Chronic graft-versus-host disease (cGVHD) remains a leading cause of late morbidity after allogeneic hematopoietic cell transplantation (HCT), but its phenotype under modern prophylaxis with post-transplant cyclophosphamide (PTCy) is not well characterized. We conducted a prospective, single-center study of 600 consecutive adults undergoing HCT with PTCy- based prophylaxis to assess incidence, clinical manifestations, treatment response, prognostic factors, and outcomes. Donors included matched siblings (36%), matched unrelated (34%), haploidentical (24%), and mismatched unrelated (6%). The 1-year cumulative incidence of moderate-to-severe cGVHD was 22% (95% confidence interval [CI]: 19-26%). The mouth was the most frequently involved organ (64%), with lichen planus-like changes as the predominant diagnostic feature, whereas sclerotic forms were uncommon. Notably, 27% of moderate-to-severe cases were managed successfully without systemic corticosteroids. The cumulative incidence of systemic therapy requirement was 15% at 1 year, with risk significantly higher in donors ≥30 years and in female-to-male transplants. Among 105 patients requiring systemic steroids, 64% achieved complete response, 32% discontinued immunosuppression, yet 18% developed cGVHD-related sequelae. Mouth ulcers and erythema, as well as a lung score ≥2 at steroid initiation independently predicted shorter failure-free survival. At 2 years, overall survival, cGVHD-free relapse-free survival, and GVHD-free relapse-free survival were 76% (95% CI: 72-79), 63% (95% CI: 60-68), and 57% (95% CI: 53-62), respectively. In conclusion, after HCT with PTCy-based prophylaxis, systemic therapy was required in only a minority of patients, with risk influenced by donor age and sex mismatch rather than donor type. While corticosteroids were generally effective, a substantial subset required salvage therapy, underscoring the burden of refractory cGVHD and the need for steroid-sparing approaches and novel interventions.

BACKGROUND:Secondary malignancies (SM) are a well-recognized long-term complication after hematopoietic cell transplantation (HCT), increasingly contributing to morbidity and mortality as post-transplant survival improves. However, the incidence, spectrum, and outcomes of SM remain incompletely defined in the context of evolving transplant practices and a growing population of long-term survivors. OBJECTIVE:To evaluate the incidence, risk factors, and outcomes of SM in a contemporary cohort of autologous and allogeneic HCT recipients. STUDY DESIGN:Observational, retrospective, single-center study including all consecutive patients undergoing a first autologous or allogeneic HCT from any donor type at the Hospital Universitario y Politécnico La Fe (Valencia, Spain) between January 2007 and December 2024. RESULTS:Among 2098 patients, 103 (4.9%) developed non-cutaneous SM, including 56 solid tumors (ST), 25 post-transplant lymphoproliferative disorders (PTLD), 15 therapy-related myelodysplastic syndromes/acute myeloid leukemia (t-MDS/AML), 2 donor cell leukemia, and 5 other hematologic malignancies. PTLD occurred earlier after allogeneic transplantation (median 3.9 months) than t-MDS/AML (median 47.0 months) and ST (median 51.5 months). Risk factors for ST included a history of prior malignancy (hazard ratio [HR] 2.96, 95% confidence interval [CI] 1.46 to 6.00; p = .003), allogeneic HCT (HR 2.44, 95% CI 1.29 to 4.60), and patient age ≥50 years (HR 1.89, 95% CI 1.07 to 3.35), whereas the risk of t-MDS/AML was higher among patients with a prior malignancy (HR 2.96, 95% CI 1.47 to 5.98). In the allogeneic setting, the use of post-transplant cyclophosphamide as graft-versus-host disease prophylaxis did not affect the risk of SM in multivariate analysis. SM ranked as the second and third leading causes of death after autologous and allogeneic HCT, respectively. Overall survival (OS) differed among SM subtypes entities, being particularly adverse for PTLD (1-year OS 19%, 95% CI 9 to 43) and better for solid tumors (5-year OS 43%, 95% CI 29 to 64). CONCLUSION:SM are a significant determinant of post-transplant mortality, with risk shaped by prior malignancy, older age, and transplant type, and outcomes varying markedly according to subtype.

Hematotoxicity after anti-CD19 chimeric antigen receptor T-cell therapy has drawn attention for potential long-term effects, and yet, recovery of lymphocyte subsets and immunoglobulin levels beyond B-cell aplasia remains poorly understood. We retrospectively analyzed 76 consecutive axicabtagene ciloleucel (axi-cel) recipients with relapsed/refractory aggressive B-cell lymphoma between 2020 and 2024, focusing on basic immune recovery patterns and their impact on outcomes. Median CD8+ T and NK cells increased to >300/mm3 and >100/mm3, respectively, within 2 months after infusion. CD4+ T-cell recovery was slower, with 42% cumulative incidence of >200/mm3 cell count at 12 months. B-cells were detectable in 18% at 12 months. Immunoglobulin levels initially declined and then plateaued, with 51% incidence of immunoglobulin G (IgG) levels > 400 mg/dL at 12 months. Modified EASIX > 2.00 was associated with delayed kinetics of CD3+ T-cells, CD4+ T-cells, and CD8+ T-cells, and cumulative dexamethasone dose > 120 mg with delayed recovery of CD4+ T-cells, NK cells, and IgG. At 1 month post-infusion, low CD4+ T-cell count and high CAR-HEMATOTOX predicted worse 12-month progression-free survival (hazard ratio [HR] 2.81 and 3.34) and overall survival (HR 3.21 and 4.41), respectively. After axi-cel, CD4+ T-cells and IgG recovered slowly during the first year, while CD8+ T and NK cells increased rapidly. A higher modified EASIX score may predict slower cellular recovery, while corticosteroids may delay both cellular and humoral recovery. Lower CD4+ T-cell count was associated with worse outcomes.

We evaluated the influence of donor type in 3006 adults with adverse-risk cytogenetic acute myeloid leukemia (AML) in first complete remission undergoing allogeneic hematopoietic cell transplantation (HCT). Donor types included matched sibling (MSD), matched unrelated (MUD), mismatched unrelated (MMUD), and haploidentical donors. At 2 years, leukemia-free survival, overall survival (OS), and graft-versus-host disease (GVHD)-free/relapse-free survival were 47

This study assessed 552 allogeneic hematopoietic cell transplantation (HCT) recipients with posttransplant cyclophosphamide (PTCy) to evaluate the incidence, characteristics, risk factors, and impact of early posttransplant cytokine release syndrome (CRS) on outcomes. The cohort included 36% matched sibling donors (MSD), 34% matched unrelated donors (MUD), 27% haploidentical donors, and 4% mismatched unrelated donors (MMUD). CRS was observed in 182 patients, with the highest incidence in haploidentical transplants (80%) compared to MMUD (32%), MUD (23%), and MSD (8%). Most CRS cases were mild, with 93% classified as grade 1 and 6% as grade 2, with only one severe case of grade 3. In haploidentical transplants, CRS was linked to a lower risk of severe chronic graft-versus-host disease (GVHD) and non-relapse mortality (NRM), leading to improved overall survival. In contrast, among HLA-matched recipients (MSD and MUD), there were no significant differences in outcomes between those with or without CRS. However, subgroup analysis revealed that CRS in patients with myeloid malignancies, including acute myeloid leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms, was associated with a reduced relapse rate, improving survival outcomes. In conclusion, while CRS is typically mild and short-lived, it significantly impacts survival, particularly in haploidentical transplants and HLA-matched patients with myeloid malignancies.

Gastrointestinal bleeding (GIB) is a serious complication following allogeneic hematopoietic stem cell transplantation (HSCT), with limited data on its incidence and characteristics, particularly for upper gastrointestinal bleeding (UGIB) of gastric origin. We aimed to evaluate the incidence, clinical, endoscopic, and histopathologic features, and outcomes of UGIB, with a focus on gastric vascular ectasias (GVEs) in patients undergoing HSCT with graft-versus-host disease (GVHD) prophylaxis using post-transplant cyclophosphamide (PTCY), sirolimus or calcineurin inhibitors, and mycophenolate mofetil. This retrospective, single-center study included all adult patients who underwent allogeneic HSCT at a single institution between January 2017 and December 2023. Data were collected on transplant procedures, complications, and GIB incidents, with UGIB cases undergoing endoscopic and histologic examination. Out of 559 patients, 38 (6.6%) experienced UGIB, with 27 cases (70%) attributed to GVE. GVE typically presented as melena or hematemesis at a median time of 68 d (range, 29 to 125) after transplant. Endoscopy revealed diffuse oozing from gastric antral mucosa without distinct lesions, while histology showed vascular congestion and mild foveolar hyperplasia. The 6-mo cumulative incidence of GVE was 5.1%. Older age (≥60 yr) and diagnosis of myelodysplastic/myeloproliferative neoplasm were significant risk factors. All cases resolved with no attributable mortality with supportive measures including transfusions, proton-pump inhibitors, and sirolimus withdrawal in some cases. GVE is a notable cause of UGIB in HSCT recipients on PTCY-based GVHD prophylaxis, presenting significant morbidity but favorable outcomes with appropriate management. The potential role of sirolimus and conditioning agents in GVE pathogenesis warrants further investigation.

We analyzed the outcomes of 217 acute myeloid leukemia patients in complete remission who underwent allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning and post-transplant cyclophosphamide-based graftversus- host disease prophylaxis, aiming to assess the prognostic significance of genetic risk categories. In the overall cohort, the 2-year overall survival (OS) and event-free survival (EFS) were 77% (95% confidence interval [CI]: 71-83) and 72% (95% CI: 66-78), respectively. European LeukemiaNet (ELN)2022 risk stratification lacked prognostic value in HCT. Instead, we identified four risk categories with distinct impact on OS: standard risk (ELN2022 favorable/intermediate and adverse risk without high-risk genetic risk under the defined subcategories), intermediate risk (≥2 myelodysplasia-related gene mutations) (hazard ratio [HR]=2.23; 95% confidence interval [CI]: 1.14-4.92), adverse risk (complex karyotype, monosomal karyotype, inv(3)/t(3;3), KMT2A rearrangement) (HR=4.24; 95% CI: 2.00-9.02), and very adverse risk (TP53 mutations) (HR=6.81; 95% CI: 3.00-15.5). These categories demonstrated similar predictive power for EFS and cumulative incidence of relapse. Moreover, integrating pre-transplant measurable residual disease (MRD) refined risk stratification, identified MRD-negative patients with ≥2 myelodysplasia-related gene mutations whose OS and EFS were comparable to standard-risk patients. This refined classification improves the prognostic value of ELN2022 for acute myeloid leukemia patients undergoing allogeneic HCT with modern platform by integrating genetic features and MRD status to better guide post-transplant management.

Engraftment syndrome (ES) is a non-infectious febrile complication of hematopoietic cell transplantation (HCT), with diagnostic challenges, particularly in the allogeneic setting. The increasing use of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease prophylaxis highlights the need for a re-examination of ES in this contemporary context. To evaluate the incidence and clinical presentation of ES, as well as its impact on transplant outcomes in the era of PTCy-based prophylaxis. We retrospectively analyzed 552 allogeneic HCT patients receiving PTCy, sirolimus, and mycophenolate mofetil across various donor types. To improve ES diagnosis in this setting, we proposed new criteria in which peri-engraftment fevers (PEFs) (d -4 to d +3 before and after myeloid engraftment) were classified as follows: definite ES (PEF meeting Spitzer, Maiolino, or Grant criteria); probable ES (PEF plus ≥1 additional ES sign); and possible ES (PEF without additional signs). Among the 80 patients (14.5%) who developed PEF, 24 (30%) fulfilled criteria for definite ES, 14 (17.5%) for probable ES, and 42 (52.5%) for possible ES. The 30-d cumulative incidence of overall ES was 15% (95% confidence interval [CI], 12 to 18), comprising 4.4% (95% CI, 2.9 to 6.4) for definite ES, 2.6% (95% CI, 1.5 to 4.2) for probable ES, and 7.8% (95% CI, 5.7 to 10) for possible ES. In addition to fever, the most frequently observed ES-related symptoms included diarrhea (n = 18), weight gain (n = 14), skin rash (n = 11), hepatic dysfunction (n = 8), and pulmonary infiltrates (n = 7). Risk factors associated with the development of ES were younger age (defined as <40 yr), underlying lymphoproliferative neoplasms, haploidentical donor transplantation, and a history of prior cytokine release syndrome. Importantly, ES resolved within 48 h in 75 of the 80 cases (94%), and no deaths were attributed to PEF or ES episodes. Interestingly, the presence of ES was significantly associated with improved overall survival and event-free survival, potentially reflecting a composite effect of trends toward lower relapse rates and reduced non-relapse mortality in affected patients. ES in PTCy-based allogeneic HCT is frequent but rarely meets traditional criteria, highlighting the potential value of a refined three-category classification. Our findings suggest an unexpected survival benefit, possibly linked to the immunomodulatory effects of PTCy, and underscore the need for further studies to validate this classification and investigate the underlying biological mechanisms.

BACKGROUND:The number of elderly patients who could benefit from an allogeneic hematopoietic stem cell transplantation (allo-HSCT) is continuously increasing; however, the most appropriate way to select elderly candidates for this procedure is still a matter of debate. METHODS:We report the clinical outcomes of a group of 529 patients aged 65 y and older who received a first allo-HSCT between 2011 and 2020 and were reported to the Grupo Español de Trasplante Hematopoyético y Terapia Celular database. RESULTS:The median age was 67.2 y (range, 65-82) and 54 patients (10.2%) were 70 y and older. The 4-y cumulative incidence (CI) of nonrelapse mortality was 32.0% (95% confidence interval [CI], 28-36), CI of relapse was 29.1% (95% CI, 25-33), of overall survival was 43.4% (95% CI, 39-48), of progression-free survival was 38.9% (95% CI, 35-43), and of graft-versus-host disease (GvHD)-free, relapse-free survival was 23.7% (95% CI, 20-28). The 100-d CI of grades II-IV and III-IV acute GvHD was 34.7% (95% CI, 31-39) and 10.4% (95% CI, 8-13), respectively, and the 2-y CI of moderate-severe chronic GvHD was 21.0% (95% CI, 18-25). In the multivariate analysis, a hematopoietic cell transplantation-specific comorbidity index of ≥3 and a high/very high disease risk index were associated with worse overall survival; however, age did not influence the outcomes. CONCLUSIONS:Advanced age alone should not serve as an exclusion criterion for allo-HSCT, as the procedure can be both safe and effective in elderly patients with careful candidate selection and optimized transplant strategies.

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a serious complication following allogeneic hematopoietic cell transplantation (HCT). Although post-transplant cyclophosphamide (PTCy) is increasingly used for graft-versus-host disease prophylaxis, data on its impact in the context of SOS/VOD remain limited. This study aimed to assess the incidence, clinical characteristics, prognostic factors, treatment approaches, and outcomes of SOS/VOD in HCT recipients receiving GVHD prophylaxis with PTCY, sirolimus or tacrolimus, and mycophenolate mofetil (MMF) across all donor types. This single-center observational study included all 532 consecutive adults who underwent HCT with PTCy between January 2017 and February 2024. Patient demographics, transplant procedures, toxicities, and complications were prospectively collected. Clinical charts were reviewed as needed to address inconsistencies or missing information. Myeloablative conditioning was administered to 96% of recipients, who received grafts from matched sibling donors (MSD, 36%), matched unrelated donors (MUD, 34%), haploidentical donors (26%), or mismatched unrelated donors (MMUD, 4%). SOS/VOD was diagnosed in 35 patients and classified according to EBMT criteria as probable (n = 10), clinical (n = 23), or proven (n = 2). Classical SOS/VOD occurred in 21 patients (60%), while 14 (40%) had late-onset disease. EBMT severity grading showed 3% mild, 20% moderate, 37% severe, and 40% very severe cases. The 100-day cumulative incidence was 6.6% (95% CI:4.7 to 8.9). Multivariable analysis identified prior transplantation, prior antibody-drug conjugates and higher CD3+ cell dose as risk factors. Patients with very severe or severe SOS/VOD (based on clinical features but not those upgraded solely due to the presence of risk factors) received defibrotide. Four patients (11.4%) died from SOS/VOD; all classified as very severe, and three of them had undergone prior transplantation (two autologous, one allogeneic). Despite high severity, SOS/VOD analyzed as a time-dependent variable showed no association with overall survival or nonrelapse mortality. SOS/VOD remains a challenging but clinically manageable complication with a modest incidence following HCT with PTCy. Although many cases were classified as severe or very severe, the associated mortality rate was relatively low. The identification of key risk factors, such as prior transplantation, antibody-drug conjugate exposure, and higher CD3⁺ cell doses, along with the notable proportion of late-onset cases, underscores the need for vigilant monitoring and individualized management strategies.

Although SARS-Cov-2 outcomes have improved in the Omicron era, the synergistic or additive effects between SARS-CoV-2 Omicron variants and other microbiological agents in adult hematologic patients have been little explored. We aimed to characterize co-infection types, identify risk factors for co-infection and determine co-infection-related mortality in hematologic patients and recipients of cellular therapy with a first episode of SARS-CoV-2 infection in the Omicron era. Retrospective national Spanish registry analysis of 692 consecutive patients with hematological disease including receptors of cellular therapy from December 2021 to May 2023. The co-infection rate was 9

Despite the high incidence of diarrhea in hematopoietic cell transplant (HCT) and the frequent involvement of infections, evidence concerning patients receiving post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis in the molecular diagnostic era is limited. This study aimed to evaluate the characteristics, incidence, risk factors, and outcomes impact of infectious enterocolitis in patients with hematologic malignancies undergoing HCT from matched sibling, matched unrelated, and haploidentical donors using PTCy as GVHD prophylaxis. Retrospective analysis of infectious enterocolitis episodes in 399 patients undergoing HCT at a single institution. Uniform GVHD prophylaxis with PTCy, sirolimus, and mycophenolate mofetil was given, irrespective of donor type or conditioning intensity. Levofloxacin was used prophylactically until myeloid engraftment. Infectious enterocolitis episodes were diagnosed by both molecular-based techniques and stool cultures. Infectious enterocolitis affected 21% of patients, with 19% having more than one episode. The median onset and duration was of 83 and 13 days, respectively, 20% were nosocomial and 58% were managed ambulatorily. The 1-year cumulative incidence was 19%, with 39% occurring beyond day 100, and was similar for Clostridioides difficile infection (CDI; 7%), non-CDI bacterial (8%), and viral enterocolitis (6%), with no differences in clinical features. However, toxin-positive CDI lasted longer (22 days) than toxin-negative cases (10 days, P = .03) Bone marrow HCT significantly increased the risk of overall infectious enterocolitis, while moderate-severe chronic GVHD increased all-cause and viral enterocolitis incidence. Infectious enterocolitis did not significantly impact overall survival, GVHD disease-free relapse-free survival, and non-relapse mortality. Approximately one-fifth of PTCy-based HCT recipients develop infectious enterocolitis in the first year, typically resolving within 2 weeks, with higher incidence in bone marrow recipients and those with moderate-severe chronic GVHD. CDI, non-CDI bacterial, and viral infections had similar incidences and clinical features. While infectious enterocolitis does not significantly impact transplant outcomes, its diagnosis remains challenging.

Bacterial bloodstream infections (BSI) are an important contributor to morbidity and mortality after hematopoietic cell transplant (HCT). Its specific characteristics with the use of post-transplant cyclophosphamide (PTCy) remain poorly defined, particularly in the HLA-matched setting. The objectives were to evaluate the characteristics, incidence, risk factors, and clinical impact of bacterial BSI in patients with hematologic malignancies undergoing HCT from matched related (MSD), matched unrelated (MUD), and haploidentical donors using PTCy-based graft-versus-host disease (GVHD) prophylaxis. We conducted a retrospective single-center analysis of bacterial BSI in 456 patients undergoing HCT. Quinolone prophylaxis was administered during neutropenia, and screening for bacterial colonization was performed during hospitalization, regardless of transplant timing. Median age at HCT was 55 yr, with 63% diagnosed with acute leukemia. HCT was performed with MSD in 40%, MUD in 34% and haploidentical donors in 26%. A total of 159 bacterial BSI episodes were observed in 128 patients. The cumulative incidence of first BSI was 28% at 2 yr at a median time of 11 d (range, 1-694). Regarding timelines, 60% of episode occurred until d +30, 19% between d +31 and +100, 14% between d +100 and one year, and 7% beyond the first year. There was a predominance of gram-negative bacterial infections, particularly in haploidentical HCT during the first 30 d. Multidrug resistance criteria was met in 55% of gram-negative and 47% of gram-positive bacteria. Haploidentical donors were independently associated with early BSI, while grade II-IV acute GVHD increased the risk after d +30. BSI-related mortality accounted for 9% of deaths, and late-onset BSI was associated with inferior OS. In conclusion, bacterial BSI affects over one-fourth of PTCy-based HCT recipients, particularly in the early post-transplant period, with a predominance of gram-negative microorganisms. Haploidentical donors and acute GVHD were independent risk factors for BSI, and late-onset BSI was associated with worse OS.