclosures Angelucci: Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Blaise:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

INTRODUCTION Allogeneic haematopoietic stem cell transplant (allo-HSCT) could be the only curative therapy for patients with hematological malignancies due to graft effect against tumor. However, approximately 40% of patients develop post-transplantation complications such as acute graft-versus-host disease (aGVHD). Cytokines and their receptors are involved in regulatory and inflammatory processes that occur during GVHD. Therefore, the analysis of polymorphisms (SNPs) that affect the expression or activity of these genes could be used as biomarkers to predict the development of these complication. The aim of this study was to select new polymorphisms in cytokine genes (interleukins, chemokines and their receptors) to build models to predict the development of aGVHD after allo-HSCT from an HLA-identical sibling donor. METHODS We retrospectively selected 88 patients with hematological malignancies who received an allo-HSCT from an HLA-identical sibling donor from 2000 to 2015. A total of 176 pre-transplant recipient (R) and donor (D) peripheral blood samples were collected. The genotyping was performed using an enrichment-capture gene panels (include 132 genes (73 interleukins, 59 chemokines) in a HiSeq platform (Illumina, USA). The bioinformatic analysis was carried out with the GeneSystemssoftware (Sistemas Genómicos, Spain). Variants located in coding region, splicing sites, and UTR, 5'upstream and 3'downstream zones (+ 200pb) were analyzed. We selected polymorphisms corresponding to non-synonymous variants, represented in at least 5% of our cohort, with readings ≥30X in the canonical isoformwith an allele frequency ≥ 0.4. Fisher test was used to compare the differences among groups. Multiple logistic regression models were performed using combination of interleukins and chemokines polymorphisms selected previously that could be applied to clinical practice to predict aGVHD. The models with the highest AUC value, sensitivity and specificity value and the lowest number of genetic variants used were selected.Statistical Package for the Social Sciences (SPSS, Chicago, USA) was used for statistical test. RESULTS The cumulative incidence rates for aGVHD of grades II-IV and III-IV at 100 days after transplantation were 48.93% and 18.08%, respectively. The clinical variables (age, gender, pathology, stem cell source and previous transplantation) were not correlated with II-IV or III-IV aGVHD. However, patients who received ablative conditioning regimen presented a lower incidence of III-IV aGVHD (p= 0.041). Using filters defined previously, we detected 481 polymorphisms (350 coincident, 68 specific R and 63 for D) in the interleukins group. On the other hand, we detected 339 polymorphisms (267 coincident, 29 specific R and 43 for D) in the group of chemokines. Finally, 17 polymorphisms were selected in the interleukin group and 10 in the chemokine group for its correlation with the aGVHD (p We developed multiple logistic regression models for II-IV and III-IV aGVHD in interleukins and chemokines genes (Table 3). The identification of these 15 polymorphisms could help us to prevent the developing II-IV and III-IV aGVHD. CONCLUSIONS We have identified new genetic polymorphisms correlate with the risk of developing aGVHD after allo-HSCT from an HLA-identical sibling donor. Based on these data, we have developed a genetic score that encompasses polymorphisms of greater relevance. In this way, patients at greatest risk for developing this type of post-transplantation complication who could benefit from personalized management through immunosuppression and other drugs. Disclosures No relevant conflicts of interest to declare.

Background: The number of non T depleted haploidentical stem cell transplantations (haplo SCT) with post transplantation cyclophosphamide (PTCy) in adult patients (pts) with acute lymphoblastic leukemia (ALL) is increasing (Shemtov N et al, Leukemia 2019). Although the original haplo SCT with PTCy were performed with bone marrow (BM) grafts, the use of peripheral blood stem cells (PBSC) as the stem cell source may provide some advantages in engraftment and anti-leukemic effect which may be of special importance in ALL. Aim: The goal of this study was to compare BM to PBSC as stem cell source for non-T-cell-depleted haplo SCT with PTCy in adult pts with ALL in first or second complete remission (CR). Methods: The study was based on the haplo SCT with PTCy in adult pts with ALL that met the study inclusion criteria and that were reported to the European Society for Blood and Marrow Transplantation (EBMT) registry from 2010 to 2018. Multivariate analyses (MVA) were performed using the Cox proportional hazard model. Results: A total of 314 pts were reported, 157 of whom received BM and 157 received PBSC as the stem cell source. The median age at transplantation was 37 years (range, 18-68 years) and 36 years (range, 18-73 years), 66% and 62% were males, respectively. Diagnosis was Ph negative B-ALL in 39% and 41% of the pts, Ph positive in 32% and 34 % and T ALL in 29% and 25%, respectively.61% and 65% were in CR1, while 39% and 35% were in CR2. Pts and donor characteristics did not differ between the groups. More pts in the BM group received myeloablative conditioning (MAC), 87% vs 71% in the PBSC group, p Conclusion: In pts with ALL in remission receiving haplo SCT with PTCy, the use of BM versus PBSC grafts resulted in better LFS, OS and GRFS. Disclosures Angelucci: Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorporated, and CRISPR Therapeutics: Other: Partecipation in DMC; BlueBirdBio: Other: Local advisory board; Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Partecipation in DMC. Socie:Alexion: Consultancy. Blaise:Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Background The intensity of a conditioning regimen has significant impact on outcomes of allogeneic hematopoietic cell transplantation in acute leukemia. In acute lymphoblastic leukemia (ALL) patients undergoing matched donor transplant, total body irradiation (TBI)- based myeloablative conditioning (MAC) regimen was associated with improved leukemia free survival (LFS) compared to chemotherapy (CT)-based MAC (Eder S. et al. 2017). Haploidentical hematopoietic cell transplantation(haplo-HCT) with post-transplant cyclophosphamide (PTCy) has emerged as a safe alternative in absence of a matched donor. The optimal MAC in haplo-HCT setting is yet to be defined. We studied the outcomes of TBI- vs. CT-based MAC in ALL patients undergoing haplo-HCT and reported to the Acute Leukemia Working Party of the EBMT. Methods The study included 427 ALL (B-ALL-75%) patients, that underwent haplo-HCT with PTCy during the years 2010-2018, following TBI- (n=188, 44%) or CT- (n=239, 56%) based MAC. Regimen intensity was defined by EBMT criteria and cases with busulfan dose Results In univariate analysis, day 100 incidences of acute GVHD II-IV and III-VI were 38% vs. 30% (p-0.07) and 19% vs. 13% (p-0.14) for TBI and CT cohort, respectively. Two-year overall and severe chronic GVHD incidences were 34% vs. 30% (p-0.51) and 17% vs. 12% (p-0.18) for TBI and CT cohort, respectively. Graft failure was reported in 6 (3%) and 19 (8%)(p-0.09) patients who received TBI and CT-based MAC, respectively. Death from veno-occlusive disease was reported in 4 (5%) TBI patients and 8 (7%) CT patients. There was no difference in reported deaths due to infection (28%) or interstitial pneumonitis (4%) among study cohorts. In multivariate analysis, TBI was associated with significant improvement in nonrelapse mortality (NRM) [HR=0.51, 95% CI:0.32-0.83, p In a subgroup univariate analysis of patients Conclusions TBI based MAC resulted in significant reduction of NRM, translating into a better LFS without impacting aGVHD III-IV, chronic GVHD, RI or OS when compared to CT based MAC. Non-significant difference in OS between TBI and CT cohorts might be related to lower number of events, short follow-up and/or salvage therapies after relapse. These novel findings based on a large cohort of ALL patients, support the use of TBI based MAC and bone marrow graft in haplo-HCT with PTCy. Disclosures Dholaria: Celgene: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Angelucci:Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Apperley:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Socie:Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Background: The use of unmanipulated Haploidentical HSCT (Haplo-HSCT) with post-transplant Cyclophosphamide (PT-Cy) as GVHD prophylaxis has widely extended. Veno-occlusive disease (VOD) is a threatening complication after both autologous and allogeneic HSCT, with high mortality rates despite early medical treatment, including the use of defibrotide. The objective of this study was to describe characteristics and outcomes of patients with refractory very severe VOD after Haplo-HSCT with PT-Cy, treated with TIPS as salvage procedure. Methods: We retrospectively analysed 176 Haplo-HSCT with Cy-post consecutively performed between 2011 and May 2019 in a single centre. VOD was defined according to modified Seattle, Baltimore or revised EBMT criteria. Severity was retrospectively graded according to revised EBMT severity criteria into four categories: mild, moderate, severe and very severe. Complete response (CR) was defined as a normal total bilirubin level ( Results: Sixteen patients (9.1%) met the modified Seattle, Baltimore or revised EBMT diagnostic criteria for VOD. Ultrasound with Doppler ultrasonography was performed in all patients, and at least indirect signs of VOD were found in all cases. Based on revised EBMT severity criteria, there were 2 mild (12.5%), 2 moderate (12.5%), 2 severe (12.5%) and 10 very severe (62.5%) grade VOD. Twelve patients (75%) were treated with defibrotide, including all patients with very severe VOD, except one with CNS hemorrhage (Patient 1). Six patients with very severe VOD, were treated with TIPS due to rapid clinical or analytical deterioration or refractory hepatorenal syndrome, despite medical treatment including defibrotide (Table 1). All were male patients, with a median age of 31 years (range 22-36), all transplanted with myeloablative conditioning regimen. TIPS insertion was performed on a median time since VOD diagnosis of 5 days (range 1-28) without technical complications in any case. Median total bilirubin, ALT, creatinine and INR the day of procedure were 3 mg/dL (range 2.2-11.2), 1120 UI/L (range 10-2595), 2.45 mg/dL (range 2.06-3.58) and 1.96 (range 1.1-4) respectively. Median hepatic venous pressure gradient (HVPG) prior to and after TIPS was 22.5 (range 14-29) and 6.5 (range 2-10) mmHg respectively, with a median drop of 16.5 mmHg (range 9-19). Following TIPS, all patients showed clinical improvement with hepatomegaly, ascites and renal failure resolution, and all showed analytical improvement with bilirubin, creatinine and ALT values reduction, except for patient 2, whose TIPS indication was refractory hepatorenal syndrome with normal ALT levels (Figure 1). The 5 patients who had iniciated defibrotide before TIPS, completed 21 days of treatment. All patients met criteria for CR in a median of 8 days after TIPS insertion (range 2-82). The 100-day overall survival (OS) was 100%. Five patients were alive with normal liver and renal function at last follow up, and one patient died due to infection 7 months after Haplo-HSCT, with VOD in complete resolution. Conclusions: Incidence of VOD after Haplo-HSCT with PT-Cy is comparable to those reported after HLA-identical HSCT series. Most of the patients developed very severe VOD according to revised EBMT severity criteria. For patients with rapid progressive VOD, early TIPS insertion allowed completion of defibrotide therapy. The use of TIPS together with defibrotide resulted in complete response and no associated complications with a 0% of VOD associated mortality in spite of high severity. ALT values may be the best predictor of CR after TIPS procedure. In our experience, timely and individualized use of TIPS significantly improves outcome of very severe VOD after Haplo-HSCT. Therefore, TIPS should be promptly considered in rapid progressive cases. Disclosures No relevant conflicts of interest to declare.