Search

Invasive fungal infections (IFI) pose a significant complication after hematopoietic stem cell transplantation (HSCT). Isavuconazole (ISV) is a new generation azole with a favourable adverse effect and interaction profile approved for the treatment of invasive aspergillosis and mucormycosis. We analyzed the indications, effectiveness, adverse event profile and drug interaction management of ISV in the real-world setting in adults who received allogeneic-HSCT (allo-HSCT) within the Spanish Group of HSCT and Cell Therapy (GETH-TC). We conducted a multicenter retrospective study of all consecutive adult allo-HSCT recipients (≥18 years) who received ISV either for IFI treatment or prophylaxis, from December 2017 to August 2021, in 20 centers within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cell Therapy (GETH-TC). A total of 166 adult allografted patients who received ISV from 2017 to 2021 were included. Median age was 48 years with 43% females. In 81 (49%) patients, ISV was used for treatment of IFI, and in 85 (51%) for prophylaxis. Median duration of ISV administration for IFI treatment was 57 days (range 31-126) and 86 days (range 33-196) for prophylaxis. Most frequent indication for treatment was invasive aspergillosis (78%), followed by mucormycosis (6%). Therapeutic success (45%) was the most frequent reason for ISV withdrawal. In the prophylaxis group, the resolution of IFI risk factors was the most frequent reason for withdrawal (62%). Six (7%) breakthrough IFI were reported. The majority of patients (80%) presented pharmacologic interactions. Twenty-one patients (13%) reported adverse events related to ISV, mainly liver biochemistry abnormalities, which led to ISV withdrawal in 7 patients (4%). ISV was effective and well tolerated for IFI treatment and prophylaxis, with a manageable interaction profile., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT). However, its characterization after haploidentical HSCT (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) is scarce. This study aimed to describe characteristics and outcomes of patients with SOS/VOD after haplo-HSCT with PT-Cy. We conducted a retrospective study of 797 patients undergoing a haplo-HSCT with PT-Cy between 2007 and 2019 in 9 centers in Spain. SOS/VOD was defined according to modified Seattle, Baltimore, or revised European Society for Blood and Marrow Transplantation (EBMT) criteria. Severity was graded retrospectively according to revised EBMT severity criteria into 4 categories: mild, moderate, severe, and very severe. From a total of 797 haplo-HSCTs performed, 46 patients (5.77%) were diagnosed with SOS/VOD at a median of 19 days (range, 4 to 84 days) after transplantation. Based on revised EBMT severity criteria, the SOS/VOD cases were classified as mild (n = 4; 8.7%), moderate (n = 10; 21.7%), severe (n = 12; 26.1%), and very severe (n = 20; 43.5%). Overall, 30 patients (65%) achieved SOS/VOD complete response, 25 (83%) of whom were treated with defibrotide. Twenty patients (43%) died before day +100 post-HSCT. Death was attributed to SOS/VOD in 11 patients, and 5 patients died of other causes without resolution of SOS/VOD. The incidence of SOS/VOD after haplo-HSCT with PT-Cy was comparable to those reported after HLA-identical HSCT series. Most of the patients developed very severe SOS/VOD according to revised EBMT severity criteria. Despite a promising SOS/VOD complete response (CR) rate (65%), 100-day mortality remained high (43%), indicating that further improvement in the management of this potentially fatal complication is needed., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

This is a retrospective cohort study of consecutive adult patients who received a haploidentical-SCT (haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) in a single centre. Poor graft function (PGF) was defined as the occurrence of either persistent neutropenia (ANC < 0.5 × 10 9 /µL) with poor response to granulocyte colony-stimulating factors (G-CSF) and/or thrombocytopenia (platelets < 20 × 10 9 /L) with transfusion dependence, with complete donor chimerism and without concurrent severe GVHD or underlying disease relapse, during the first 12 months after transplantation. Forty-four (27.5%) out of 161 patients were diagnosed with PGF. Previous CMV reactivation was significantly more frequent in patients with PGF (88.6% versus 73.5%, p = 0.04) and the number of reactivations was also higher in these patients. Besides, early CMV reactivations in the first 6 months post-SCT were also significantly more frequent among patients with PGF (88.6% versus 71.8% p = 0.025). Thirty-two percent of patients with PGF were treated with increasing doses of thrombopoietin-receptor agonists (TRA) and 7 patients were treated with a donor CD34 + selected boost. In total, 93.2% of patients reached adequate peripheral blood counts in a median time of 101 days (range 11-475) after diagnosis. PGF is a frequent complication after haplo-SCT with PT-Cy. CMV reactivation might be the most relevant factor associated to its development. Even when most patients recover peripheral counts with support therapy, there is a group of patients with persistent cytopenias who can effectively be treated with TRA and/or a boost of CD34 + selective cells., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for patients with hematologic malignances. Haploidentical HSCT (Haplo-HSCT) is an alternative option for patients who do not have an HLA-matched donor. The use of post-transplantation high dose cyclophosphamide (PT-Cy) is commonly employed for graft-versus-host disease (GVHD) prophylaxis in haplo-HSCT. Cyclophosphamide (Cy) is an alkylating agent with antineoplastic and immunosuppressive activity, whose bioactivation requires the activity of polymorphic enzymes in the liver to produce phosphoramide mustard, which is a DNA alkylating agent. To identify polymorphisms in the genes of Cy metabolism and correlate them with post-HSCT complications [GVHD, sinusoidal obstruction syndrome (SOS), hemorrhagic cystitis (HC) and transplant-related mortality (TRM)], we designed a custom next-generation sequencing panel with Cy metabolism enzymes. We analyzed 182 patients treated with haplo-HSCT with PT-Cy from 2007 to 2019, detecting 40 variants in 11 Cy metabolism genes. Polymorphisms in CYP2B6, a major enzyme involved in Cy activation, were associated with decreased activity of this enzyme and a higher risk of Graf-versus-host disease (GVHD). Variants in other activation enzymes (CYP2A6, CYP2C8, CYP2C9, CYP2C19) lead to decreased enzyme activity and were associated with GVHD. Polymorphisms in detoxification genes such as glutathione S-transferases decreased the ability to detoxify cyclophosphamide metabolites due to lower enzyme activity, which leads to increased amounts of toxic metabolites and the development of III-IV acute GVHD. GSMT1*0 a single nucleotide polymorphism previously recognized as a risk factor for SOS was associated with a higher risk of SOS. We conclude that polymorphisms of genes involved in the metabolism of cyclophosphamide in our series are associated with severe grades of GVHD and toxicities (SOS and TRM) after haplo-HSCT and could be used to improve the clinical management of transplanted patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Muñiz, Andrés-Zayas, Carbonell, Chicano, Bailén, Oarbeascoa, Suárez-González, Gómez Centurión, Dorado, Gallardo, Anguita, Kwon, Díez-Martín, Martínez-Laperche and Buño.)

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., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) with high-dose cyclophosphamide (PTCy) has resulted in a low incidence of graft-vs.-host disease (GVHD), graft failure, and non-relapse mortality. However, post-transplantation relapse remains a common cause of treatment failure in high-risk patients. Unraveling the mechanisms of relapse is therefore crucial for designing effective relapse treatment strategies. One of these mechanisms is the loss of the mismatched HLA on the recipient's leukemic cells. To study the incidence and clinical relevance of this phenomenon, we analyzed 181 patients treated with Haplo-HSCT with PTCy (2007-2019), of which 37 relapsed patients after transplantation. According to the kit employed for HLA-loss analysis, among 22 relapsed patients, we identified HLA loss at relapse in 6 of the 22 patients (27%) studied. Based on the results obtained, the genomic loss of HLA was more common in females than males (66 vs. 33%) and HLA-loss relapses occurred later than classical relapses (345 vs. 166 days). Moreover, the patients with HLA-loss had a greater presence of active disease at the time of transplantation and had undergone a larger number of treatment lines than the group with classical relapses (66 vs. 43% and 66 vs. 18%, respectively). Four of these relapses were studied retrospectively, while two were studied prospectively, the results of which could be considered for patient management. Additionally, two relapsed patients analyzed retrospectively had myeloid neoplasms. One patient had not undergone any treatment, and three had undergone donor lymphocyte infusions (DLIs) and chemotherapy. All presented severe GVHD and disease progression. In contrast, the two patients studied prospectively had a lymphoid neoplasm and were not treated with DLIs. One of them was treated with chemotherapy but died from disease progression, and the other patient underwent a second Haplo-HSCT from a different donor and is still alive. We can conclude that the detection of HLA-loss at the onset of relapse after Haplo-HSCT with PTCy could help in clinical practice to select appropriate rescue treatment, thereby avoiding the use of DLIs or a second transplantation from the same donor., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Muñiz, Kwon, Carbonell, Chicano, Bailén, Oarbeascoa, Suárez-González, Andrés-Zayas, Menárguez, Dorado, Gómez-Centurión, Anguita, Díez-Martín, Martínez-Laperche and Buño.)

Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT), with high mortality rates despite early medical treatment, including the use of defibrotide (DF). We retrospectively analyzed 185 unmanipulated haploidentical (haplo-) HSCT with post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis performed consecutively between 2011 and June 2019 in a single center. Seventeen patients (9.2%) were diagnosed with VOD/SOS. Based on revised European Society for Blood and Marrow Transplantation severity criteria, the VOD/SOS cases were classified as mild in 2 patients (11.7%), moderate in 2 (11.7%), severe in 2 (11.7%), and very severe in 11 (64.9%). Thirteen patients (76%) were treated with DF, including all patients with severe or very severe VOD/SOS, except 1 patient with CNS hemorrhage. Sixteen patients (94%) were alive at day +100 after HSCT. Seven patients (41%) with very severe VOD/SOS were treated with transjugular intrahepatic portosystemic shunt (TIPS) owing to rapid clinical or analytical deterioration or refractory hepatorenal syndrome despite medical treatment, including DF. TIPS insertion was performed at a median time since VOD/SOS diagnosis of 4 days (range, 1 to 28 days) without technical complications in any case. The median hepatic venous pressure gradient before and after TIPS treatment was 24 mmHg (range, 14 to 29 mmHg) and 7 mmHg (range, 2 to 11 mmHg), respectively, with a median drop of 16 mmHg (range, 9 to 19 mmHg). Following TIPS insertion, all patients showed clinical improvement with hepatomegaly, ascites, and renal failure resolution, and all showed analytical improvement with reduced alanine aminotransferase (ALT), creatinine, and international normalized ratio values, except for patient 2, whose indication for TIPS was refractory hepatorenal syndrome with a normal ALT level. The 6 patients who had initiated DF before TIPS insertion completed 21 days of treatment. All patients met the criteria for complete remission (CR) at a median of 8 days after TIPS insertion (range, 2 to 82 days). The 100-day overall survival was 100%. For patients with rapid progressive VOD/SOS, early TIPS insertion allowed completion of DF therapy. The use of TIPS together with DF resulted in CR and no associated complications with no VOD/SOS-associated mortality despite high severity. In our experience, timely and individualized use of TIPS significantly improves outcomes of very severe VOD/SOS after haplo-HSCT. Therefore, TIPS should be promptly considered in rapidly progressive cases., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)