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Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GvHD) represent life-threatening syndromes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In both conditions, endothelial dysfunction is a common denominator, and development of relevant biomarkers is of high importance for both diagnosis and prognosis. Despite the fact that soluble urokinase plasminogen activator receptor (suPAR) and growth differentiation factor-15 (GDF-15) have been determined as endothelial injury indices in various clinical settings, their role in HSCT-related complications remains unexplored. In this context, we used immunoenzymatic methods to measure suPAR and GDF-15 levels in HSCT-TMA, acute and/or chronic GVHD, control HSCT recipients, and apparently healthy individuals of similar age and gender. We found considerably greater SuPAR and GDF-15 levels in HSCT-TMA and GVHD patients compared to allo-HSCT and healthy patients. Both GDF-15 and suPAR concentrations were linked to EASIX at day 100 and last follow-up. SuPAR was associated with creatinine and platelets at day 100 and last follow-up, while GDF-15 was associated only with platelets, suggesting that laboratory values do not drive EASIX. SuPAR, but not GDF-15, was related to soluble C5b-9 levels, a sign of increased HSCT-TMA risk. Our study shows for the first time that suPAR and GDF-15 indicate endothelial damage in allo-HSCT recipients. Rigorous validation of these biomarkers in many cohorts may provide utility for their usefulness in identifying and stratifying allo-HSCT recipients with endothelial cell impairment. [ABSTRACT FROM AUTHOR]

Abstract: Immunized against hepatitis B virus (HBV) recipients are at risk of developing HBV postallogeneic stem cell transplantation because of the potential loss of their HBV immunity. The aim of the study was to evaluate: (1) the HbsAb eradication incidence posttransplant and potential risk factors, (2) the impact of donor’s immunity on HbsAb loss, (3) the incidence of hepatitis B in patients with HbsAb disappearance. We studied, retrospectively, in 26 vaccinated and 56 naturally immunized recipients, the posttransplant HbsAb titers for a median period of 36 (6-132) months. The probability of HbsAb loss and HBV-related hepatitis was determined in all recipients. The impact of donor’s immunity origin in the HBsAb disappearance was evaluated in the subgroup of, actively or naturally, immunized recipients/donors pairs. The 5-year probability of HbsAb disappearance was 90% for all patients with 18% probability of developing hepatitis at 12 years, for those who lost HbsAb. Marrow graft, antithymocyte globulin administration, age <30 years and chronic graft-versus-host disease were significant risk factors for HbsAb loss. In the subgroup of immunized recipients/donors, the donor’s active immunization significantly affected this loss. Allotransplanted patients are at high risk of losing protection against HBV. The adoptive transfer of active HBV immunity does not seem to offer sustained protection posttransplant. [Copyright &y& Elsevier]

Abstract: Fresh frozen plasma (FFP) contains natural anticoagulants, such as antithrombin (AT) and Protein C (Prot-C). We hypothesized that FFP given in addition to heparin, could potentially replace the consumption of endogenous anticoagulants occurring during conditioning and moreover, corrected AT levels could augment heparin''s anticoagulant function. This could therefore result in an effective anti-VOD prophylaxis. In this study, we retrospectively analyzed the incidence of hepatic VOD in 403 consecutive bone marrow transplants (BMTs) comparing 2 prophylactic regimens and no prophylaxis. Patients received no prophylaxis (70/403), heparin-only (27/403) or heparin+2FFP daily during conditioning (306/403). VOD was significantly lower in the heparin+FFP group (5.9%) compared to heparin (20%) and no prophylaxis group (15.7%) [p < 0.01]. Day 8 AT and Prot-C levels, were lower in the VOD- compared to the non-VOD group (AT: 69±26% vs. 89±19%, Prot-C:68±26% vs. 91±29%, respectively, p =0.001). In a multivariate logistic regression, risk factors for developing VOD were: the administration of >2 hepato-nephrotoxic drugs, previous history of hepatitis B or C and number of BMT. Multivariate analysis in a subset of 198 patients (all having recorded AT, Prot-C), demonstrated as VOD-related factors, the low day 8 Prot-C, number of BMT>1 and prior abdominal radiotherapy. Our study implies that FFP during conditioning, in addition to heparin, potentially has an anti-VOD prophylactic effect, presumably by minimizing the drop of natural anticoagulants around day 8. In order to evaluate if there truely is a beneficial effect of heparin+FFP in VOD prophylaxis, we have initiated a prospective randomized trial. [Copyright &y& Elsevier]

Changes in gut microbiome composition have been implicated in the pathogenesis of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our objective was to explore the microbial abundance in patients with GvHD after allo-HSCT. We conducted a single-center, prospective study in patients who underwent allo-HSCT and developed grade II or higher acute GvHD and/or moderate or severe chronic GvHD, to explore the microbial abundance of taxa at the phylum, family, genus, and species level, and we utilized alpha and beta diversity indices to further describe our findings. We collected fecal specimens at −2 to +2 (T1), +11 to +17 (T2), +25 to +30 (T3), +90 (T4), and +180 (T5) days to assess changes in gut microbiota, with day 0 being the day of allo-HSCT. We included 20 allo-HSCT recipients in the study. Compared with timepoint T1, at timepoint T4 we found a significant decrease in the abundance of Proteobacteria phylum (14.22% at T1 vs. 4.07% at T4, p = 0.01) and Enterobacteriaceae family (13.3% at T1 vs. <0.05% at T4, p < 0.05), as well as a significant increase in Enterococcus species (0.1% at T1 vs. 12.8% at T4, p < 0.05) in patients who developed acute GvHD. Regarding patients who developed chronic GvHD after allo-HSCT, there was a significant reduction in the abundance of Eurobactereaceae family (1.32% at T1 vs. 0.53% at T4, p < 0.05) and Roseruria genus (3.97% at T1 vs. 0.09% at T4, p < 0.05) at T4 compared with T1. Alpha and beta diversity analyses did not reveal a difference in the abundance of bacteria at the genus level in GvHD patients at T4 compared with T1. Our study reinforces results from previous studies regarding changes in gut microbiota in patients with acute GvHD and provides new data regarding the gut microbiome changes in chronic GvHD. Future studies will need to incorporate clinical parameters in their analyses to establish their association with specific changes in gut microbiota in patients with GvHD after allo-HSCT. [ABSTRACT FROM AUTHOR]

Loss of microbiota diversity has been clearly associated with poor outcomes in the allogeneic hematopoietic stem cell transplantation setting. However, the choice of the optimal antibiotic prophylaxis during the pre-engraftment phase remains unclear. We designed a prospective randomized study to compare our standard-of-care neutropenia prophylaxis (ciprofloxacin) with rifaximin. We enrolled 38 consecutive adult patients who underwent allogeneic hematopoietic stem cell transplantation setting and were randomly assigned to receive ciprofloxacin (20 patients) or rifaximin (18 patients) at day -1. Pretransplant and transplant characteristics did not differ between groups. Cumulative incidence (CI) of acute graft-vs-host disease grade II to IV and moderate/severe chronic graft-vs-host disease was similar in both groups. With a median follow-up of 13.2 months (range, 6.8-30.2) in surviving patients, the 1-year CI of relapse was 20.8% in ciprofloxacin vs 17.8% in rifaximin (P =.616). Importantly, the 1-year CI of treatment-related mortality was significantly reduced in the ciprofloxacin group (10.2% vs 27.8%, P =.032), leading to higher 1-year overall survival (88.9% vs 74.6%, P =.038). In Cox-regression multivariate analysis, antibiotic prophylaxis remained the only predictor of overall survival, independently of donor type, disease risk index, and moderate/severe chronic graft-vs-host disease. Further studies are needed to assess the effects on microbiota diversity and confirm these outcomes. [ABSTRACT FROM AUTHOR]

Post-transplant lymphoproliferative disease (PTLD) is a fatal complication of hematopoietic cell transplantation (HCT) associated with the Epstein–Barr virus (EBV). Multiple factors such as transplant type, graft-versus-host disease (GVHD), human leukocyte antigens (HLA) mismatch, patient age, and T-lymphocyte-depleting treatments increase the risk of PTLD. EBV reactivation in hematopoietic cell transplant recipients is monitored through periodic quantitative polymerase chain reaction (Q-PCR) tests. However, substantial uncertainty persists regarding the clinically significant EBV levels for these patients. Guidelines recommend initiating EBV monitoring no later than four weeks post-HCT and conducting it weekly. Pre-emptive therapies, such as the reduction of immunosuppressive therapy and the administration of rituximab to treat EBV viral loads are also suggested. In this study, we investigated the occurrence of EBV-PTLD in 546 HCT recipients, focusing on the clinical manifestations and risk factors associated with the disease. We managed to identify 67,150 viral genomic copies/mL as the cutoff point for predicting PTLD, with 80% sensitivity and specificity. Among our cohort, only 1% of the patients presented PTLD. Anti-thymocyte globulin (ATG) and GVHD were independently associated with lower survival rates and higher treatment-related mortality. According to our findings, prophylactic measures including regular monitoring, pre-emptive therapy, and supportive treatment against infections can be effective in preventing EBV-related complications. This study also recommends conducting EBV monitoring at regular intervals, initiating pre-emptive therapy when viral load increases, and identifying factors that increase the risk of PTLD. Our study stresses the importance of frequent and careful follow-ups of post-transplant complications and early intervention in order to improve survival rates and reduce mortality. [ABSTRACT FROM AUTHOR]

• We studied isolated extramedullary relapse (iEMR) in a large population with long-term follow-up. • iEMR was associated only with the disease phase at transplantation. • iEMR and bone marrow relapse conferred similarly poor outcomes. Limited and conflicting data exist on outcomes of patients with extramedullary relapses (EMRs) after allogeneic hematopoietic cell transplantation (allo-HCT) for acute leukemias. We retrospectively reviewed charts of consecutive allo-HCT recipients who underwent transplantation in our center with the indication of acute leukemia (July 1990 to July 2018). Incidences of isolated EMR (iEMR) and bone marrow relapse (BMR) were calculated using cumulative incidence (CI) analysis, with each and treatment-related mortality considered a competing risk. We studied 554 allo-HCT recipients for 1.8 years (range,.04 to 27.75). Ten-year CI of 10.5% for iEMR was associated only with advanced disease phase at transplantation, whereas 10-year CI of 34.8% for BMR was independently associated with pretransplant disease phase, lines of treatment, and fungal infections. Most iEMR and BMR patients (75% and 81%, respectively) received systemic treatment combined with local radiation for iEMR (26%) and donor lymphocyte infusions (16% and 28%, respectively) when feasible. Extensive chronic graft-versus-host disease (GVHD) was recorded in 47% of iEMR and 48% of BMR patients. Outcomes were poor both in iEMR (10-year overall survival [OS], 18.3%) and BMR (10-year OS, 19.1%). Independent predictors of OS were disease phase, type of donor, acute and chronic GVHD, fungal infections, iEMR, and BMR. In a large population with long-term follow-up, incidence of iEMR was relatively high, developed at the late post-transplant period, and was associated only with disease phase at transplantation. Furthermore, iEMR and BMR conferred similarly poor outcomes despite systemic treatment or extensive chronic GVHD. [ABSTRACT FROM AUTHOR]

Abstract: Renewed interest has emerged in transplant‐associated thrombotic microangiopathy (TA‐TMA) with novel prognostic, diagnostic, and treatment algorithms. We aimed to investigate the incidence, prognostic factors, morbidity, and mortality of TA‐TMA in allogeneic hematopoietic cell transplantation (HCT) recipients. We enrolled consecutive HCT recipients (1990‐2017). Among 758 patients, 116 (15.5%) were diagnosed with TA‐TMA. In the multivariate analysis, TBI‐based conditioning, viral infections, acute and chronic GVHD remained independent predictors of TA‐TMA. With a median follow‐up of 23 (range 0.1‐329) months, TA‐TMA resulted in significantly lower overall survival (OS). In the multivariate analysis, TA‐TMA remained an independent predictor of OS, along with relapse, acute, and chronic GVHD. Among 116 TA‐TMA patients, 70 developed renal (56) and/or neurologic (26) dysfunction that would be necessary for TA‐TMA diagnosis according to the Bone Marrow Transplant Clinical Trials Network criteria. TA‐TMA patients with renal dysfunction showed increased rates of acute GVHD, but no difference in OS compared to patients without renal dysfunction. However, neurologic dysfunction resulted in significantly lower OS. In conclusion, TA‐TMA is associated with increased morbidity and mortality in allogeneic transplant recipients. Successful prevention and treatment strategies of infections and GVHD need to be timely employed to improve survival in this complex setting. [ABSTRACT FROM AUTHOR]

Simple Summary: Invasive fungal infections (IFD) are a significant cause of morbidity and mortality in patients with hematological malignant disorders. The aim of this retrospective study was to investigate the prevalence and outcome of IFD in patients who received cellular therapies. Adult hematopoietic cell transplantation (HCT), chimeric antigen receptor (CAR) T cell, and gene therapy recipients were retrospectively enrolled. We studied 950 patients who received cellular therapies. No CAR T cell and gene therapy patient showed IFD whereas 3/456 autologous HCT recipients who suffered from primary refractory/relapsed lymphomas presented with probable IFD. A total of 11/473 allogeneic HCT recipients developed probable IFD, possible IFD was found in 31/473 and IFD was proven in 10/473. Three patients were reported to have a second episode of IFD. IFDs were associated with poor outcomes in allogeneic HCT recipients. Further studies are needed to improve diagnostics and therapeutics in high-risk populations, such as allogeneic HCT recipients in whom IFD is associated with poor outcomes. (1) Background: Autologous, allogeneic hematopoietic cell transplantation (HCT) and other cellular therapies, including CAR T cell and gene therapy, constitute a cornerstone in the management of various benign and malignant hematological disorders. Invasive fungal infections (IFD) remain a significant cause of morbidity and mortality in HCT recipients. Therefore, we investigated the prevalence and risk factors of IFD following HCT and other cellular therapies in an era of novel antifungal prophylaxis. (2) Methods: In this study, we retrospectively enrolled adult HCT recipients who were treated at our JACIE-accredited center according to standard operating procedures over the last decade (2013–2022). (3) Results: 950 patients who received cellular therapies were studied. None of the 19 CAR T cell and neither of the two gene therapy recipients developed IFD whereas 3/456 autologous HCT recipients who suffered from primary refractory/relapsed lymphomas presented with probable IFD. Overall, 11 patients who received allogeneic HCT experienced probable IFD, possible IFD was found in 31/473, and IFD was proven in 10/473. A second IFD episode was present in three patients. Four-year OS was significantly lower in proven compared to probable IFD (p = 0.041) and was independently associated with HCT-CI (p = 0.040) and chronic GVHD (p = 0.045). (4) Conclusions: In this real-world cohort, the prevalence of proven and probable IFD in an era of novel antifungal prophylaxis was found to be relatively low. However, IFDs were associated with poor outcomes for patients who received allogeneic HCT. [ABSTRACT FROM AUTHOR]

Transplant-associated thrombotic microangiopathy (TMA) occurs in a significant percentage of patients after allogeneic stem cell transplantation (allo-SCT) and is associated with significant morbidity and mortality. The aim of the present study was to examine the association of serum angiopoetin-2 (Ang2) levels and the presence of antibodies against angiotensin II type 1 (AT1R) and ndothelin A Recreptor (ETAR) with the outcome of patients with TMA and/or graft-versus-host disease (GVHD) after allo-SCT. Analysis of our data showed that elevated serum Ang2 levels at the time of TMA diagnosis are significantly associated with increased non-relapse mortality and decreased overall survival. To our knowledge, this is the first study demonstrating an association between raised Ang2 levels and poor outcomes in patients with TMA. Antibodies against AT1R (AT1R-Abs) and ETAR (ETAR-Abs) were detected in 27% and 23% of the patients, respectively, but there was no association between the presence of autoantibodies and the outcome of patients with TMA. However, a significant finding was the strong positive correlation between the presence of AT1R-Abs with the occurrence of chronic fibrotic GVHD, such as scleroderma and cryptogenic organizing pneumonia, raising the possibility of the contribution of autoantibodies in the pathogenesis of fibrotic GVHD manifestations. [ABSTRACT FROM AUTHOR]

Opposing acute lymphoblastic leukemia, sparse data about AYAs with acute myeloid leukemia (AML) is available. Overall, 125 AYAs (age 10–35 years) treated during the last two decades were evaluated and compared to 385 older patients. CBF leukemia was more frequent in AYAs (21.6% vs. 8%, p < 0.001); however, many presented high-risk features. AYAs showed improved complete remission rate (CR, 80% vs. 65%, p = 0.01), lower cumulative incidence of relapse and TRM and longer survival (5 year-OS 53% vs. 24%, p < 0.0001), observed mainly in intermediate-risk karyotype. Adolescents displayed even better outcomes (5 year-OS 69%). AlloHCT in CR1 was beneficial for nonadolescent AYAs (5 year-OS 66.7% vs. 44.4% without HCT, p = 0.04). Among 50 APL patients, 19 AYAs experienced better outcomes than older, mainly attributed to reduced treatment-related mortality (TRM, 5% vs. 19%, p = 0.1). We observed an important (>10%) survival gain for AYAs during the last decade. However, AYAs have still unmet needs to obtain optimal cure rates. [ABSTRACT FROM AUTHOR]

Optimal conditioning remains a challenge in lymphomas. We designed a regimen consisting of Busulfex, etoposide and melphalan (BuEM). We retrospectively analyzed the outcome of patients conditioned with carmustine, etoposide, cytarabine and melphalan (BEAM) or BuEM in matched-pair analysis on a planned 2:1 ratio. Eighty-seven patients treated with BEAM who fulfilled the matching criteria were randomly selected. Two-year progression-free survival/overall survival (PFS/OS) were 63.2%/76.7% for BEAM vs. 65.6%/79.8% for BuEM after 64.7 and 42.7 months, respectively. Furthermore, marginally better PFS and OS were noted in Hodgkin lymphoma (HL) after BuEM. In multivariate analysis, PFS was superior in HL, chemosensitive disease and complete remission post-transplant. BEAM correlated with faster engraftment, reduced infections, less mucositis and liver toxicity, and BuEM with less need for blood cell and platelet transfusions and granulocyte colony-stimulating factor administration. In conclusion, BuEM was well tolerated and equally highly efficacious as BEAM for non-Hodgkin lymphoma and offered marginally significantly improved PFS and OS in HL with acceptable toxicity and zero mortality. [ABSTRACT FROM AUTHOR]

Prior to gene therapy, the patient received iron chelation treatment with deferasirox and deferoxamine and had an intact spleen, with good adherence to standard-of-care treatment. This Greek patient was one of the oldest patients treated in gene therapy trials for -thalassaemia. Keywords: gene therapy; thalassaemia; haemoglobinopathies EN gene therapy thalassaemia haemoglobinopathies 1401 1404 4 03/22/22 20220315 NES 220315 Transfusion-dependent -thalassaemia (TDT) is a severe, rare genetic disease where impaired production of the -globin chain of adult haemoglobin (Hb) results in a deficiency of functional red blood cells (RBCs), bone marrow expansion and ineffective erythropoiesis, chronic anaemia and haemolysis, leading to serious complications, reduced quality of life and a shortened lifespan.1,2 Patients require lifelong supportive care with chronic blood transfusions and iron chelation that are burdensome and many patients fail to comply with the standard of care.1-4 Even under optimal monitoring, transfusion and iron chelation treatment, patients with TDT experience a high proportion of disease- and treatment-related complications.5 Allogeneic haematopoietic stem cell (HSC) transplantation is potentially curative, but is limited by donor availability and patient age, and associated with transplant-related complications.1,2,6 Gene therapy with betibeglogene autotemcel (beti-cel; LentiGlobin for -thalassaemia) showed positive results in patients with TDT and SP + sp genotypes in phase I-II studies7; however, six of nine patients with severe -thalassaemia genotypes (i.e. SP 0 sp / SP 0 sp or homozygous IVS1-110 mutation) did not achieve transfusion independence (TI). [Extracted from the article]

• We studied transplant-associated thrombotic microangiopathy (TA-TMA) in patients with overlap or chronic graft vs host disease (GVHD). • TA-TMA was independently associated with GVHD severity and ruxolitinib use. • Time-dependent analysis confirmed ruxolitinib's association with TA-TMA. • Given the expanding use of ruxolitinib in GVHD and ongoing trials on chronic GVHD, further studies are warranted. Recent data suggest that novel biologic agents are associated with increased risk of thrombotic microangiopathy (TMA). Ruxolitinib, an approved treatment for graft-vs-host-disease (GVHD), has been associated with thrombocytopenia of unclear etiology. We investigated factors and outcomes associated with transplant-associated thrombotic microangiopathy (TA-TMA) in patients with GVHD. We retrospectively enrolled consecutive allogeneic hematopoietic cell transplantation recipients with overlap or chronic GVHD at our Joint Accreditation Committee ISCT-Europe & EBMT-accredited unit (January 2016-June 2019). Ruxolitinib has been administered off-label since 2016. Among 160 patients with GVHD, 18 were diagnosed with TA-TMA. TA-TMA developed at a median of 150 posttransplant days (range, 98-3013). Among pre- and posttransplant factors, TA-TMA was associated only with ruxolitinib administration and severe GVHD. Interestingly, these 2 variables did not correlate with each other. In the multivariate analysis, both were independent predictors of TA-TMA. Time-dependent analysis confirmed ruxolitinib's association with TA-TMA. With a follow-up of 38.4 months (4.6-83.9) in surviving patients, 5-year overall survival was 52.9%, independently predicted by TA-TMA, severe acute GVHD, and CD34+ cells infused. Ruxolitinib was not associated with survival outcomes. Our data suggest that ruxolitinib and GVHD severity are associated with TA-TMA. Given the expanding use of ruxolitinib in GVHD and ongoing trials on chronic GVHD, further studies are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Despite advances in the field, diagnosis and management of the wide spectrum of neurological events post allogeneic hematopoietic cell transplantation (alloHCT) remain challenging. Therefore, we investigated their incidence, diagnosis, management and long-term prognosis in alloHCT recipients. Methods: We retrospectively recorded data from consecutive alloHCT recipients with or without neurological complications in our center. Results: Among 758 alloHCT recipients, 127 (16.8%) presented with neurological complications. Complications developed in central nervous system (89.7%) during the late post-transplant period. Neurological adverse events included a wide spectrum of infectious and non-infectious etiologies. With a median follow-up of 11.4 months, incidence of chronic graft-versus-host disease (GVHD) was 52.8%, relapse mortality 48.6%, transplant-related mortality 39.1% and 5-year overall survival (OS) 25.8% in patients with neurological complications. Timing of appearance of neurological complications, early or late, was associated only with acute and chronic graft-versus-host-disease/GVHD. Independent pre-transplant risk factors of neurological complications in the multivariate model were unrelated or alternative donors, ALL diagnosis and non-myeloablative conditioning. In multivariate analysis of post-alloHCT events, favorable OS was independently associated with resolution of neurological syndromes, absence of chronic GVHD and sibling transplantation. In our cohort, 10-year OS was significantly lower in patients with neurological complications and independently associated with acute and chronic GVHD, relapse, fungal and bacterial infections and neurological complications. Conclusions: Our large study with long-term follow-up highlights the wide spectrum of neurological complications in alloHCT. Accurate recognition is required for adequate management, a major determinant of survival. Thus, long-term increased awareness and collaboration between expert physicians is warranted. [ABSTRACT FROM AUTHOR]

Rituximab is known to affect T cell immune responses. We and others have reported expansions of T large granular lymphocytes (T-LGLs) in lymphoma patients after Rituximab. We report here the immunogenetic profiling of the T cell receptor (TR) gene repertoire in 14 patients who received Rituximab post allo-HCT and explore clinicobiological correlations. All experienced antigenic triggers, CMV, EBV re-activation and chronic GvHD and had been treated with Rituximab. Skewing of TRBV genes was observed: 3 TRBV genes accounted for half of the repertoire. Oligoclonal pattern with expanded clonotypes was common. Patients with oligoclonality exhibited frequently cGvHD. Longitudinal samples in one revealed distinct clonotypes, suggesting clonal drift. T-LGL leukemia of donor origin with mixed chimerism eventually developed. In conclusion, we report development of oligoclonal T-LGLs after Rituximab post allo-HCT, alluding to antigen selection. Persistence of this phenomenon likely reflects strong antigenic stimulation by viruses and/or cGVHD aggravated by Rituximab. [ABSTRACT FROM AUTHOR]

The role of total body irradiation (TBI) in allogeneic hematopoietic stem cell transplantation (HCT) for adult acute lymphoblastic leukemia (ALL) remains controversial. Therefore, we investigated long-term treatment outcomes of transplanted ALL patients aiming to identify prognostic factors and the impact of conditioning. We enrolled consecutive ALL patients transplanted from 1990 to 2016, following TBI- or busulfan (Bu)-based conditioning regimen. We studied 151 ALL patients transplanted in first complete remission (CR) (60), other CR (33), or relapsed/refractory disease (58) from sibling (87), and HLA-matched (42) or mismatched (17) unrelated and alternative donors (5). High-dose fractionated TBI-based conditioning was administered in 84. No differences were observed in baseline characteristics, except for disease stage at transplant, donor type, and graft source. With a follow-up of 19.0 (0.5-170.5) in TBI and 14.5 (1.2-319.1) months in non-TBI patients, there was no difference in acute (grades II-IV) or chronic GVHD, thrombotic microangiopathy, and bacterial or fungal infections. Only viral infections were significantly increased in the non-TBI group. There was no significant difference in the cumulative incidence (CI) of treatment-related or relapse mortality and disease-free or overall survival (OS). In the multivariate analysis, unfavorable pre-transplant predictors of OS were age (p = 0.024), advanced disease stage (p = 0.007), and female-to-male donor (p = 0.006). Interestingly, TBI patients younger than 40 years had significantly higher OS (55.1%, p = 0.023) and DFS (48.6%, p = 0.020). In conclusion, high-dose TBI is feasible in younger patients providing better survival. The choice between TBI- or Bu-conditioning regimens remains challenging. [ABSTRACT FROM AUTHOR]

Treosulfan has been incorporated in conditioning regimens for sustained remission without substantial toxicity and treatment-related mortality (TRM). We aimed to analyze the safety and efficacy of a fludarabine 150 mg/m 2 and treosulfan 42 g/m 2 (FluTreo) conditioning regimen in medically infirm patients. Outcomes were compared with those of a similar historical group treated with fludarabine 150 mg/m 2 to 180 mg/m 2 , busulfan 6.4 mg/kg, and antithymocyte globulin (ATG) 5 mg/kg to 7.5 mg/kg (FluBuATG). Thirty-one consecutive patients with acute myeloid leukemia (AML; n = 21), myelodysplastic syndrome (MDS; n = 6), or treatment-related AML (n = 4) received FluTreo conditioning. The historical group consisted of 26 consecutive patients treated with FluBuATG. In the FluTreo group, engraftment was prompt in all patients and 74% achieved >99% donor chimerism by day +30. No grades III or IV organ toxicities were noted. One-year cumulative incidences (CI) of acute and chronic graft-versus-host disease (GVHD) were 19.4% and 58.4%. The groups were similar for age, disease risk, lines of treatment, hematopoietic cell transplantation–specific comorbidity index, and acute or chronic GVHD incidence, except that there were more matched unrelated donor recipients in the FluTreo group ( P  < .001). With 20 (range, 2 to 36) months follow-up for FluTreo and 14 (range, 2 to 136) for FluBuATG, the 1-year cumulative overall survival (OS) probability was 76% versus 57%, respectively ( P  = .026); 1-year disease-free survival (DFS) was 79% versus 38% ( P  < .001). In multivariate analysis, the only significantly favorable factor for OS and DFS was FluTreo ( P  = .010 and P  = .012). The CI of relapse mortality was markedly decreased in FluTreo versus FluBuATG (7.4% versus 42.3%, P  < .001). In conclusion, the treosulfan-based regimen resulted in favorable OS and DFS with acceptable toxicity and low relapse rates compared with busulfan-based conditioning. [ABSTRACT FROM AUTHOR]

Abstract: The Hellenic experience regarding the efficacy of extracorporeal photopheresis (ECP) in the treatment of 58 patients with chronic graft-versus-host disease (cGVHD) is presented in this article. All 58, except one patient, had failed at least one line of immunosuppressive treatment including steroids. Thirty-three out of 58 patients showed an objective overall response to ECP in a median time of 10weeks after the onset of treatment. The cumulative incidence of overall response was 65.1%. In multivariate analysis, the presence of severe chronic GVHD was the only parameter associated with a significantly lower probability of response to treatment (RR=0.4, CI 95% 0.2–0.9, p =0.03). Responders to treatment with ECP were more likely to discontinue immunosuppression, had a lower probability of non-relapse mortality (RR=0.2, CI 95% 0.1–0.5, p =0.002), and a higher probability of overall survival (RR=7.8, CI 95% 3–20, p <0.001) in comparison with non-responders. Eight out of 58 patients experienced relapse of the original disease. The cumulative incidence of relapse in the group of responders to ECP was 6%, while it was 25% in the group of non-responders to ECP. In multivariate analysis, response to treatment with ECP was the only parameter statistically associated with a significantly decreased hazard of relapse (RR=0.1, CI 95% 0.1–0.7, p =0.02). ECP should be tested as first-line treatment in patients with cGVHD with the aim to minimize the duration of immunosuppression and the rate of relapse of the malignant disease. [Copyright &y& Elsevier]

The safety and efficacy of hematopoietic stem cell (HSC) mobilization was investigated in adult splenectomized (SPL) and non-SPL patients with thalassemia major, in two clinical trials, using different mobilization modes: granulocyte-colony-stimulating factor (G-CSF)-alone, G-CSF following pretreatment with hydroxyurea (HU), plerixafor-alone. G-CSF-mobilization was both safe and effective in non-SPL patients. However, in SPL patients the procedure resulted in excessive response to G-CSF, expressed as early hyperleukocytosis necessitating significant dose reduction, and suboptimal CD34+ cells yields. One-month HU-pretreatment prevented hyperleukocytosis and allowed successful CD34+ cell collections when an optimal washout period was maintained, but it significantly prolonged the mobilization procedure. Plerixafor resulted in rapid and effective mobilization in both SPL and non-SPL patients and was well-tolerated. For gene therapy of thalassemia, G-CSF or Plerixafor could be used as mobilization agents in non-SPL patients whereas Plerixafor appears to be the mobilization agent of choice in SPL adult thalassemics in terms of safety and efficacy. [ABSTRACT FROM AUTHOR]

For end-stage liver disease, liver transplantation provides the only definite cure; however, many patients die while in the waiting list for donation. Various stem cell populations have been described to contribute to liver regeneration and there is accumulating evidence for the participation of hematopoietic stem cells (HSCs) in this process. We here report two cases treated with boost infusions of autologous mobilized HSCs to regenerate cirrhotic liver. The procedure was safe and well tolerated. Both patients showed a lasting amelioration in the clinical course of the disease during the 30 months of follow-up. These results suggest that the procedure may be considered in a clinical study setting as a bridging therapy until organ transplantation becomes available or to reverse a decompensated cirrhosis to a compensated one. Additional studies in this area will be required to document efficacy and evaluate toxicity. [Copyright &y& Elsevier]

Objective: On the basis of the recently recognized potential of bone marrow (BM) cells to give rise to hepatocytes, we investigated the possibility that granulocyte colony-stimulating factor (G-CSF)–mobilized BM cells could home to the injured liver and promote tissue repair. We also examined the origin of cells (endogenous or BM) reconstituting liver after damage. Methods: Acute and chronic liver injury models were generated by injecting CCl4 in C57Bl6 mice and G-CSF was administered in hematopoietic stem cell (HSC) mobilization doses. After sex-mismatched BM transplantation into lethally irradiated recipients and treatment with CCl4 ± G-CSF, sry (sex-determining region for Y chromosome) protein was detected by immunohistochemistry in liver sections. Double immunohistochemistry for sry and ki-67 protein was used to define the origin of proliferating cells reconstituting liver after injury. Results: In both acute and chronic liver injury model, G-CSF administration ameliorated the histological damage and accelerated the regeneration process. This was accompanied by a strong survival benefit in G-CSF–treated group vs CCl4 group. Quantitative analysis showed higher percentage of BM-origin hepatocytes in the CCl4+G-CSF group compared with the CCl4 group, although the liver engraftment rate still remained rather low. Double staining for ki-67 and sry demonstrated that the recovery acceleration after chemical injury and G-CSF treatment was mainly mediated by increased proliferation of host hepatocytes (ki-67+/sry-) with less support from BM-origin cells (ki-67+/sry+). Conclusion: G-CSF treatment significantly improved survival and liver histology in chemically injured mice, predominantly by promoting endogenous repair mechanisms. Therefore, mobilization with G-CSF might offer a novel therapeutic approach for the treatment of acute and chronic liver diseases in humans. [Copyright &y& Elsevier]

(1) Background: survivors of allogeneic hematopoietic cell transplantation (alloHCT) suffer from morbidity and mortality due to cardiovascular events. We hypothesized that vascular injury and pro-coagulant activity are evident in alloHCT survivors without existing alloHCT complications or relapse. (2) Methods: we enrolled consecutive adult alloHCT survivors without established cardiovascular disease and control individuals matched for traditional cardiovascular risk factors (January–December 2019). Circulating microvesicles (MVs) of different cellular origins (platelet, erythrocyte, and endothelial) were measured by a standardized flow cytometry protocol as novel markers of vascular injury and pro-coagulant activity. (3) Results: we recruited 45 survivors after a median of 2.3 (range 1.1–13.2) years from alloHCT, and 45 controls. The majority of patients suffered from acute (44%) and/or chronic (66%) graft-versus-host disease (GVHD). Although the two groups were matched for traditional cardiovascular risk factors, alloHCT survivors showed significantly increased platelet and erythrocyte MVs compared to controls. Within alloHCT survivors, erythrocyte MVs were significantly increased in patients with a previous history of thrombotic microangiopathy. Interestingly, endothelial MVs were significantly increased only in alloHCT recipients of a myeloablative conditioning. Furthermore, MVs of different origins showed a positive association with each other. (4) Conclusions: endothelial dysfunction and increased thrombotic risk are evident in alloHCT recipients long after alloHCT, independently of traditional cardiovascular risk factors. An apparent synergism of these pathophysiological processes may be strongly involved in the subsequent establishment of cardiovascular disease. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Cardiac Involvement and Treatment-Related Mortality After Non-Myeloablative Haemopoietic Stem-Cell Transplantation With Unselected Autologous Peripheral Blood for Patients With Systemic Sclerosis: A Retrospective Analysis" by Richard Burt and colleagues published in the March 30, 2013 issue.