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.

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..

Introduction: Although a number of patients with HIV infection and hematological disease have successfully undergone allogeneic hematopoietic stem-cell transplantation (HSCT), short and long-term outcomes remain not well known. We report the largest Spanish experience treating HIV-infected adult patients with high-risk hematological malignancies with allogeneic HSCT. Methods: We retrospectively reviewed 22 HIV-positive patients who received allogeneic HSCT in five centers in Spain. Results: A total of 22 patients with high-risk hematological malignancies were transplanted between 1999 and 2018. Median age was 44 years. With a median follow-up of 65 months (8-112), overall survival and event-free survival were 46%. Nonrelapse mortality was 14% at 12 months and relapse was 24% at 24 months. Grade II-IV acute graft-versus-host disease (GVHD) rate was 44%, and moderate/severe chronic GVHD rate was 41% at 24 months. All patients received combination antiretroviral therapy. Two patients showed severe toxicity related to drug interaction with antiretroviral therapy. 68% of patients showed infectious complications with viral infections as the most frequent cause. Two patients had invasive aspergillosis and one patient presented disseminated tuberculosis. All survivors except one maintained undetectable HIV load at last follow-up after HSCT. Conclusion: Allogeneic HSCT is an effective therapy for high-risk hematological malignancies in patients with HIV infection, and long-term HIV suppression with combination antiretroviral therapy is feasible. However, drug interactions with antiretroviral agents, occurrence of GVHD, and frequent infectious complications account for a complex procedure in this population. Selected HIV-infected patients with hematologic malignancies should be considered for allo-HSCT when indicated, in experienced centers. Copyright (C) 2019 Wolters Kluwer Health, Inc. All rights reserved.

Precise identification of patients at highest risk for developing Cytomegalovirus (CMV) DNAemia may improve CMV infection management in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) setting. Here, we studied the potential use of detecting free CMV micro(mi)RNAs circulating in plasma for predicting CMV DNAemia in this clinical scenario. A total of 62 adult allo-HSCT recipients were included in this prospective observational multicenter study. Plasma CMV DNA load was monitored using the CMV RealTime CMV PCR (Abbott Molecular, Des Plaines, IL, USA). Detection of mature CMV miRNAs in plasma drawn by days + 7, + 14 and + 30 after allo-HSCT was performed using the miScript PCR System (Qiagen, Hilden, Germany). Assays could be optimized for five out of the seven targeted CMV miRNAs: UL36-5p, US33-5p, UL148D, UL22A-5p and UL112-3p. Of the 62 patients included in the study, 42 developed a first episode of CMV DNAemia at a median of 35 days after allo-HSCT. All targeted CMV miRNA were detected early after transplantation, with CMV miRNA US33-5p and UL112-3p the most commonly found species at any time point; nevertheless, neither the detection rate of CMV miRNAs nor their abundance allowed discrimination between patients with subsequent CMV DNAemia and those with no CMV DNAemia. The data presented herein do not support any predictive utility of these CMV miRNAs for first episodes of CMV DNAemia in a cohort consisting primarily of allo-HSCT patients receiving haploidentical allografts.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a curative procedure for several hematological malignancies. Haploidentical HSCT (haplo-HSCT) using high-dose post-transplantation cyclophosphamide (PTCy) makes transplantation possible for patients with no HLA-matched sibling donor. However, this treatment can cause complications, mainly infection, graft-vs.-host disease (GVHD), and conditioning-related toxicity. In recent years, different biomarkers in the form of tissue-specific proteins have been investigated; these may help us to predict complications of allo-HSCT. In this study we explored two such biomarkers, suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3α (REG3α), 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. ST2 and REG3α levels at day +15 were not associated with post-transplant complications. ST2 levels at day +30 were higher in patients with grade II-IV acute GVHD, mainly those who received reduced intensity conditioning (RIC; median 2,503 vs. 1,830 ng/ml; p = 0.04). Of note, patients with higher plasma ST2 levels at day +30 also presented a higher incidence of non-relapse mortality (HR, 7.9; p = 0.004) and lower 2-year overall survival (25 vs. 44 months; p = 0.02) than patients with lower levels. Patients with REG3α levels higher than 1,989 pg/ml at day +30 presented a higher incidence of acute gastrointestinal GVHD in the whole cohort (HR, 8.37; p = 0.003) and in the RIC cohort (HR 6.59; p = 0.01). These data suggest that measurement of ST2 and REG3α might be useful for the prognosis and prediction of complications in patients undergoing haplo-HSCT with PTCy.

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.

BACKGROUND:Conflicting data have been published as to the risk of cytomegalovirus (CMV) DNAemia and CMV disease in patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide.METHODS:We conducted a multicenter retrospective study including 118 patients subjected to unmanipulated haplo-HSCT to further clarify this issue. An historic cohort comprising 165 patients undergoing other transplant modalities (HLA-matched related, matched unrelated or mismatched) was built for comparison purposes. Plasma CMV DNA monitoring was performed using two highly sensitive real-time PCR assays.RESULTS:Overall, the cumulative incidence of CMV DNAemia, recurrent CMV DNAemia, and CMV DNAemia requiring preemptive antiviral therapy in patients undergoing haplo-HSCT was 63.9%, 34.9%, and 50.1%, respectively. These figures were rather comparable for other transplant modalities (P = .22, P = .13 and P = .72, respectively). A trend toward longer duration of episodes and shorter CMV DNA doubling times was observed in haplo-HSCT patients in comparison with other transplant modalities. Furthermore, median CMV DNA peak load was significantly higher in haplo-HSCTs (P = .008), yet overall mortality by day 180 and 365 was the same across comparison groups. There were five cases of CMV disease, and all occurred in haplo-HSCT patients. This latter observation is worrying and merits further investigation.CONCLUSIONS:The incidence of initial and recurrent episodes of CMV DNAemia either requiring or not antiviral therapy in unmanipulated haplo-HSCT was comparable to other transplant modalities in our cohort.

BACKGROUND:Poor mobilization results are unexpected after G-CSF-induced peripheral blood stem cell collection in healthy donors. However, 2%-5% of the donors are poor mobilizers. Factors predicting CD34+-cell yield after mobilization in related alternative donors are still poorly known. PATIENTS AND METHODS:Baseline characteristics and efficacy results of G-CSF induced mobilization of 159 adult healthy donors in our institution from 2008 to 2016 were retrospectively analyzed. All donors received 10 μg/kg of G-CSF once a day subcutaneously for 4 days. Leukapheresis started on the 5th day of G-CSF treatment. Donors were classified as poor mobilizers if they had less than 20 000 CD34 + cell/mL peripheral blood count in the 5th day of G-CSF treatment or if they needed three or more leukapheresis for graft collection. RESULTS:Age, weight, and platelet count before and after mobilization were significantly different between poor and good mobilizers. Poor mobilizers (n = 16) were older (50.6 vs 41.7 years, P = 0.002), weight lower (64 vs 75 kg, P = 0.00) and showed a lower platelet count before (199.5 vs 219.0 × 109 /L, P = 0.03) and after (192.5 vs 206 × 109 /L, P = 0.019) mobilization. In the multivariate analysis only the 30% of the variability of mobilization was explained by the model (sensitivity 80%, specificity 70%). CONCLUSION:In this cohort of healthy donors in a single institution, older age, less weight, and lower platelet count was associated with poorer mobilization. With clinical and analytic factors it is not possible to predict more than 30% of the variability. Further studies are needed to investigate new variables.

BackgroundExtracorporeal photopheresis (ECP) is an efficient and established therapy to treat acute and chronic graft vs host disease (GVHD). Using an “off‐line” method, the first step (mononuclear cell [MNC] collection) is decisive, as long as a high MNC yield and purity in the collected product is desirable. Two “off‐line” devices were compared: the COBE Spectra and the Spectra Optia (Terumo BCT), using both continuous and intermittent protocols.Patients and methodsTwelve patients with GvHD (7 acute/5 chronic) were enrolled between June 2014 and May 2015 and were alternatively assigned for each procedure to either the COBE Spectra or the Spectra Optia cell separator. Patients characteristics and procedure/product parameters were analyzed.ResultsTwo hundred procedures (100 per device) were included. The Spectra Optia system showed higher total nucleated cells and MNC collection efficiencies (18.6(10.2‐29.7) vs 7.9(4.1‐14.8)% and 43.6(20.3‐59.5) vs 23.3(11.4‐37.1)%, P < .001) and monocyte and lymphocyte collection efficiencies (55.2(17.7‐83.2) vs 22.8(9‐38.9)% and 38.3(26.7‐53.4) vs 22.2(9‐38.9)%, respectively, P < .001). Absolute platelet loss (PL) and PL per liter of blood processed were significantly lower in the Spectra Optia group (22.9(18.3‐28.1) vs 33.6(26.5‐41.1)%, P < .001 and 3.7(3.1‐4.5) vs 4.3(3.5‐4.2)%, P = .01, respectively). However, granulocyte contamination was higher (4.5(1.3‐36) vs 1.2(0.4‐5.7)%, P < .001) and a higher product haematocrit was obtained with the Spectra Optia (1(0.5‐1.6) vs 0.3(0.2‐0.5)%, P < .001), without an impact on irradiation time.ConclusionsIn our study, Spectra Optia proved to be safe and effective in collecting MNC with high yield and purity for ECP in GvHD.

Autoimmune hemolytic anemia (AIHA) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT) associated with poor outcome. However, an optimal therapeutic approach is lacking.

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.

Abstract Introduction: Invasive Fungal Infection (IFI) is a serious complication after allogeneic stem cell transplantation (alloSCT). Its incidence and outcome are not well characterized in the setting of peripheral blood, non-manipulated haploidentical stem cell transplantation with postransplant cyclophosphamide (HaploSCT). The aim of the study is to analyze our experience among patients who underwent HaploSCT at our institution and developed an IFI, in order to identify the incidence, risk factors and its impact in survival. Materials and methods: One hundred and thirty-three patients underwent peripheral blood HaploSCT with postransplant cyclophosphamide at our institution between 2011 and 2017. IFI was classified according to the EORTC definitions. Proven and probable IFI were included. Results: Patients´ characteristics are shown in Table 1. Patients received primary antifungal prophylaxis with micafungin from the day before stem cell infusion, during admission and until neutrophil engraftment was stablished. Patients on steroid treatment due to GVHD received prophylaxis with micafungin or posaconazole. Twenty-three episodes of IFI were observed in 20 patients, 10 proven and 13 probable, with a cumulative incidence of IFI of 15% at 500 days. Most commonly isolated organism was Aspergillus spp (5 cases), followed by Candida spp (4 cases: 1 C. kruseii and 3 C. parapsilosis) and Fusarium spp (2 cases). Additionally we observed some isolated cases of Inonotus spp,Mucor spp and Trichosporon Ashii. Pulmonary involvement was the most frequent presentation (11 cases), followed by fungemia (5 cases, 4 Candida and 1 Trichosporon Ashii) and skin-pulmonary involvement (2 cases). Thirteen cases were diagnosed early, in the pre-engraftment period, 5 just after the engraftment and 5 cases developed later. Among patients with late occurrence of IFI, median time of IFI was 220 days, and all of them were associated with GVHD (3 grade III-IV acute GVHD and 2 moderate/severe chronic GVHD). IFI outcome was favorable in 14 out of the 23 documented IFI, with antifungal therapy. Treatment chosen was liposomal amphotericin B in 7 cases, voriconazole in 5 and combined treatment (with amphotericin B and azole) in 6. Death related to IFI was documented in 7 out of the 20 patients, with an IFI mortality cumulative incidence of 6.4%. Prior transplant (OR 4.5, p <0.01) and especially alloHSCT were associated to IFI development (OR 8.2, p <0.01). We did not find any other risk factor associated to IFI, like time of engraftment, disease, conditioning regimen, sequential regimen, grades II-IV GVHD or severe/moderate chronic GVHD. Conclusions: In our experience, cumulative incidence of IFI in the setting of HaploSCT was similar than the one observed in other studies with alloSCT. Mortality associated to IFI in the whole cohort was low (6.4 %). The most significant factor related to IFI development was having received a previous transplant, especially alloSCT. Therefore, this high risk population should be closely monitored and could benefit from prophylaxis with azoles. Disclosures No relevant conflicts of interest to declare.

Despite considerable advances in our understanding of the pathophysiology of graft-versus-host disease (GVHD), its prediction remains unresolved and depends mainly on clinical data. The aim of this study is to build a predictive model based on clinical variables and cytokine gene polymorphism for predicting acute GVHD (aGVHD) and chronic GVHD (cGVHD) from the analysis of a large cohort of HLA-identical sibling donor allogeneic stem cell transplant (allo-SCT) patients. A total of 25 SNPs in 12 cytokine genes were evaluated in 509 patients. Data were analyzed using a linear regression model and the least absolute shrinkage and selection operator (LASSO). The statistical model was constructed by randomly selecting 85% of cases (training set), and the predictive ability was confirmed based on the remaining 15% of cases (test set). Models including clinical and genetic variables (CG-M) predicted severe aGVHD significantly better than models including only clinical variables (C-M) or only genetic variables (G-M). For grades 3-4 aGVHD, the correct classification rates (CCR1) were: 100% for CG-M, 88% for G-M, and 50% for C-M. On the other hand, CG-M and G-M predicted extensive cGVHD better than C-M (CCR1: 80% vs. 66.7%, respectively). A risk score was calculated based on LASSO multivariate analyses. It was able to correctly stratify patients who developed grades 3-4 aGVHD (P<.001) and extensive cGVHD (P<.001). The novel predictive models proposed here improve the prediction of severe GVHD after allo-SCT. This approach could facilitate personalized risk-adapted clinical management of patients undergoing allo-SCT.

Abstract Introduction: Immune reconstitution (IR) has a significant impact in HSCT outcome with a role against opportunistic infections and in disease control. In the setting of unmanipulated haploidentical transplantation (Haplo-HSCT), some groups have identified the absolute leukocyte count on day +30 (ALC30) as an independent prognostic factor in terms of overall survival (OS), disease free survival (DFS) and infection related mortality (IM). The aim of this study was to evaluate the impact of early IR on different HSCT outcomes in patients who underwent Haplo-HSCT with postransplant cyclophosphamide (PTCy) at our institution. Patients and methods: Eighty-eight patients received a Haplo-HSCT from 2011 to 2016. Thirty-six percent of the patients received myeloablative conditioning regimen and 64% received reduced intensity regimen. Graft-versus-host disease (GVHD) prophylaxis was based on PTCy, cyclosporine and mycophenolate mofetil. Early IR was assessed through the analysis of different lymphocyte subpopulations at days +30 and +90 after transplantation, including ALC30 (cellular analyzer DXH, Beckman Coulter®); CD3+ lymphocyte count and their different subpopulations (CD4+ and CD8+ lymphocytes, naive and memory T cells) and NK cells count. Lymphocytes subpopulations were determined by multiparametric flow cytometry (FC500 and Navios, Beckman Coulter®). ROC curves were used to determine the optimal cut-off values for each of the studied variables. Results: Eighty-one patients were studied, excluding 7 who died before day +30. Median follow-up was 26 months (10-43). Patient´s characteristics are shown in Table 1. CMV reactivation was documented in 76% (62) of the patients, 4% (3) developed a proven invasive fungal infection, and 31% (25) presented hemorrhagic cystitis. Median OS and DFS were 26 months (10-43) and 24 months (9-39), respectively. IM rate and NRM rate were 10% and 24%, respectively, at the end of follow up. Median lymphocyte populations counts at day +30 are shown in Table2. ALC30 below 100 cells/uL (p= 0.027) and CD4+ naïve lymphocytes below 12 cells/uL (p=0.033) (both corresponding to the 25 percentile) were associated with lower OS compared to patients with higher counts at day +30 (Figure 1). Patients with ALC30 lower than 300 cells/uL (p=0.026) showed significantly higher NRM; CD8+ count lower than 20 cells/uL (p=0.022) also showed higher NRM. NK cells counts at day +30 lower than 14 cells/uL (p=0.014), near to percentile 25, predicted higher IM (62.5% vs 37.5%). We did not identify any lymphocyte subpopulation that could predict DFS. Patients with acute GVHD grades II-IV showed values of ALC30 lower than 200 cells/uL (p=0.051), although non-statistically significant. No relationship was found between lymphocytes subpopulations at day +90 and HaploSCT outcomes. Conclusions: Our study supports the prognostic significance of early IR after unmanipulated haploidentical transplantation with PTCy, as previously described by other groups. ALC30, CD4+ naïve lymphocytes, and CD8+ lymphocyte count at day +30 may be good early predictors for OS and NRM in this setting. On the other hand, low NK cells counts (lower than percentile 25) predicted higher IM. Patients with very low lymphocyte counts should be monitored closely as they are at high risk for infectious complications, NRM and OS. Disclosures No relevant conflicts of interest to declare.

The incidence of non-Hodgkin's lymphoma and Hodgkin's lymphoma is higher in patients with HIV infection than in the general population. Following the introduction of combination antiretroviral therapy (cART), the prognostic significance of HIV-related variables has decreased, and lymphoma-related factors have become more pronounced. Currently, treatments for lymphomas in HIV-infected patients do not differ from those used in the general population. However, differentiating characteristics of seropositive patients, such as the need for cART and specific prophylaxis and treatment of certain opportunistic infections, should be considered. This document updates recommendations on the diagnosis and treatment of lymphomas in HIV infected patients published by GESIDA/PETHEMA in 2008.

La incidencia de linfoma no hodgkiniano y linfoma de Hodgkin es mayor en pacientes con infección por el VIH que en la población general. Tras la introducción del tratamiento antirretroviral de combinación (TARc) ha disminuido la importancia pronóstica de variables relacionadas con el VIH, adquiriendo mayor peso factores relacionados con el linfoma. Actualmente, los tratamientos de los linfomas en pacientes infectados por VIH no difieren de los empleados en la población general. Pero existen algunos aspectos diferenciales de los pacientes con VIH como la necesidad de TARc, de profilaxis y de tratamientos de algunas infecciones oportunistas. En este documento se actualizan las recomendaciones sobre el diagnóstico y el tratamiento de los linfomas en pacientes infectados por VIH publicadas por GESIDA/PETHEMA en 2008.