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A convolutional neural network-based model that predicts acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
Jo, T., Arai, Y., Kanda, J., Kondo, T., Ikegame, K., Uchida, N., Doki, N., Fukuda, T., Ozawa, Y., Tanaka, M., et al
Communications medicine. 2023;3(1):67
Abstract
BACKGROUND Forecasting acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) is highly challenging with conventional statistical techniques due to complex parameters and their interactions. The primary object of this study was to establish a convolutional neural network (CNN)-based prediction model for aGVHD. METHOD We analyzed adult patients who underwent allogeneic HSCT between 2008 and 2018, using the Japanese nationwide registry database. The CNN algorithm, equipped with a natural language processing technique and an interpretable explanation algorithm, was applied to develop and validate prediction models. RESULTS Here, we evaluate 18,763 patients between 16 and 80 years of age (median, 50 years). In total, grade II-IV and grade III-IV aGVHD is observed among 42.0% and 15.6%. The CNN-based model eventually allows us to calculate a prediction score of aGVHD for an individual case, which is validated to distinguish the high-risk group of aGVHD in the test cohort: cumulative incidence of grade III-IV aGVHD at Day 100 after HSCT is 28.8% for patients assigned to a high-risk group by the CNN model, compared to 8.4% among low-risk patients (hazard ratio, 4.02; 95% confidence interval, 2.70-5.97; p < 0.01), suggesting high generalizability. Furthermore, our CNN-based model succeeds in visualizing the learning process. Moreover, contributions of pre-transplant parameters other than HLA information to the risk of aGVHD are determined. CONCLUSIONS Our results suggest that CNN-based prediction provides a faithful prediction model for aGVHD, and can serve as a valuable tool for decision-making in clinical practice. Hematopoietic stem cell transplantation (HSCT) is a procedure used in patients to reestablish blood cell production. It involves the transplant of cells from a donor to the patient. In some patients the transplanted cells damage cells within the patients. This is called graft-versus-host disease (GVHD). We developed a computational code that can predict the likelihood a person will develop GVHD soon after HSCT. Using this computer program will enable doctors to better identify those at risk of GVHD and initiate treatments when required. eng COIS- The authors declare no competing interests.
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Population-based real-world registry study to evaluate clinical outcomes of chronic graft-versus-host disease
Novitzky-Basso, I., Schain, F., Batyrbekova, N., Webb, T., Remberger, M., Keating, A., Mattsson, J.
PloS one. 2023;18(3):e0282753
Abstract
INTRODUCTION Chronic graft-versus-host disease (cGVHD) is a serious immune-mediated complication after allogeneic haematopoietic stem cell transplantation (HSCT), but in patients with malignancy, cGVHD development is associated with superior survival. Lack of reliable biomarkers and clinical underreporting means there is insufficient understanding of cGVHD clinical outcomes and balance between cGVHD treatment and maintaining beneficial graft-versus-tumour effects. METHODS We performed a Swedish population-wide registry study following patients who underwent allogeneic HSCT 2006-2015. cGVHD status was retrospectively classified using a real-world method based on the timing and extent of systemic immunosuppressive treatment. RESULTS cGVHD incidence among patients surviving ≥6 months post-HSCT (n = 1246) was 71.9%, significantly higher than previously reported. 5-year overall survival in patients surviving ≥6 months post-HSCT was 67.7%, 63.3%, and 65.3%, in non-, mild, and moderate-severe cGVHD, respectively. Non-cGVHD patients had a mortality risk almost five-fold higher compared to moderate-severe cGVHD patients 12-months post-HSCT. Moderate-severe cGVHD patients had greater healthcare utilization compared with mild and non cGVHD patients. CONCLUSION cGVHD incidence was high among HSCT survivors. Non-cGVHD patients had higher mortality during the first 6 months of follow-up; however, moderate-severe cGVHD patients had more comorbidities and healthcare utilization. This study highlights the urgent need for new treatments and real-time methods to monitor effective immunosuppression after HSCT.
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3.
The clinical benefit of acute GVHD depends on the age at transplantation in patients with adult T-cell leukemia-lymphoma on behalf of the ATL Working Group of the Japan Society for Transplantation and Cellular Therapy
Fuji, S., Inoue, Y., Makiyama, J., Nakano, N., Ito, A., Kawakita, T., Eto, T., Suehiro, Y., Itonaga, H., Sawayama, Y., et al
Bone marrow transplantation. 2023
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Mild Acute Graft-Versus-Host Disease Improves Outcomes After HLA-Haploidentical-Related Donor Transplantation Using Posttransplant Cyclophosphamide and Cord Blood Transplantation
Wada, F., Kanda, J., Kamijo, K., Nishikubo, M., Yoshioka, S., Ishikawa, T., Ueda, Y., Akasaka, T., Arai, Y., Izumi, K., et al
Cell transplantation. 2023;32:9636897231194497
Abstract
Haploidentical-related donor transplantation using posttransplant cyclophosphamide (PTCy-haplo) and cord blood transplantation (CBT) are valid alternatives for patients with hematological malignancies when HLA-matched donor transplantation (MDT) is unavailable. However, the effects of graft-versus-host disease (GVHD) on outcomes after these transplants have not been fully elucidated. Therefore, we evaluated the effects of acute and chronic GVHD on transplant outcomes after PTCy-haplo transplants and compared them with CBT and MDT. We included a total of 914 adult patients with hematological malignancies in the Kyoto Stem Cell Transplantation Group registry who received PTCy-haplo (N = 120), CBT (N = 402), and MDT (N = 392), and achieved neutrophil engraftment. A multivariate analysis revealed that grade I-II acute GVHD improved of overall survival (OS) after PTCy-haplo [hazard ratio (HR) = 0.39, P = 0.018] and CBT (HR = 0.48, P < 0.001), but not after MDT (HR = 0.80, P = 0.267) compared with patients without acute GVHD. Grade I-II acute GVHD had a trend toward reducing the risk of nonrelapse mortality (NRM) after PTCy-haplo (HR = 0.13, P = 0.060) and this positive effect was significant after CBT (HR = 0.39, P = 0.003). A negative impact of grade III-IV acute GVHD on NRM was observed after CBT and MDT, but not after PTCy-haplo. Limited chronic GVHD had a positive impact on OS after CBT and MDT, but not after PTCy-haplo. In conclusion, mild acute GVHD improved outcomes after PTCy-haplo and CBT, and limited chronic GVHD improved outcomes after CBT and MDT. These data indicated that the effects of GVHD on transplant outcomes depended on transplant platforms.
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Incidence of cutaneous graft-versus-host disease in a Singapore academic medical centre - A retrospective cohort study
Tan, W. H., Ho, A., Kadir, H. A., Zin, T. K., Jordan, H. C. C., Lee, H. Y., Pang, S. M., Yeo, Y. W., Choo, K. J. L., Oh, C. C.
The Australasian Journal of Dermatology. 2023;64(1):e26-e33
Abstract
BACKGROUND Cutaneous graft-versus-host disease (GVHD) is common in allogeneic haematopoietic stem cell transplantation. HLA mismatch is the most significant determinant of GVHD. Our study aimed to compare the incidence of cutaneous GVHD haploidentical (Haplo) and matched donors in an Asian population. METHODS Retrospective cohort study of the 2015-2019 bone marrow transplant registry was conducted in a transplant centre. We compared the incidence of cutaneous GVHD in Haplo with allogeneic matched unrelated donor (MUD) and matched-sibling donor (MSD) transplant recipients. Secondary objectives include acute and chronic GVHD incidence, dermatology referrals, and histological findings. RESULTS One hundred and seventy-nine out of 203 cases were reviewed; 17 (9.5%) Haplo, 80 (44.7%) MUDs and 82 (45.8%) MSDs. The median follow-up for Haplo, MUD and MSD was 15.2, 34.2 and 35.7 months, respectively. Haplo had a higher cumulative incidence of cutaneous GVHD than MUD and MSD (p = 0.053). Chronic GVHD was only reported in MSD. The most common histology was vacuolar interface changes (13 [44.8%]) with a wide range of onset post-transplant (19-456 days). CONCLUSIONS Haplo donors may have a higher GVHD incidence than MUD and MSD in our predominantly Asian cohort. This information may be helpful when counselling patients pre-transplant. Further prospective studies are required.
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Impact of GVHD on lymphoma progression: Nationwide study from Japanese Society for Transplantation and Cellular Therapy
Watanabe, M., Kanda, J., Fukuda, T., Uchida, N., Ikegame, K., Kataoka, K., Kobayashi, H., Ara, T., Ishikawa, J., Matsuoka, K. I., et al
British journal of haematology. 2023
Abstract
The graft-versus-lymphoma (GVL) effect and its association with acute and chronic GVHD (aGVHD, cGVHD) has not been comprehensively elucidated. We retrospectively analysed 2204 Japanese patients with non-Hodgkin lymphomas (NHLs; indolent B-NHLs, n = 689; aggressive B-NHLs, n = 720; mature T/NK-NHLs, n = 795) receiving a first allo-HSCT in 2003-2017. Pre-transplant lymphoma control showed complete response (CR) in 759 and non-CR in 1445. We assessed the impact of aGVHD/cGVHD on lymphoma progression and other outcomes. Although aGVHD/cGVHD showed no statistical impact on lymphoma progression in the overall cohort, their impact was clear in certain groups: Grade I-II aGVHD in CR patients (HR, 0.63; 95% CI, 0.43-0.91), especially in mature T/NK-NHL (HR, 0.46; 95% CI, 0.26-0.83) and extensive cGVHD in patients with mature aggressive B-NHLs (HR, 0.55; 95% CI, 0.31-0.97). In total, limited cGVHD was associated with superior survivals (progression-free survival: HR, 0.71; 95% CI, 0.56-0.90), whereas severe GVHDs showed negative impacts on them. Our results support the presence of GVL effects differentially associated with GVHD in different lymphoma subtypes/controls. Meanwhile, it was also suggested that we should manage GVHDs within a limited activity, considering the negative impact of severe GVHDs. As pre-transplant lymphoma control remains a strong factor influencing transplant outcomes, improving its management is an important issue to be addressed.
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Real-world clinical characterization, healthcare resource utilization and productivity loss in chronic graft versus host patients exposed to extracorporeal photopheresis in Sweden
Schain, F., Boissin, C., Laczik, T., Fedeli, S., Remberger, M., Blennow, O., Dykes, J., Eich, T., Jones, C., Mattsson, J., et al
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2023;:103705
Abstract
BACKGROUND Extracorporeal photopheresis (ECP) is frequently used to treat moderate-severe chronic graft versus host disease (cGVHD), however limited data exists describing ECP treatment effects on healthcare and societal costs. We aimed to characterize clinical and health economic outcomes and productivity loss in cGVHD patients exposed to ECP. METHODS We identified 2708 patients aged ≥ 18 years with a record of allogeneic hematopoietic stem cell transplantation (HSCT) in the Swedish Patient Register between 2006 and 2020. Patients exposed to ECP from 3-months post HSCT (index) were included (n= 183). Data was linked to the Prescribed Drug Register, the Cause of Death Register, and the Longitudinal Integrated Database for Health Insurance and Labor Market Studies (LISA). RESULTS The median patient age at index was 51 years (IQR1-3; 38-61). In the 3-month period before ECP initiation compared to 9-12 months post-ECP, the cumulative three-month dose per patient decreased prednisolone/prednisone (1,381 mg vs. 658 mg, p < 0.001) and cyclosporin (12,242 mg vs. 3,501 mg, p < 0.001). Infection incidence also decreased over the same period (79.2% vs 59.1%, p < 0.001). Time spent in healthcare decreased from 68.9% to 22.1% from the first and fifth follow-up year respectively, and corresponding annual healthcare cost reduced from €27,719 to €1,981. Among patients < 66 years of age, sickness-related workplace absence decreased from 73.2% to 31.9% between the first and fifth follow-up year, with median annual productivity loss decreasing from €20,358 to €7,211 per patient. CONCLUSIONS ECP was associated with reduced use of corticosteroids, immunosuppressive agents, and fewer infections. Furthermore, cost and healthcare utilization decreased over time.
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Association of Chronic Graft-versus-Host Disease with Late Effects Following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy
Lee, C. J., Wang, T., Chen, K., Arora, M., Brazauskas, R., Spellman, S. R., Kitko, C., MacMillan, M. L., Pidala, J. A., Auletta, J. J., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality-of-life among long-term survivors of pediatric HCT. Late effects of HCT are well documented in this population and cGVHD has been reported as a risk factor for subsequent neoplasms (SN) and several non-malignant late effects. However, the correlation between cGVHD and late effects varies between studies. OBJECTIVE We compared late effects occurring ≥ 2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of late effects. STUDY DESIGN This was a systematic retrospective analysis using data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large and representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant and non-malignant late effects following a diagnosis of cGVHD versus those who never developed cGVHD. The cumulative incidence (CI) of any first LE, subsequent neoplasm (SN), and non-malignant LE (NM-LE) was estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD vs. no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first late effects. RESULTS The estimated 10-year cumulative incidence of any late effect in patients with and without cGVHD was 43% (95% CI, 38%-48.2%) vs. 32% (95% CI, 28.5%-36.3%) (P<0.001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any late effect (HR 1.38, 95% CI, 1.13-1.68, P=.001) and non-malignant late effects (HR 1.37, 95% CI, 1.10-1.70, P=.006), but not SN (HR 1.30, 95% CI, 0.73-2.31, P=.38). Chronic GVHD-related factors linked with the development of a non-malignant late effect included having extensive grade (HR 1.60, 95% CI 1.23 - 2.08, P=.0005), severe cGVHD (HR 2.25, 95% CI 1.60 - 3.17, P<.0001), interrupted onset type (HR 1.57, 95% CI 1.21 - 2.05, P=.0008), and both mucocutaneous and visceral organ involvement (HR 1.59, 95% CI 1.24 - 2.03, P=.0002). No significant association between cGVHD-specific variables and SN was identified. Lastly, duration of cGVHD treatment with systemic immunosuppression was not significantly associated with SN or non-malignant late effects. CONCLUSIONS cGVHD was more closely associated with non-malignant late effects than SN amongst survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SN was strongly associated with myeloablative total body irradiation. Chronic GVHD-related characteristics consistent with a state of higher immune dysregulation were more closely linked to non-malignant late effects.
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Disease-specific impact of anti-thymocyte globulin in allogeneic hematopoietic cell transplantation: a nationwide retrospective study on behalf of the JSTCT, transplant complications working group
Fuji, S., Hirakawa, T., Takano, K., Doki, N., Sawa, M., Kanda, Y., Uchida, N., Ara, T., Miyamoto, T., Eto, T., et al
Bone marrow transplantation. 2022
Abstract
The disease-specific impact of anti-thymocyte globulin (ATG) in allogeneic hematopoietic cell transplantation (allo-HCT) has not been determined. We retrospectively assessed the impact of ATG in allo-HCT using nationwide registry data from the Japan Society for Transplantation and Cellular Therapy. We included patients who received their first allo-HCT between 2007 and 2018 for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or malignant lymphoma (ML). In total, 8747 patients were included: 7635 patients did not receive ATG and 1112 patients received ATG as GVHD prophylaxis. The median follow-up period of surviving patients was 1457 days. There was no significant impact of pretransplant ATG on the OS or NRM rates in patients with ALL, AML, or ML. In patients with MDS, the probability of 3-year OS was 53.3% in the non-ATG group and 64.2% in the ATG group (P = 0.001). The cumulative incidence rates of relapse and NRM at 3 years were 14.2% and 30.3% (95% CI 27.2-33.3%), respectively, in the non-ATG group and 17.1% and 18.1% in the ATG group (P = 0.15 and P < 0.001). The same finding was observed in a propensity-score matched cohort. Our study suggests that the clinical benefit of ATG could vary among hematological diseases.
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10.
Improved outcome of patients with graft-versus-host disease after allogeneic hematopoietic cell transplantation for hematologic malignancies over time: an EBMT mega-file study
Greinix, H. T., Eikema, D. J., Koster, L., Penack, O., Yakoub-Agha, I., Montoto, S., Chabannon, C., Styczynski, J., Nagler, A., Robin, M., et al
Haematologica. 2021
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Editor's Choice
Abstract
Acute graft-versus-host disease (aGvHD) remains a major threat to successful outcome after allogeneic hematopoietic cell transplantation. Advances in prophylaxis and supportive care have taken place over the years. The aim of this study is to test whether incidence and mortality of aGvHD have been reduced over time. 102 557 patients with a median age of 47.6 years with malignancies after first allogeneic sibling or unrelated donor (URD) transplant were studied in the following periods: 1990-1995, 1996-2000, 2001-2005, 2006-2010, 2011-2015. Findings: 100-day-incidences of aGvHD grades II-IV decreased from 40%, to 38%, 32%, 29% and 28% over calendar time (p.
PICO Summary
Population
Patients undergoing first allogeneic sibling or unrelated donor transplant (URD) between 1990 and 2015 (n=102 557)
Intervention
Registry data study assessing incidence of acute GvHD (aGvHD)
Comparison
Patients were compared in the following time periods: 1990-1995, 1996-2000, 2001-2005, 2006-2010, 2011-2015
Outcome
In multivariate analysis URD, not in CR at transplant or untreated, and female donor for male recipient were associated with increased risk whereas use of ATG/alemtuzumab decreased aGvHD incidence. Median follow-up was 214, 169, 127, 81 and 30 months for periods analyzed. 3-year-survival after aGvHD grades II-IV increased significantly from 38% to 40%, 43%, 44%, and 45%. In multivariate analysis URD, not in CR at transplant, peripheral blood as stem cell source, female donor for male recipient, and use of ATG/alemtuzumab were associated with increased mortality whereas reduced-intensity conditioning with lower one. Mortality increased with increasing patients‘ age but decreased in the recent cohorts.