Efficacy of CAR T-cell therapy is not impaired by previous bispecific antibody treatment in large B-cell lymphoma.

ABSTRACT: In this retrospective study, chimeric antigen receptor T cells remained effective in patients with relapsed/refractory large B-cell lymphoma after prior exposure to bispecific antibodies (BsAbs) targeting different antigens. These results are relevant to clinical practice, particularly given the increasing use of BsAbs in earlier treatment lines.

Immune reconstitution after single-unit umbilical cord blood transplantation using anti-thymoglobulin and myeloablative conditioning in adults with hematological malignancies.

This study aimed to investigate the kinetics of immune recovery following umbilical cord blood transplantation (UCBT) in adults who received a myeloablative conditioning (MAC) regimen and antithymocyte globulin (ATG). While the immune recovery kinetics has been extensively studied in pediatric UCBT recipients, limited data exist for adults. We conducted a comprehensive analysis of 221 consecutive adult patients who underwent UCBT with MAC and ATG at a single institution. Our objective was to evaluate the influence of patient, disease, and transplant factors, along with acute graft-versus-host disease (aGVHD), on immune reconstitution and overall survival. Our findings confirm a delayed recovery of T cells, while B and NK cell reconstitution exhibited rapid progress, with NK cell counts reaching normal levels within 3 months post-transplantation and B cells within 6 months. Within CD3+ T cells, CD8+ T cells also experienced a delayed recovery (12 months), but to a lesser extent compared to CD4+ T cells (18 months). Delayed immune recovery of T-cell subsets was associated with the development of aGVHD grade II-IV, older age, CMV negativity, and a female donor. Patients with lymphoproliferative diseases showed slower NK cell recovery. Our study demonstrates that adult patients undergoing MAC with ATG and receiving a single unit UCBT for hematologic malignancies experienced rapid reconstitution of NK and B cells. However, T cell recovery, particularly CD4+ T cells, was significantly delayed. To enhance T cell recovery, it may be crucial to consider UCB units with higher cellularity and optimize ATG doses in conditioning.

Outcome of Human Parainfluenza Virus infection in allogeneic stem cell transplantation recipients: possible impact of ribavirin therapy.

BACKGROUND: This retrospective study focused on analyzing community-acquired respiratory virus (CARV) infections, in particular human parainfluenza virus (hPIV) after allogeneic stem cell transplant (allo-SCT) in adults recipients. It aimed to assess the impact of ribavirin treatment, clinical characteristics, and risk factors associated with lower respiratory tract disease (LRTD) progression and all-cause mortality. PATIENTS AND METHODS: The study included 230 allo-SCT recipients diagnosed with hPIV between December 2013 and June 2023. Risk factors for the development of LRTD, disease severity, and mortality were analyzed. Ribavirin treatment was administered at physician discretion in 61 out of 230 cases (27%). RESULTS: Risk factors for LRTD progression in multivariate analysis were corticosteroids > 30 mg/day (Odds ratio (OR) 3.5, 95% Confidence Interval (C.I.) 1.3-9.4, p = 0.013), fever at the time of hPIV detection (OR 3.89, 95% C.I. 1.84-8.2, p < 0.001), and absolute lymphocyte count (ALC) < 0.2 × 109/L (OR 4.1, 95% C.I. 1.42-11.9, p = 0.009). In addition, the study found that ribavirin therapy significantly reduced progression to LRTD [OR 0.19, 95% C.I. 0.05-0.75, p = 0.018]. Co-infections (OR 5.7, 95% C.I. 1.4-23.5, p = 0.015) and ALC < 0.2 × 109/L (OR 17.7, 95% C.I. 3.6-87.1, p < 0.001) were independently associated with higher day + 100 after hPIV detection all-cause mortality. There were no significant differences in all-cause mortality and infectious mortality at day + 100 between the treated and untreated groups. CONCLUSION: ALC, corticosteroids, and fever increased the risk for progression to LRTD while ribavirin decreased the risk. However, mortality was associated with ALC and co-infections. This study supports further research of ribavirin therapy for hPIV in the allo-HSCT setting.

Cytomegalovirus-driven early-onset lymphocytosis in hematopoietic allogeneic transplant mimicking a T-cell lymphoma progression.

Hepatosplenic T-cell lymphoma (HSTCL) is an uncommon and highly aggressive subtype of peripheral T-cell lymphoma characterized by liver, spleen, and bone marrow involvement. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative treatment for HSTCL, but it carries a significant risk of relapse. Cytomegalovirus (CMV) reactivation is a frequent complication after alloHSCT, particularly in patients undergoing lymphocyte-toxic therapies. A 27-year-old man diagnosed with HSTCL underwent an alloHSCT with active disease after six lines of therapy. A CMV reactivation was successfully treated with foscarnet. A sudden reappearance of symptomatic lymphocytosis (15,550/µL) by day +20, prior to engraftment, raised suspicion of disease progression. A comprehensive diagnostic work-up revealed an oligoclonal expansion of donor lymphocytes along with complete donor chimerism, leading to an alternative diagnosis of a CMV-driven T-cell expansion. This was confirmed by an in vitro assay testing T-cell specificity against CMV. The patient achieved both complete response and complete donor chimerism despite persisting lymphocytosis, but ultimately relapsed. This case highlights the importance of diagnostic tools in understanding disease progression and guiding treatment decisions.

Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma.

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-targeted chimeric antigen receptor (CAR) T cells approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We performed a retrospective study to evaluate safety and efficacy of axi-cel and tisa-cel outside the setting of a clinical trial. Data from consecutive patients with R/R LBCL who underwent apheresis for axi-cel or tisa-cel were retrospectively collected from 12 Spanish centers. A total of 307 patients underwent apheresis for axi-cel (n=152) and tisa-cel (n=155) from November 2018 to August 2021, of which 261 (85%) received a CAR T infusion (88% and 82%, respectively). Median time from apheresis to infusion was 41 days for axi-cel and 52 days for tisa-cel (P=0.006). None of the baseline characteristics were significantly different between both cohorts. Both cytokine release syndrome and neurologic events (NE) were more frequent in the axi-cel group (88% vs. 73%, P=0.003, and 42% vs. 16%, P<0.001, respectively). Infections in the first 6 months post-infusion were also more common in patients treated with axi-cel (38% vs. 25%, P=0.033). Non-relapse mortality was not significantly different between the axi-cel and tisa-cel groups (7% and 4%, respectively, P=0.298). With a median follow-up of 9.2 months, median PFS and OS were 5.9 and 3 months, and 13.9 and 11.2 months for axi-cel and tisa-cel, respectively. The 12-month PFS and OS for axi-cel and tisa-cel were 41% and 33% (P=0.195), 51% and 47% (P=0.191), respectively. Factors associated with lower OS in the multivariate analysis were increased lactate dehydrogenase, ECOG ≥2 and progressive disease before lymphodepletion. Safety and efficacy results in our real-world experience were comparable with those reported in the pivotal trials. Patients treated with axi-cel experienced more toxicity but similar non-relapse mortality compared with those receiving tisa-cel. Efficacy was not significantly different between both products.

Respiratory virus infections after allogeneic stem cell transplantation: Current understanding, knowledge gaps, and recent advances.

Before the COVID-19 pandemic, common community-acquired seasonal respiratory viruses (CARVs) were a significant threat to the health and well-being of allogeneic hematopoietic cell transplant (allo-HCT) recipients, often resulting in severe illness and even death. The pandemic has further highlighted the significant risk that immunosuppressed patients, including allo-HCT recipients, face when infected with SARS-CoV-2. As preventive transmission measures are relaxed and CARVs circulate again among the community, including in allo-HSCT recipients, it is crucial to understand the current state of knowledge, gaps, and recent advances regarding CARV infection in allo-HCT recipients. Urgent research is needed to identify seasonal respiratory viruses as potential drivers for future pandemics.

Features of cytomegalovirus DNAemia and virus-specific T-cell responses in allogeneic hematopoietic stem-cell transplant recipients during prophylaxis with letermovir.

BACKGROUND: There is scarce information on the natural kinetics of cytomegalovirus (CMV) DNAemia and dynamics of CMV-specific T-cell reconstitution in allogeneic hematopoietic transplant recipients (allo-HSCT) undergoing letermovir (LMV) prophylaxis. METHODS: Twelve adult CMV-seropositive high-risk recipients (median age, 53 years; 9 males/3 females) undergoing LMV prophylaxis and 13 non-LMV allo-HSCT controls (median age, 58 years; 7 males/6 females) were included. CMV DNAemia in plasma was monitored by real-time polymerase chain reaction. Preemptive antiviral therapy (PET) was administered upon detection of ≥1500 IU/ml. CMV-specific interferon-gamma (IFN-γ)-producing CD8+ and CD4+ T cells were enumerated by flow cytometry around days +30, +60, and +90 after allo-HSCT. Ex vivo experiments assessing of the potential effect of LMV on CMV-specific T-cell expansion in a single CMV-seropositive donor were also conducted. RESULTS: Five LMV patients (41.6%) developed CMV DNAemia that cleared spontaneously. Four patients (33.3%) developed CMV DNAemia after LMV cessation, of which two required PET. Nine non-LMV patients (69.2%) developed CMV DNAemia (five required PET). The percentage of LMV and non-LMV patients exhibiting detectable CMV-specific T-cell responses was comparable (7/10 vs. 10/13; p = .71). Nevertheless, median CMV-specific CD4+ and CD8+ T-cell counts were lower in LMV patients by days +60 (p = .006 and .02, respectively) and +90 (p = .08 and .02). Ex vivo, CMV-specific CD8+ T cells expanded to the same level either in the presence (19.8%) or in the absence of LMV (20.6%). CONCLUSIONS: In our series, episodes of CMV DNAemia in LMV patients cleared spontaneously. A diminished degree of CMV-specific T-cell reconstitution in LMV patients compared to non-LMV patients was observed.

Resistance to empirical ß-lactams recommended in febrile neutropenia guidelines in Gram-negative bacilli bloodstream infections in Spain: a multicentre study.

OBJECTIVES: To describe current resistance to the ß-lactams empirically recommended in the guidelines in bloodstream infection (BSI) episodes caused by Gram-negative bacilli (GNB). METHODS: Retrospective, multicentre cohort study of the last 50 BSI episodes in haematological patients across 14 university hospitals in Spain. Rates of inappropriate empirical antibiotic therapy (IEAT) and impact on mortality were evaluated. RESULTS: Of the 700 BSI episodes, 308 (44%) were caused by GNB, mainly Escherichia coli (141; 20.1%), Klebsiella spp. (56; 8%) and Pseudomonas aeruginosa (48; 6.9%). Among GNB BSI episodes, 80 (26%) were caused by MDR isolates. In those caused by Enterobacterales, 25.8% were ESBL producers and 3.5% were carbapenemase producers. Among P. aeruginosa BSI episodes, 18.8% were caused by MDR isolates. Overall, 34.7% of the isolated GNB were resistant to at least one of the three ß-lactams recommended in febrile neutropenia guidelines (cefepime, piperacillin/tazobactam and meropenem). Despite extensive compliance with guideline recommendations (91.6%), 16.6% of BSI episodes caused by GNB received IEAT, which was more frequent among MDR GNB isolates (46.3% versus 6.1%; P < 0.001). Thirty day mortality was 14.6%, reaching 21.6% in patients receiving IEAT. CONCLUSIONS: Current resistance to empirical ß-lactams recommended in febrile neutropenia guidelines is exceedingly high and IEAT rates are greater than desired. There is an urgent need to adapt guidelines to current epidemiology and better identify patients with a high risk of developing MDR GNB infection.

SARS-CoV-2-reactive antibody detection after SARS-CoV-2 vaccination in hematopoietic stem cell transplant recipients: Prospective survey from the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group.

This is a multicenter prospective observational study that included a large cohort (n = 397) of allogeneic (allo-HSCT; (n = 311) and autologous (ASCT) hematopoietic stem cell transplant (n = 86) recipients who were monitored for antibody detection within 3-6 weeks after complete severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination from February 1, 2021, to July 20, 2021. Most patients (n = 387, 97.4%) received mRNA-based vaccines. Most of the recipients (93%) were vaccinated more than 1 year after transplant. Detectable SARS-CoV-2-reactive antibodies were observed in 242 (78%) of allo-HSCT and in 73 (85%) of ASCT recipients. Multivariate analysis in allo-HSCT recipients identified lymphopenia < 1 × 109 /ml (odds ratio [OR] 0.33, 95% confidence interval [95% CI] 0.16-0.69, p = .003), active graft versus host disease (GvHD; OR 0.51, 95% CI 0.27-0.98, p = .04) and vaccination within the first year of transplant (OR 0.3, 95% CI 0.15-0.9, p = .04) associated with lower antibody detection whereas. In ASCT, non-Hodgkin's lymphoma (NHL; OR 0.09, 95% CI 0.02-0.44, p = .003) and active corticosteroid therapy (OR 0.2, 95% CI 0.02-0.87, p = .03) were associated with lower detection rate. We report an encouraging rate of SARS-CoV-2-reactive antibodies detection in these severe immunocompromised patients. Lymphopenia, GvHD, the timing of vaccine, and NHL and corticosteroids therapy should be considered in allo-HSCT and ASCT, respectively, to identify candidates for SARS-CoV-2 antibodies monitoring.

An investigation of the potential association between gastrointestinal viral and bacterial infection and development of intestinal acute graft versus host disease following allogeneic hematopoietic stem cell transplantation.

It is uncertain whether gastrointestinal (GI) infection caused by viral and bacterial pathogens may predispose to gastrointestinal acute Graft-versus-host disease (aGvHD-GI) in allogeneic hematopoietic stem cell transplant recipients (allo-HSCT). We investigated the potential association between detection of enteropathogenic viruses or bacteria in stools and subsequent occurrence of aGvHD-GI in a cohort of 121 allo-HSCT patients. Eighty-six out of 121 patients (71%) had acute diarrhea and underwent screening for primary GI pathogens by molecular diagnostic methods. One or more GI pathogens were detected in 27 out of the 86 patients with diarrhea (31.3%). Specifically, Clostridioides difficile was found in 16 patients (18.6%), enteropathogenic viruses in 11 patients (12.7%) (Astrovirus, n = 4; Norovirus, n = 2; Sapovirus, n = 2; Adenovirus, n = 2; and Rotavirus, n = 1), and Campylobacter spp. in two patients (2.3%). Thirty patients were diagnosed with all grade aGvHD-GI by histopathology. Detection of primary GI pathogens was achieved in 12 out of 30 patients (Clostridium difficile, n = 5; enteric viruses, n = 8; Campylobacter spp., n = 1) who either subsequently developed (n = 9) or previously had (n = 3) grade I-IV IaGvHD (n = 9). Neither the detection of these microorganisms (all combined), enteric viruses, nor C. difficile was significantly associated with subsequent aGvHD-GI development in Cox models (hazard ratio [HR] = 1.11, p = .80; HR = 1.64, p = .62; HR = 0.75, p = .64, respectively). Analogous results were obtained when grade II-IV aGvHD-GI was selected as the clinical outcome. In summary, data in the current study did not support an association between GI infection and subsequent occurrence of aGvHD-GI in an unselected cohort of allo-HSCT recipients.

Ex vivo T-cell depletion vs post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil as graft-vs-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: To compare the efficacy and safety of CD34+ selected ex vivo T-cell depletion (TCD) vs post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil (PTCy-Sir-MMF) as graft-vs-host disease (GVHD) prophylaxis. METHODS: We retrospectively included patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with either TCD (n = 38) or PTCy-Sir-MMF (n = 91). RESULTS: Cumulative incidence of neutrophil and platelet recovery was 92% vs 99% (P = .06) and 89% vs 97% (P = .3) in TCD and PTCy-Sir-MMF, respectively. Cumulative incidences of aGHVD grade II-IV, III-IV, and moderate to severe cGVHD were 11% vs 19% (P = .2), 3% vs 2% (P = .9), and 3% vs 36% (P < .001) in TCD and PTCy-Sir-MMF, respectively. The 2-year non-relapse mortality, relapse, disease-free and overall survival were 25% vs 8% (P = .01), 20% vs 16% (P = .2), 55% vs 76% (P = .004), 57% vs 83% (P = .004) for TCD and PTCy-Sir-MMF, respectively. Cumulative incidence of cytomegalovirus and Epstein-Barr infection requiring therapy was 76% vs 40% (P < .001) and 32% vs 0% (P < .001) in TCD and PTCy-Sir-MMF, respectively. PTCy-Sir-MMF platform showed faster T-cell reconstitution. CONCLUSIONS: PTCy-Sir-MMF provides better survival outcomes but is associated with higher risk of cGVHD compared to TCD.

Defibrotide in hematopoietic stem cell transplantation: A multicenter survey study of the Spanish Hematopoietic Stem Cell Transplantation Group (GETH).

BACKGROUND: Defibrotide is approved in European Union for the treatment of severe sinusoidal obstruction syndrome (SOS) after HSCT. However, it has also been used for SOS prophylaxis, moderate SOS and in other complications such as transplant-associated thrombotic microangiopathy (TAM). The objective of this study was to evaluate current uses, effectiveness and safety of defibrotide in patients with HSCT. METHODS: This multicenter, retrospective study included patients treated with defibrotide for any indication at 28 HSCT centers of the Grupo Español de Trasplante Hematopoyetico (GETH) including the pediatric subgroup Grupo Español de Trasplante de Medula en Niños (GETMON). RESULTS: Three hundred and eighty eight patients treated with defibrotide between January 2011 and December 2018 were included. 253 patients were children, and 135 patients were adults. In total, 332 transplants were allogeneic, and the remainder were autologous. Main indications for defibrotide use were severe/very severe SOS in 173 patients, SOS prophylaxis in 135 patients, moderate SOS in 41 patients, TAM in six patients and suspected SOS in 33 patients. Overall survival (OS) at day +100 in the SOS prophylaxis group was 89% (95% CI, 87%-91%). In the group of patients with moderate and severe/very severe SOS, the OS at day +100 was 80% (95% CI, 74%-86%) and 62% (95% CI, 59%-65%), respectively (P = .0015). With a longer follow-up, median of 2 years (4 months-7 years), OS was 63% (95% CI, 59%-67%) in the SOS prophylaxis patients. OS for patients with moderate and severe/very severe SOS groups was 53% (95% CI, 47%-61%) and 26% (95% CI, 22%-30%), respectively (P = .006). 191 patients died, and SOS was the main cause of death in 23 patients (12%). CONCLUSIONS: Defibrotide has an acceptable safety profile with an improved response in severe/very severe SOS compared with historical controls, mainly in pediatric patients. Use of defibrotide for prophylaxis may improve prognosis of patients at high risk of complications due to endothelial damage such as those who receive a second transplant. SOS has an important impact on the HSCT long-term survival, as can be concluded from our study.

Kinetics of Torque Teno virus DNA in stools may predict occurrence of acute intestinal graft versus host disease early after allogeneic hematopoietic stem cell transplantation.

Torque Teno virus (TTV) DNA load in blood may act as a marker of immune competence after allogeneic hematopoietic stem cell transplant recipients (allo-HSCT). Conflicting data have been reported as to the value of this biomarker for anticipating acute Graft versus host disease (aGvHD) occurrence. Here, we hypothesized that quantitation of TTV DNA load in stool specimens early after allo-HSCT could be used to identify patients at high risk of acute intestinal graft versus host disease (aIGvHD). In this prospective two-center study, we recruited a total of 83 nonconsecutive adult patients undergoing allo-HSCT. The study period comprised the first 120 days after allo-HSCT. TTV DNA was quantitated in paired stool samples collected at a median of 2 days prior to cell infusion and at a median of 14 days after allo-HSCT by real-time PCR. Thirty-seven patients developed aGVHD, of whom 25 had aIGVHD (diagnosed at a median of 42 days after allo-HSCT). Median TTV DNA load values in posttransplant stools specimens were comparable (P = .34) in patients with or without subsequent aIGvHD; nevertheless, a falling trajectory (decrease in TTV DNA load >0.5 log10 copies/0.1 g) in paired pretransplant and posttransplant specimens was independently associated with the occurrence of aIGvHD (OR, 5.2; 95% CI, 1.3-21.3; P = .02). Notably, displaying a rising trajectory had a negative predictive value of 87.5% for aIGvHD. In summary, in this hypothesis-generating study, we suggest that the decrease in TTV DNA load from baseline in stool specimens may identify patients at risk of aIGVHD.

Adoptive transfer of ex vivo expanded SARS-CoV-2-specific cytotoxic lymphocytes: A viable strategy for COVID-19 immunosuppressed patients?

Cellular and humoral response to acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is on focus of research. We evaluate herein the feasibility of expanding virus-specific T cells (VST) against SARS-CoV-2 ex vivo through a standard protocol proven effective for other viruses. The experiment was performed in three different donors' scenarios: (a) SARS-CoV-2 asymptomatic infection/negative serology, (b) SARS-CoV-2 symptomatic infection/positive serology, and (c) no history of SARS-CoV-2 infection/negative serology. We were able to obtain an expanded VST product from donors 1 and 2 (1.6x and 1.8x increase of baseline VST count, respectively) consisting in CD3 + cells (80.3% and 62.7%, respectively) with CD4 + dominance (60% in both donors). Higher numbers of VST were obtained from the donor 2 as compared to donor 1. T-cell clonality test showed oligoclonal reproducible peaks on a polyclonal background for both donors. In contrast, VST could be neither expanded nor primed in a donor without evidence of prior infection. This proof-of-concept study supports the feasibility of expanding ex vivo SARS-CoV-2-specific VST from blood of convalescent donors. The results raise the question of whether the selection of seropositive donors may be a strategy to obtain cell lines enriched in their SARS-CoV-2-specificity for future adoptive transfer to immunosuppressed patients.

Extracorporeal photopheresis vs standard therapies for steroid-refractory chronic graft-vs-host disease: Pharmacoeconomic assessment of hospital resource use in Spain.

BACKGROUND: This study assessed pharmacoeconomic costs associated with extracorporeal photopheresis (ECP) compared with other available second-line therapies for chronic graft-vs-host disease (cGvHD) in a tertiary Spanish institution. METHODS: Patients (≥18 years) diagnosed with steroid-refractory cGvHD were eligible. Data were collected retrospectively from index date until 1 year or relapse. Patients were distributed in two cohorts (ECP vs non-ECP), matched by age (≤ or > 40), hematopoietic stem cell transplant (HLA-identical sibling donor or other) and number of previous immunosuppressive lines (1, 2, or ≥ 3). Costs were assigned using the 2016 diagnosis-related group (DRG) system: DRG 579 (€22 383) overnight stay due to major complication (ie, sepsis, pneumonia, parenteral nutrition, or respiratory failure), and DRG 875 (€5154) if no major complication. The primary endpoint was healthcare resource utilization per patient. RESULTS: Forty patients (n = 20 per cohort) were included. Median age was 49, and 37.5% were female. Mean total cost per patient was €25 319 (95% CI: €17 049-€33 590) across the two cohorts, with a slightly lower mean cost per ECP-treated patient (€23 120) compared with the non-ECP cohort (€27 519; P = .597). Twenty-seven inpatient hospitalizations occurred among ECP-treated patients, vs 33 in the non-ECP cohort. Day hospital and external consultations were more frequent in the ECP cohort. However, fewer inpatient admissions included DRG 579 compared with the non-ECP cohort (44% vs 58%). Inpatient length of stay was slightly shorter in the ECP cohort (30 vs 49 days; P = .298). CONCLUSIONS: ECP treatment may yield economic savings in Spain through resource savings and moving costs toward outpatient care.

Prospective Randomized Study Comparing Myeloablative Unrelated Umbilical Cord Blood Transplantation versus HLA-Haploidentical Related Stem Cell Transplantation for Adults with Hematologic Malignancies.

In this prospective randomized study, we compared the outcomes of single-unit umbilical cord blood transplantation (UCBT) and unmanipulated haploidentical stem cell transplantation (haplo-SCT) with post-transplantation cyclophosphamide (PTCy) in adults with hematologic malignancies. All patients received a myeloablative conditioning (MAC) regimen consisting of thiotepa, busulfan, and fludarabine, with antithymocyte globulin (ATG) added for UCBT recipients. Nineteen patients were randomized to UCBT and the other 26 to haplo-HSCT. Four patients (15%) allocated to the haplo-HSCT arm lacked a suitable donor and were crossed over to the UCBT arm. Finally, 23 underwent UCBT and 22 underwent haplo-HSCT. The cumulative incidence of neutrophil recovery was 87% at a median of 19 days (range, 13 to 24 days) in the UCBT arm versus 100% at a median of 17 days (range, 13 to 25 days) in the haplo-SCT arm (P = .04). Platelet recovery was 70% at a median of 40 days (range, 18 to 129 days) in the UCBT arm versus 86% at a median of 24 days (range, 12 to 127 days) in the haplo-HCT arm (P = .02). Rates of acute graft-versus-host disease (GVHD) grade II-IV or grade III-IV, overall chronic GVHD, and extensive chronic GVHD in the UCBT and Haplo-SCT arms were 43% versus 36% (P = .8), 9% versus 9% (P = 1), 66% versus 43% (P = .04), and 41% versus 23% (P = .2), respectively. Two-year nonrelapse mortality and relapse in the 2 arms were 52% versus 23% (P = .06) and 17% versus 23% (P = .5), respectively. Two-year disease-free survival, overall survival, and GVHD/relapse-free survival in the 2 arms were 30% versus 54% (P = .2), 35% versus 59% (P = .1), and 17% versus 40% (P = .04), respectively. Our data show that in the context of an MAC regimen, haplo-SCT with PTCy provides improved outcomes compared with ATG-containing single-unit UCBT.

Partial T Cell-Depleted Peripheral Blood Stem Cell Transplantation from HLA-Identical Sibling Donors for Patients with Severe Aplastic Anemia.

We analyzed the outcomes of 26 consecutive patients with acquired severe aplastic anemia (SAA) undergoing peripheral blood stem cell transplantation (PBSCT) with partial ex vivo T cell depletion with a targeted T cell dose from HLA-identical sibling donors. The median patient age was 37 years (range, 3 to 63 years). Four patients with uncontrolled pneumonia at the time of transplantation died, on days +1, +2, +21, and +26. All evaluable patients engrafted, with a median time to neutrophil recovery of 11 days (range, 10 to 14 days) and a median time to platelet recovery of 19 days (range, 8 to 53 days). Two patients had transient grade I acute graft-versus-host disease (GVHD) with skin involvement, but no patients developed grade II-IV acute GVHD. Two patients had mild skin chronic GVHD, and 1 patient had moderate chronic GVHD with ocular involvement. No relapse was observed after a median follow-up of 114 months (range, 4 to 233 months). The overall cumulative incidence of TRM at 10 years was 19%, whereas it was 5% for those with a Karnofsky Performance Status (KPS) score >60 at the time of transplantation. Disease-free survival, overall survival, and GVHD and relapse-free survival at 10 years were 81%, 81%, and 80%, respectively, for all patients and 95%, 95%, and 90%, respectively, for patients with a KPS score >60 at transplantation. Our data indicate that PBSCT with partial ex vivo T cell-depleted targeted cell dose grafts from an HLA-identical sibling donor is a feasible, safe, and effective approach to reduce GVHD and cure patients with SAA.

Assessment of immunodeficiency scoring index performance in enterovirus/rhinovirus respiratory infection after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Enterovirus/rhinoviruses (EvRh) are the most common cause of respiratory virus infections in recipients of allogeneic stem cell transplantation (allo-HSCT). OBJECTIVE: We sought to analyze the value of the immunodeficiency scoring index (ISI) in predicting lower respiratory tract disease (LRTD) progression and mortality in a prospective cohort of consecutive adult (>16 years) allo-HSCT recipients with EvRh infection from December 1 2013 to December 1 2019 at two Spanish transplant centers. RESULTS: We included 234 allo-HSCT recipients with 383 EvRh episodes. Out of 383 EvRh episodes, 98 (25%) had LRTD. Multivariate logistic regression analysis identified three independent factors associated with LRTD progression: Ig G < 400 mg/dL, community-acquired respiratory virus (CARV) co-infection and high-risk ISI. Inclusion of Ig G levels and CARV co-infection in the ISI improved its performance by significantly increasing the area under the receiver operator characteristic curve (AUROC) from 0.643 to 0.734 (P = .03). Likewise, the two conditions identified by multivariate analyses as associated with higher probability of mortality were high-risk ISI and EvRh infection within 6 months after transplant. CONCLUSIONS: Our findings confirm the value of high-risk ISI in predicting both probability of EvRh LRTD and 3-month overall mortality. We also demonstrate that the original ISI could be adapted to other CARV types by including additional variables to improve its performance.

Cytomegalovirus DNA load monitoring in stool specimens for anticipating the occurrence of intestinal acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: Is it of any value?

BACKGROUND: Data have been published suggesting a bidirectional interaction between cytomegalovirus (CMV) infection and acute graft-versus-host disease (aGvHD) in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we hypothesized that prospective CMV DNA monitoring in stool specimens may be useful for predicting subsequent occurrence of intestinal aGvHD (IaGvHD). METHODS: This two-center study enrolled 121 consecutive adult patients undergoing any modality of allo-HSCT. A total of 1,009 stool specimens were collected (a median of 7 specimens/patient; range, 1-18). CMV DNA monitoring in stools and plasma was performed using real-time PCR assays. RESULTS: CMV DNA was detected in stools in 20 patients (cumulative incidence, 16.9%; 95% CI, 6.3%-31.8%). Median CMV DNA level in stool specimens was 1,258 IU/0.1g (range, 210-4,087 IU/0.1 g). All these patients and their donors were CMV seropositive, and 16 of the 20 patients also had CMV DNAemia, while 4 patients had CMV DNA detected in stools without CMV DNAemia. No correlation was found between CMV DNA loads in plasma and stools (P = .40). Prior CMV DNAemia, aGvHD, or IaGvHD were not associated with presence of CMV DNA in feces. IaGvHD was present in 30 patients, in 5 of whom CMV DNA was detected in stools. Neither detection of CMV DNA in feces nor in plasma was associated with subsequent IaGvHD (OR, 0.67; 95% CI, 0.18-2.52; P = .55 and OR, 0.86; 95% CI, 0.38-1.96; P = .71, respectively). No patient in this cohort had CMV end-organ disease within the study period. CONCLUSION: Our study failed to provide evidence pointing to a reciprocal interaction between GI CMV infection and IaGvHD. CMV DNA monitoring in stools seems of no value to anticipate occurrence of IaGvHD.

Noninfectious Neurologic Complications after Allogeneic Hematopoietic Stem Cell Transplantation.

Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be associated with neurologic complications, data on noninfectious etiologies are scanty. Therefore, we analyzed the incidence, clinical characteristics, risk factors, and influence on outcomes of noninfectious neurologic complications (NCs) in 971 consecutive patients with hematologic malignancies undergoing allo-HSCT at our center between January 2000 and December 2016. We evaluated NCs affecting the central nervous system (CNS) and peripheral nervous system (PNS). The median duration of follow-up of survivors was 71 months (range, 11 to 213 months). A total of 467 patients received a matched sibling donor (MSD) transplant, 381 received umbilical cord blood (UCB), 74 received a haploidentical transplant, and 49 received a matched unrelated donor (MUD) transplant. One hundred forty-nine (15.3%) NCs were documented at a median of 78 days after transplantation (range, 5 days before to 3722 days after). The cumulative incidence risk of developing NC was 7.5% (95% confidence interval, 6% to 8.2%) at day +90 and 13% at 5 years. The 5-year cumulative incidence of NCs was 10.8% after MSD allo-HSCT and 15.3% after alternative donor (UCB, MUD, haploidentical) allo-HSCT (P = .004). There were 101 (68%) CNS complications, including encephalopathy, n = 46 (31%); headache, n = 20 (13%); stroke, n = 15 (10%); seizures, n = 9 (6%), posterior reversible encephalopathy syndrome, n = 6 (4%), and myelopathy, n = 5 (3%). PNS complications (32%) included neuropathies, n = 25 (17%), and myopathies and neuromuscular junction disorders, n = 23 (17%), with 17% of the total PNS complications being immune-related. In multivariable analysis, donor type other than MSD, age ≥40 years, development of acute graft-versus-host disease (GVHD) grade II-IV (hazard ratio [HR], 3.3; P < .00001), and extensive chronic GVHD (HR, 3.2; P = .0002) were independently associated with increased risk of NCs. The 5-year overall survival (OS) was 21% in patients who developed NCs and 41% for those who did not (P < .0001). This difference in OS was observed in patients developing CNS NCs, but not in those developing PNS complications. In conclusion, our study reveals NCs as a frequent and heterogeneous complication that, when affecting CNS, is associated with poor prognosis following allo-HSCT.