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1.
Risk factors for hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation in a letermovir-exposed CMV-free population receiving PTCy
Galli, E., Metafuni, E., Gandi, C., Limongiello, M. A., Giammarco, S., Mattozzi, A., Santangelo, R., Bacigalupo, A., Sorà, F., Chiusolo, P., et al
European journal of haematology. 2024
Abstract
Hemorrhagic cystitis (HC) is a highly impacting complication in allogeneic hematopoietic stem cell transplantation (HSCT), occurring in 12%-37% of patients. The impact of transplant- and patient-specific variables has been described, with a possible role for JCV and BKV, which may be cooperating with cytomegalovirus (CMV). Here, we analyze 134 letermovir-exposed, CMV-free patients, treated with the same cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, describing risk factors for HC. The overall incidence of HC was 23%. Patients with HLA mismatched transplant, higher comorbidity score, and receiving three alkylating agents with TBF (thiotepa, busulfan, and fludarabine) conditioning regimen had a higher risk of HC in multivariate analysis (OR: 4.48, 6.32, and 1.32, respectively). A HC-score including male gender, TBF conditioning, and HLA-mismatch stratifies the risk of HC in the first 100 days after HSCT. The role of BKV and JCV was not highly impacting in those patients, suggesting a possible synergistic effect between CMV and JCV in causing HC. HC can be interpreted as the combination of patient-related factors, chemotherapy-related toxicities-especially due to alkylating agents-and immunological elements.
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2.
Utilization of Photobiomodulation for the Prevention and Treatment of Oral Mucositis
Pritchard, M., Ogg, S. W., Bosi, J., Mandrell, B. N.
Journal of pediatric hematology/oncology nursing. 2024;:27527530231214525
Abstract
Background: Oral mucositis is a significant and common toxicity experienced by patients who receive high-dose chemotherapy as a preparatory regimen for a hematopoietic cell transplant (HCT). Photobiomodulation (PBM) has been found to be feasible with significant efficacy in preventing the progression of oral mucositis in adult patients undergoing HCT. The purpose of this study was to determine the feasibility and efficacy of PBM in pediatric oncology patients undergoing HCT. Method: Forty children and adolescents admitted to the transplant unit for an allogeneic HCT for acute lymphoblastic leukemia or acute myeloid leukemia were treated daily at six sites until day + 20 or engraftment. Results: There were 1,035 patient encounters, with successful treatment of four or more sites during 979 patient encounters for a feasibility 93.3% CI [0.926, 0.039]. We had estimated a meaningful effect size of 20% for PBM and estimated 51% of patients treated with PBM would have at least one day or more of Grade 3 mucositis. The rate of patients who received PBM and developed Grade 3 mucositis was 20% CI [0.091, 0.356]. Patients treated with PBM had fewer days of hospitalization (p = .009) and less severe mucositis in comparison to the matched control group (p = .03). Conclusion: PBM is feasible and effective in preventing and treating oral mucositis and is now supported by the Children's Oncology Group for prevention and treatment of oral mucositis in patients undergoing an allogeneic HCT or receiving head/neck radiation.
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3.
Temporal trends in critical care utilization and outcomes in allogeneic hematopoietic stem cell transplant recipients
Heybati, K., Ochal, D., Hogan, W., Al-Khateeb, H., Sklar, D., Herasevich, S., Litzow, M., Shah, M., Torghabeh, M. H., Durani, U., et al
Annals of hematology. 2024
Abstract
Historically, the prognosis of allogeneic hematopoietic stem cell transplant (allo-HCT) recipients who require intensive care unit (ICU) admission has been poor. We aimed to describe the epidemiological trends of ICU utilization and outcomes in allo-HCT patients. We conducted a retrospective cohort study including adults (≥ 18) undergoing allo-HCT between 01/01/2005 and 31/12/2020 at Mayo Clinic, Rochester. Temporal trends in outcomes were assessed by robust linear regression modelling. Risk factors for hospital mortality were chosen a priori and assessed with multivariable logistic regression modelling. Of 1,249 subjects, there were 486 ICU admissions among 287 individuals. Although older patients underwent allo-HCT (1.64 [95% CI: 1.11 to 2.45] years per year; P = 0.025), there was no change in ICU utilization over time (P = 0.91). The ICU and hospital mortality rates were 19.2% (55/287) and 28.2% (81/287), respectively. There was a decline in ICU mortality (-0.38% [95% CI: -0.70 to -0.06%] per year; P = 0.035). The 1-year post-HCT mortality for those requiring ICU admission was 56.1% (161/287), with no significant difference over time, versus 15.8% (141/891, 71 missing) among those who did not. The frequency and duration of invasive mechanical ventilation (IMV) declined. In multivariable analyses, higher serum lactate, higher sequential organ failure assessment (SOFA) scores, acute respiratory distress (ARDS), and need for IMV were associated with greater odds of hospital mortality. Over time, rates of ICU utilization have remained stable, despite increasing patient age. Several trends suggest improvement in outcomes, notably lower ICU mortality and frequency of IMV. However, long-term survival remains unchanged. Further work is needed to improve long-term outcomes in this population.
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4.
Incidence, management and outcome of Hepatic Veno-Occlusive disease /Sinusoidal Obstruction Syndrome after hematopoietic stem cell transplant in Thalassemia major patients: A prospective study of Pakistani BMT
Nisar, H., Khan, M., Khattak, T. A., Ghafoor, T., Chaudhry, Q. U. N.
Pakistan journal of medical sciences. 2024;40(3Part-II):259-264
Abstract
OBJECTIVES Hepatic Veno occlusive disease (VOD), also known as sinusoidal obstruction syndrome (VOD/SOS), is a post-transplant life threatening complication. In this study, we aimed to discuss the incidence, management and outcome of VOD in post allogenic transplant patients of beta thalassemia major (BTM). METHODS A prospective study was conducted in Armed Forces Bone Marrow Transplant Center, between 2001-2022. A total of 385 fully Human Leucocyte Antigen (HLA) matched BTM patients, with Ursodeoxycholic acid for prophylaxis, were included in the study. Incidence of VOD was calculated through cumulative incidence estimates. Chi square test and Mann Whitney test were used to compare discrete and continuous variables respectively. VOD was diagnosed and graded according to European Society for Blood and Marrow Transplantation EBMT Pediatric diagnostic criteria. Risk factors for VOD were grouped as recipient, transplant and donor related. Univariate analysis was performed by log-rank test. All patients who developed VOD were managed primarily with fluid restriction and strict input output monitoring. Statistical analyses were performed using SPSS v 25.0. RESULTS Out of 385 transplant patients, forty developed VOD. Median time from date of transplant till onset of VOD was 14 days (range 6-30). Cumulative incidence of all grade VOD was 10.39% (95% CI, 7-14). Eleven out of 40 patients who developed VOD died. Cumulative incidence of Transplant related mortality (TRM) for patients with and VOD was 20.5% (95% CI, 16.6-25.1) vs 27.5% (95% CI, 16.1-42) (p value 0.318) respectively. Among risk factors, age of recipient and fibrosis (p value of 0.04 and 0.000 respectively) were found to be significantly associated with VOD. CONCLUSIONS Careful selection of transplant candidates before transplant can help reduce the incidence of VOD.
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5.
Late transplant-associated thrombotic microangiopathy verified in bone marrow biopsy specimens is associated with chronic GVHD and viral infections
Hill, W., Sotlar, K., Hautmann, A., Kolb, H. J., Ullmann, J., Hausmann, A., Schmidt, M., Tischer, J., Pham, T. T., Rank, A., et al
European journal of haematology. 2024
Abstract
OBJECTIVES To describe late transplant-associated thrombotic microangiopathy (TA-TMA) as chronic endothelial complication in bone marrow (BM) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS BM specimens along with conventional diagnostic parameters were assessed in 14 single-institutional patients with late TA-TMA (more than 100 days after HCST), including 11 late with history of early TA-TMA, 10 with early TA-TMA (within 100 days), and 12 non TA-TMA patients. Three non-HSCT patients served as control. The time points of BM biopsy were +1086, +798, +396, and +363 days after HSCT, respectively. RESULTS Late TA-TMA patients showed an increase of CD34+ and von Willebrand Factor (VWF)+ microvascular endothelial cells with atypical VWF+ conglomerates forming thickened VWF+ plaque sinus in the BM compared to patients without late TA-TMA and non-HSCT. Severe chronic (p = .002), steroid-refractory GVHD (p = .007) and reactivation of HHV6 (p = .002), EBV (p = .003), and adenovirus (p = .005) were pronounced in late TA-TMA. Overall and relapse-free survival were shorter in late TA-TMA than in patients without late TA-TMA (5-year OS and RFS: 78.6% vs. 90.2%, 71.4% vs. 86.4%, respectively). CONCLUSION Chronic allo-immune microangiopathy in BM associated with chronic, steroid-refractory GVHD and/or viral infections are key findings of late, high-risk TA-TMA, which deserves clinical attention.
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6.
Multiplex proteomics in the identification of potential biomarkers of very severe sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) in allogeneic hematopoietic cell transplant patients treated with defibrotide
Vasudevan Nampoothiri, R., Avery, L., Pasic, I., Prassas, I., Diamandis, E., Michelis, F. V.
Acta haematologica. 2024
Abstract
Introduction Despite well-established clinical criteria for diagnosis of SOS/VOD following allogeneic HCT, there is a lack of established diagnostic protein biomarkers. Methods Prospective samples were collected from patients with very severe SOS/VOD at diagnosis and days +3, +7, +14, and +30 post-initiation of defibrotide. Samples from age-matched controls with no VOD were collected at day +14, +30, +60, +90 and +180 following allogeneic HCT. Serum samples were analyzed for 2925 protein levels by antibody-based proximity extension assay (PEA). Mean differences in the log-transformed abundance values were compared using t-tests in a volcano plot. Results Five patients with very severe SOS/VOD and five control patients were compared. Ten proteins were identified that showed a statistically significant and log-transformed 3-fold increase in concentration. They were CALCA, CCL20, GPR37, IGFBP4, IL1RL1, SLC39A14, SPINK4, FABP3, MYL3, and CHCHD10. Four different proteins, namely CD83, LAIR2, CD7, and HEM6 showed a significant decrease with defibrotide treatment. SOS/VOD resolved in 80% (n=4) of patients, while one patient deceased due to SOS/VOD. Conclusion PEA technology identified 10 proteins that were significantly elevated in patients with very severe SOS/VOD. Prospective studies in a larger cohort using this technology may be able to conclusively identify diagnostic protein biomarkers for SOS/VOD.
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7.
[Risk Factors of Late-Onset Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation]
Zhang, L. Y., Xiong, Y. Y., Liao, M. Y., Xiao, Q., Tang, X. Q., Luo, X. H., Zhang, H. B., Wang, L., Liu, L.
Zhongguo shi yan xue ye xue za zhi. 2024;32(1):250-256
Abstract
To analyze the risk factors for late-onset hemorrhagic cystitis (LOHC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the risk factors for the progression of LOHC to severe LOHC, and the effect of LOHC on survival. METHODS The clinical data of 300 patients who underwent allo-HSCT at the First Affiliated Hospital of Chongqing Medical University from January 2015 to December 2021 were retrospectively analyzed. The relevant clinical parameters that may affect the occurance of LOHC after allo-HSCT were selected for univariate and multivariate analysis. Then, the differences in overall survival (OS) and progression-free survival (PFS) between different groups were analyzed. RESULTS The results of multivariate analysis showed that the independent risk factors for LOHC after allo-HSCT were as follows: age≤45 years old (P =0.039), intensified conditioning regimen with fludarabine/cladribine and cytarabine (P =0.002), albumin≤30 g/L on d30 after transplantation (P =0.007), CMV-DNA positive (P =0.028), fungal infection before transplantation (P =0.026), and the occurrence of grade Ⅱ - Ⅳ aGVHD (P =0.006). In the transplant patients who have already developed LOHC, the occurance of LOHC within 32 days after transplantation (P =0.008) and albumin≤30 g/L on d30 after transplantation (P =0.032) were independent risk factors for the progression to severe LOHC. The OS rate of patients with severe LOHC was significantly lower than that of patients without LOHC (P =0.041). CONCLUSION For the patients aged≤45 years old and with intensified conditioning regimen, it is necessary to be vigilant about the occurrence of LOHC; For the patients with earlier occurrence of LOHC, it is necessary to be vigilant that it develops into severe LOHC. Early prevention and treatment of LOHC are essential. Regular monitoring of CMV-DNA and albumin levels, highly effective antiviral and antifungal therapies, and prevention of aGVHD are effective measures to prevent the occurrence and development of LOHC.
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8.
D-dimer and sinusoidal obstructive syndrome-novel poor prognostic features of thrombotic microangiopathy in children after hematopoietic cellular therapy in a single institution prospective cohort study
Schoettler, M. L., French, K., Harris, A., Bryson, E., Deeb, L., Hudson, Z., Obordo, J., Chandrakasan, S., Parikh, S., Watkins, B., et al
American journal of hematology. 2024
Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is a common, severe complication of allogeneic hematopoietic cellular therapy (HCT). Even when treated in many studies, morbidity and mortality rates are high. This prospective single-institution cohort study serially enrolled all allogeneic HCT recipients from August 2019-August 2022. Patients were universally screened for TA-TMA and intermediate and high-risk patients were immediately treated with eculizumab. Sub-distribution cox-proportional hazards models were used to identify sub-distribution hazard ratios (sHR) for multi-organ dysfunction (MOD) and non-relapse-related mortality (NRM). Of 136 patients, 36 (26%) were diagnosed with TA-TMA and 21/36 (58%) developed MOD, significantly more than those without TA-TMA, (p < .0001). Of those with TA-TMA, 18 (50%) had high-risk TA-TMA (HR-TA-TMA), 11 (31%) had intermediate-risk TA-TMA (IR-TA-TMA), and 8 (22%) had standard risk (SR-TA-TMA). Twenty-six were treated with eculizumab (1/8 SR, 7/11 IR, and 18/18 HR). Elevated D-dimer predicted the development of MOD (sHR 7.6, 95% confidence interval [CI] 1.8-32.3). Children with concurrent sinusoidal obstructive syndrome (SOS) and TA-TMA had an excess risk of MOD of 34% and data supported a biologic interaction. The adjusted NRM risk was significantly higher in the TA-TMA patients (sHR 10.54, 95% CI 3.8-29.2, p < .0001), despite prompt treatment with eculizumab. Significant RF for NRM in TA-TMA patients included SOS (HR 2.89, 95% 1.07-7.80) and elevated D-dimer (HR 3.82, 95% CI 1.14-12.84). An unrelated donor source and random urine protein to creatine ratio ≥2 mg/mg were significantly associated with no response to eculizumab (odds ratio 15, 95% CI 2.0-113.6 and OR 6.5, 95% CI 1.1-38.6 respectively). TA-TMA was independently associated with NRM despite early diagnosis and treatment with eculizumab in this large pediatric transplant cohort. Prognostic implications of D-dimer in TA-TMA merit further investigation as this is a readily accessible biomarker. Concurrent SOS is an exclusion criterion of many ongoing clinical trials, but these data highlight these patients could benefit from novel therapeutic approaches. Multi-institutional clinical trials are needed to understand the impact of TA-TMA-targeted therapies.
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9.
Incidence and Risk Factors of Early Onset VOD/SOS Differ in Younger vs Older Adults After Stem Cell Transplantation
Marcoux, C., Saliba, R. M., Wallis, W., Khazal, S. J., Ragoonanan, D., Rondon, G., Tewari, P., Popat, U. R., Oran, B., Olson, A. L., et al
Blood advances. 2024
Abstract
Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-SCT). While increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with post-transplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single center analysis of adult patients 18 years or older undergoing allo-SCT (N=1561) using predominately PTCy as GVHD prophylaxis (72%). We found a higher rate of VOD at 16.8% (20/119) in those aged ≤ 25 years compared to 3.8% (55/1442) in those >25 years, with unique predictors of VOD within each cohort. Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD. Within patients aged 18-25 years, disease risk index (DRI) (31% with high/very high DRI vs 12% low/intermediate DRI; p=0.03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1, p=0.03) were the strongest predictors of VOD. Incidence of VOD in patients > 25 years of age consistently ranged between 3-5% across most risk factors evaluated, with only hepatic factors (baseline elevation of bilirubin, aspartate transferase (AST), alanine aminotransferase (ALT)) or gemtuzumab exposure associated with increased rates of VOD. There was no significant difference in rates of VOD in those receiving PTCy compared to those receiving alternate GVHD prophylaxis. Our data highlight the differences in incidence and predictors in VOD between younger (≤25) and older (>25) adults undergoing allo-SCT.
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10.
Current incidence, severity, and management of veno-occlusive disease/sinusoidal obstruction syndrome in adult allogeneic HSCT recipients: an EBMT Transplant Complications Working Party study
Ruutu, T., Peczynski, C., Houhou, M., Polge, E., Mohty, M., Kröger, N., Moiseev, I., Penack, O., Salooja, N., Schoemans, H., et al
Bone marrow transplantation. 2023
Abstract
The current incidence, diagnostic policy, management, and outcome of VOD/SOS at EBMT centers were studied. All centers that had performed allogeneic HSCTs in adult patients within one defined year were invited to the study. Seventy-one centers participated with a total of 2886 allogeneic transplantations and 93 cases of VOD/SOS in 2018. The cumulative incidence of VOD/SOS at day 21 was 1.8% and at day 100 2.4%. Of 67 cases with detailed data, 52 were classical and 15 (22%) late onset (>day 21). According to the EBMT criteria, 65/67 patients had at least two VOD/SOS risk factors. The severity grades were: mild 0, moderate 3, severe 29, very severe 35. Fifty-four patients were treated with defibrotide. VOD/SOS resolved in 58% of the patients, 3/3 with moderate, 22/28 with severe, and 12/33 with very severe grade (p < 0.001). By day 100, 57% of the patients were alive; 3/3 with moderate, 22/29 with severe, and 13/35 with very severe VOD/SOS (p = 0.002). In conclusion, the incidence of VOD/SOS was low. Severe and very severe grades dominated. Very severe grade predicted poor outcome compared to severe grade further supporting the concept of early diagnosis and treatment to avoid a dismal outcome.