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Reduced incidence of neurologic complications after allogeneic hematopoietic stem cell transplantation with calcineurin-free graft-versus-host disease prophylaxis
Balaguer-Roselló, A., Gil-Perotín, S., Montoro, J., Bataller, L., Lamas, B., Villalba, M., Facal, A., Guerreiro, M., Chorão, P., Bataller, A., et al
Transplantation and cellular therapy. 2023
Abstract
Calcineurin inhibitors (CNI), including cyclosporine and tacrolimus, are frequently associated with neurological complications after allogeneic hematopoietic stem cell transplantation (HSCT). However, there is a lack of studies comparing the incidence and characteristics of NCs in patients undergoing HSCT based on CNI-free or CNI-based GVHD prophylaxis. This retrospective single-center study analyzed the neurologic complications in two subsequent cohorts of patients undergoing HSCT with either CNI-based GVHD prophylaxis (n=523) or CNI-free prophylaxis with posttransplant cyclophosphamide, sirolimus, and mycophenolate mofetil (n=371). The latter cohort included older patients, received more reduced-intensity conditioning and transplants from matched unrelated and haploidentical donors. The 2-year cumulative incidence of neurologic complications was significantly lower in the CNI-free cohort (6.9% vs. 11.9%; P=0.016), and GVHD prophylaxis was the only statistically significant variable in multivariate analysis (HR, 2.2; 95% confidence interval [CI], 0.25-3.13; P=0.0017). Distribution of neurologic types was similar in both cohorts, with encephalopathy being the most prevalent complication, except for headaches and myopathy, which decreased equally from 15% in the CNI-based group to 4% in the CNI-free group. Neurologic complications negatively impacted on mortality and survival rates, with a significantly higher 2-year cumulative incidence of non-relapse mortality (44% [95%CI, 34-54] vs. 16% [95%CI, 13-18]; P < 0.0001) and inferior overall survival (66% [95%CI, 62-69] vs. 46% [95%CI, 37-58]; P < 0.0001) in patients with neurologic complications. The study suggests that CNI-free GVHD prophylaxis with PTCy, sirolimus and MMF may reduce not only GVHD incidence, but also NCs and NRM rates, leading to improved survival outcomes in patients undergoing HSCT.
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Haploidentical donor stem cell transplantation had a lower incidence of bronchiolitis obliterans syndrome compared with HLA-matched sibling donor transplantation in patients with hematologic malignancies: Benefit from ATG?
Weng, G., Fan, Z., Xue, H., Huang, F., Xu, N., Jin, H., Yu, S., Ye, Z., Fan, J., Xuan, L., et al
Frontiers in immunology. 2022;13:1036403
Abstract
BACKGROUND Haploidentical donor stem cell transplantation (HID-SCT) based on antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis had achieved a similar incidence of chronic graft-versus-host disease (cGVHD) with human leukocyte antigen (HLA)-matched sibling donor stem cell transplantation (MSD-SCT). However, bronchiolitis obliterans syndrome (BOS), which serves as pulmonary cGVHD, was rarely compared between HID and MSD transplantation. METHODS One thousand four hundred five patients with hematologic malignancies who underwent allogeneic SCT were enrolled in this retrospective study. Based on donor type, we divided the patients into three groups: HID, MSD, and match unrelated donor (MUD) groups. The cumulative incidences and risk factors of BOS were analyzed. RESULTS The 5-year cumulative incidence of BOS was 7.2% in the whole population. HID transplantation had a lower 5-year cumulative incidence of BOS than MSD transplantation (4.1% vs. 10.0%, p < 0.001) and a similar incidence with MUD transplantation (4.1% vs. 6.2%, p = 0.224). The 5-year cumulative incidence of BOS was lower in the ATG group than that in the non-ATG group in both the whole and MSD populations (4.6% vs. 11.2%, p < 0.001, and 4.1% vs. 11.2%, p = 0.042, respectively). The 5-year incidence of BOS in mixed grafts [peripheral blood stem cell (PBSC) plus bone marrow] group was also lower than that in the PBSC group (4.2% vs. 9.1, p = 0.001). Multivariate analysis showed that HID, ATG, and mixed grafts were protective factors for BOS [odds ratio (OR) 0.3, 95% CI 0.2-0.6, p < 0.001; OR 0.3, 95% CI 0.2-0.7, p = 0.001; OR 0.3, 95% CI 0.1-0.8, p = 0.013], and acute graft-versus-host disease (aGVHD) and cGVHD were independent risk factors for BOS (OR 2.1, 95% 1.1-4.3, p = 0.035; OR 10.1, 95% CI 4.0-25.0, p < 0.001). CONCLUSIONS HID transplantation had a lower incidence of BOS than MSD transplantation, which might be associated with ATG and mixed grafts.
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3.
Three-year outcomes in recipients of mismatched unrelated bone marrow donor transplants using post-transplant cyclophosphamide: follow-up from a National Marrow Donor Program-sponsored prospective clinical trial
Shaw, B. E., Jimenez-Jimenez, A. M., Burns, L. J., Logan, B. R., Khimani, F., Shaffer, B. C., Shah, N. N., Mussetter, A., Tang, X. Y., McCarty, J. M., et al
Transplantation and cellular therapy. 2022
Abstract
The use of Post-Transplant Cyclophosphamide (PTCy) as Graft Versus Host Disease (GVHD) prophylaxis has resulted in reductions in GVHD and improved outcomes in allogeneic hematopoietic cell transplant (HCT) using HLA-mismatched related donors. We report the 3-year outcomes of the first multi-center prospective clinical trial using PTCy in the setting of mismatched unrelated donor (MMUD) bone marrow HCT. The study enrolled 80 patients (Either myeloablative (MAC) (N=40) or reduced intensity conditioning (RIC) (N=40)) with the primary endpoint of 1-year overall survival (OS). The median follow-up for this report is 34 months (range 12-46) in RIC and 36 months (range 18-49) in MAC. Three-year OS and non-relapse mortality (NRM) were 70% and 15%, and 62% and 10% in the RIC and MAC strata, respectively. No GVHD was reported after 1 year. Relapse incidence was 29% and 51% in RIC and MAC strata. OS did not differ based on HLA match grade (63% in the 7/8 strata and 71% in the 4-6/8 strata). These encouraging outcomes, sustained 3 years post-HCT, support the continued exploration of MMUD HCT using a PTCy platform. Important future areas to address include relapse reduction and furthering our understanding of optimal donor selection based on HLA and non-HLA factors.
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4.
New-onset post-transplant diabetes mellitus after haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide
Mangan, B. L., Patel, D., Chen, H., Gatwood, K. S., Byrne, M. T., Sengsayadeth, S., Goodman, S., Dholaria, B., Kassim, A. A., Jagasia, M., et al
EJHaem. 2020;1(2):576-580
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Abstract
Haploidentical hematopoietic cell transplant (haplo-HCT) with post-transplant cyclophosphamide (PTCY) is utilized for patients with hematological disorders but without conventional donors. The effects of new-onset post-transplant diabetes mellitus (PTDM) following haplo-HCT are unknown. We examined PTDM incidence and outcomes after haplo-HCT with PTCY. Patients without diabetes receiving haplo-HCT (n=64) were analyzed for PTDM diagnosis (defined as blood glucose= 200 mg/dL). By day 100, 14 (22%) patients developed PTDM (median, 18 days). Hyperglycemia (blood glucose = 200 mg/dL) preceded corticosteroids in 11 (79%) individuals. PTDM patients had increased death/relapse (p=0.029). PTDM occurs frequently, precedes corticosteroids, and leads to inferior outcomes following haplo-HCT. PTDM prophylaxis/treatment may improve HCT survival.
Clinical Commentary
What is known?
NIHMS1640876
What did this paper set out to examine?
What did they show?
What are the implications for practice and for future work?
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5.
Cyclosporine A for the Prevention of Ocular Graft versus Host Disease in Allogeneic Hematopoietic Stem Cell Transplant Recipients Is Safe and Feasible
Cantu-Rodriguez, O. G., Vazquez-Mellado, A., Gonzalez-Trevino, J. L., Martinez-Garza, D. M., Gomez-De Leon, A., Hawing-Zarate, J. A., Jaime-Perez, J. C., Gutierrez-Aguirre, C. H., Garza-Acosta, A. C., Mancias-Guerra, C., et al
Acta haematologica. 2019;:1-7
Abstract
PURPOSE To evaluate the safety and efficacy of ocular cyclosporine in the prevention of the development of ocular graft versus host disease (oGVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT) in comparison with historic data. DESIGN We developed a longitudinal, observational, prospective nonrandomized study. We evaluated the feasibility of prophylactic use of topical cyclosporine A (CsA) to prevent or decrease the incidence of oGVHD and compared this with historic data. METHODS Patients undergoing AHSCT were treated with prophylactic topical CsA for 12 months after engraftment, followed by serial ophthalmic evaluations, including the Schirmer test. RESULTS Twenty patients were included. No serious adverse effects were reported. Poor adherence was documented in 15% of patients. In spite of observing extra-ocular GVHD (acute and chronic GVHD incidence of 50 and 45%, respectively), only 1 in 20 patients developed oGVHD over the 20-month follow-up for the entire cohort. No statistically significant difference was observed in the incidence of oGVHD when compared to a historical cohort. CONCLUSIONS Topical CsA as a prophylactic measure for oGVHD, administered over a period of 1 year after grafting, is safe and feasible and may decrease the incidence of ophthalmic manifestations of GVHD. These findings must be confirmed in a randomized trial.
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Topical Cyclosporine Pretreatment of Ocular Surface in Allogeneic Hematopoietic Stem Cell Transplant Recipients
Chun, Y. H., Beak, J. U., Kim, H. S., Na, K. S.
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics. 2018
Abstract
PURPOSE Dry eye disease (DED) of ocular graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT). Ongoing inflammation and irreversible fibrotic changes of the ocular surface and adnexa are obstacles for effective treatment of ocular GVHD. We hypothesized that topical cyclosporine A (CsA) pretreatment might be effective in preventing ocular GVHD. METHODS In this prospective, randomized, comparative study, patients were randomly assigned to the topical CsA treatment (4 times daily in both eyes for a month before allogeneic HSCT and continued use of eye drops after transplantation) or control (no treatment) groups. Participants underwent thorough ophthalmic examination-including Ocular Surface Disease Index questionnaire survey, Schirmer test, tear break-up time (TBUT) evaluation, and corneal fluorescein staining-before and 1, 2, and 3 months after allogeneic HSCT. RESULTS Fifty-eight participants completed the study. Among patients with baseline Schirmer values <10 mm and TBUT <5 s before allogenic HSCT, those in the topical CsA treatment group exhibited significantly better corresponding values after transplantation than patients in the control group. CONCLUSIONS Topical CsA pretreatment might be beneficial in the early stage of DED and might prevent further inflammation and consequent irreversible fibrosis, especially in patients with preexisting DED components.
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Low incidence of severe cGvHD and late NRM in a phase II trial of thymoglobulin, tacrolimus and sirolimus for GvHD prevention
Al-Kadhimi, Z., Gul, Z., Abidi, M., Lum, L. G., Deol, A., Chen, W., Jang, H., Ozust, C., Langston, A., Waller, E., et al
Bone Marrow Transplantation. 2017;52(9):1304-1310
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Chronic GvHD (cGvHD) is the leading cause of late non-relapse mortality (NRM) and morbidity after allogeneic hematopoietic stem cell transplant (AHSCT). We analyzed the late effects of a phase II trial testing the efficacy of intermediate dose rabbit anti-thymocyte globulin (Thymoglobulin Thymo) in combination with tacrolimus and sirolimus (TTS) in 47 patients (pts) for the prevention of acute and chronic GvHD after unrelated AHSCT. The median follow-up was 45.2 months. The cumulative incidence of NIH severe cGvHD at 48 months was 6.4% with no new occurrences past 6 months for the entire follow-up period. The overall cumulative incidence of cGvHD was 44.7%. Out of 20 pts who are alive and disease-free at the last follow-up, only 4 pts continue to need systemic immune suppression. We observed low late NRM with only 3 transplant-related deaths after 6 months post transplant. At 4 years of follow-up, the overall cumulative incidence of NRM and disease relapse was 27.7% and 30.0%, respectively. PFS and overall survival (OS) at 4 years were 42 and 47%. At long term follow-up, TTS was associated with low incidence of severe cGvHD and late NRM.
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Cardiomyopathy in patients after posttransplant cyclophosphamide-based hematopoietic cell transplantation
Lin, C. J., Vader, J. M., Slade, M., DiPersio, J. F., Westervelt, P., Romee, R.
Cancer. 2017;123(10):1800-1809
Abstract
BACKGROUND The use of posttransplant cyclophosphamide (PT-Cy) has contributed significantly to the success of haploidentical hematopoietic cell transplantation (HCT). Furthermore, several studies have shown promising results in the human leukocyte antigen-matched setting. However, the use of high-dose cyclophosphamide has been associated with the development of cardiomyopathy. There is a paucity of data concerning posttransplant cardiac complications in patients undergoing PT-Cy-based HCT. METHODS A retrospective analysis of 176 patients undergoing HCT with PT-Cy was performed. The overall survival, left ventricular ejection fractions, brain natriuretic peptide levels, and cardiac comorbidities were reviewed. The associations between comorbidities and the onset of heart failure were assessed with a Cox proportional hazards model. RESULTS Pretransplant cardiomyopathy was found in 16 patients (9.1%) but had no effect on their posttransplant overall survival. Thirty-five patients (21.9%) developed posttransplant cardiomyopathy, which correlated with increased mortality, but this was not statistically different from the frequency-matched non-PT-Cy cohort. The majority of these cardiomyopathies occurred in the setting of an infectious milieu. An age greater than 60 years and an HCT comorbidity index score equal to or greater than 4 were the only risk factors that correlated with posttransplant cardiomyopathy. CONCLUSIONS The presence of pretransplant cardiomyopathy does not negatively affect overall survival for patients who undergo HCT with PT-Cy. Furthermore, cardiomyopathy in PT-Cy patients is not caused by PT-Cy but is mostly concurrent with infectious complications and is associated with reduced overall survival. Traditional cardiovascular risk factors do not fully predict the occurrence of posttransplant cardiomyopathy. Future research is required to unravel predictive factors for cardiomyopathy after PT-Cy-based HCT. Cancer 2017;123:1800-1809. © 2017 American Cancer Society.