scholarly journals Myeloablation-associated deletion of ORF4 in a human coronavirus 229E infection

2017 ◽  
Author(s):  
Alexander L. Greninger ◽  
Gregory Pepper ◽  
Ryan C. Shean ◽  
Anne Cent ◽  
Isabel Palileo ◽  
...  

AbstractWe describe metagenomic next-generation sequencing (mNGS) of a human coronavirus 229E from a patient with AML and persistent upper respiratory symptoms, who underwent hematopoietic cell transplantation (HCT). mNGS revealed a 548-nucleotide deletion, which comprised the near entirety of the ORF4 gene, and no minor allele variants were detected to suggest a mixed infection. As part of her pre-HCT conditioning regimen, the patient received myeloablative treatment with cyclophosphamide and 12 Gy total body irradiation. Iterative sequencing and RT-PCR confirmation of 4 respiratory samples over the 4-week peritransplant period revealed that the pre-conditioning strain contained an intact ORF4 gene, while the deletion strain appeared just after conditioning and persisted over a 2.5-week period. This sequence represents one of the largest genomic deletions detected in a human RNA virus and describes large-scale viral mutation associated with myeloablation for HCT.

2021 ◽  
Vol 28 (1) ◽  
pp. 903-917
Author(s):  
Mitchell Sabloff ◽  
Steven Tisseverasinghe ◽  
Mustafa Ege Babadagli ◽  
Rajiv Samant

Total body irradiation (TBI), used as part of the conditioning regimen prior to allogeneic and autologous hematopoietic cell transplantation, is the delivery of a relatively homogeneous dose of radiation to the entire body. TBI has a dual role, being cytotoxic and immunosuppressive. This allows it to eliminate disease and create “space” in the marrow while also impairing the immune system from rejecting the foreign donor cells being transplanted. Advantages that TBI may have over chemotherapy alone are that it may achieve greater tumour cytotoxicity and better tissue penetration than chemotherapy as its delivery is independent of vascular supply and physiologic barriers such as renal and hepatic function. Therefore, the so-called “sanctuary” sites such as the central nervous system (CNS), testes, and orbits or other sites with limited blood supply are not off-limits to radiation. Nevertheless, TBI is hampered by challenging logistics of administration, coordination between hematology and radiation oncology departments, increased rates of acute treatment-related morbidity and mortality along with late toxicity to other tissues. Newer technologies and a better understanding of the biology and physics of TBI has allowed the field to develop novel delivery systems which may help to deliver radiation more safely while maintaining its efficacy. However, continued research and collaboration are needed to determine the best approaches for the use of TBI in the future.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1924-1924
Author(s):  
Raya Mawad ◽  
Ted A. Gooley ◽  
Joseph G Rajendran ◽  
Darrell R. Fisher ◽  
Ajay K. Gopal ◽  
...  

Abstract Abstract 1924 Innovative therapeutic approaches are needed to reduce the morbidity and high relapse rates in patients with advanced AML or high-risk MDS following myeloablative hematopoietic cell transplantation (HCT). Success with stable donor chimerism and low toxicity following infusion of allogeneic peripheral blood stem cells (PBSC) with reduced-intensity regimens affords an opportunity to induce a graft-versus-leukemia (GVL) effect with minimal acute morbidity. GVL effects, however, appear to be most potent in patients with low tumor burden at the time of HCT. In an attempt to improve outcomes, we previously transplanted 58 patients older than age 50 with advanced AML (beyond first remission) or high-risk MDS (≥5% marrow blasts at the time of HCT) in a Phase I trial using 131I-labeled anti-CD45 antibody (BC8) in conjunction with fludarabine (FLU) and 2Gy total-body irradiation (TBI). Data from this study suggested that 131I-anti-CD45-targeted radiotherapy could be safely integrated into a reduced-intensity conditioning regimen for older, high-risk patients with AML or MDS yielding encouraging survival outcomes. These results prompted us to evaluate a similar strategy in younger patients (ages 16–50) with advanced AML or high-risk MDS who may not be able to receive a high dose HCT conditioning regimen. In this phase I dose–escalation trial 14 patients received a dose of 131I-BC8 that delivered 10–27 Gy of targeted radiation to the healthy organ receiving the highest dose combined with FLU (30 mg/m2 daily for 3 days), 2 Gy TBI, and HLA-matched related (n = 7) or unrelated (n = 7) PBSC grafts. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. The 131I radiation dose was escalated until the maximum planned dose of 28 Gy was reached without any appreciable dose limiting toxicity. The median patient age was 39.5 (range, 23.8–49.7) years. Thirteen patients had AML, with 9 patients in second complete remission, 3 with primary refractory disease, and 1 in active relapse. One patient had advanced CMML with >5% blasts. Treatment with the 131I-BC8 Ab/FLU/TBI regimen produced a complete remission in 7 patients (50%), and 11 of the 12 evaluable patients had 100% donor CD3+ and CD33+cell engraftment by day 28 after HCT; an additional patient had 79% CD3 and 82% CD33 positive donor marrow cells at day 28. The absolute neutrophil count surpassed 500/μL at a median of 15 (range, 13–22) days. Self-sustained platelet levels of 20,000/μL were reached at a median of 11 (range, 11–27) days after HCT. Five patients (36%) are surviving relapse-free 46 to 99 months (median 87 months) after HCT. Seven patients (50%) have died, with five patients relapsing 0.9 to 45 months after HCT. No non-relapse mortality occured by day 100; however, two patients died 14 and 18 months after HCT of cardiomyopathy and GVHD complications, respectively. This study demonstrates that, in addition to a standard reduced intensity conditioning regimen, an average of 27 Gy of targeted 131I radiotherapy can be delivered to bone marrow, an average of 20Gy to the liver, and an average of 84 Gy to the spleen without a marked increase in day 100 mortality for younger patients. This strategy may thus provide a reasonable alternative for patients with high-risk AML/MDS who may not be able to tolerate a high dose conditioning HCT. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5739-5739
Author(s):  
Hamza Hashmi ◽  
Jeffrey Lancet ◽  
Asmita Mishra ◽  
Kendra L. Sweet ◽  
Rami S. Komrokji ◽  
...  

BACKGROUND: Outcomes of patients with acute promyelocytic leukemia (APL) have improved; however, a number of patients, particularly those with high-risk APL, still relapse despite all-trans-retinoic acid (ATRA) and arsenic-based therapies. We present single institution outcomes of autologous (auto) and allogenic (allo) hematopoietic cell transplantation (HCT) in patients with relapsed APL. PATIENTS AND METHODS: We retrospectively reviewed outcomes in patients with relapsed APL who underwent either auto- or allo- HCT at Moffitt Cancer Center from 1990 to 2018 utilizing the clinical data obtained from BMT Research & Analysis Information Network (BRAIN). Survival data were analyzed using Kaplan-Meier estimates. RESULTS: Autologous HCT Cohort: A total of 15 received auto-HCT with a median age at HCT of 39 (range, 21-60) years. Disease status at HCT were first complete remission (CR1) in 5 (33%) and CR2 in 10 (67%). Majority of patients (13/15, 87%) received busulfan/cyclophosphamide (Bu/Cy) conditioning and remaining (2/15, 13%) Bu/Cy/etoposide. All (n=15) patients received peripheral blood (PB) stem cell grafts. Median time to neutrophil engraftment was 11 (range, 10-14) days and platelet recovery was 14 (range 9-44) days. The median progression-free survival (PFS) for auto HCT was 12.9 (95% confidence interval (CI): 1.2-24.8) months. With a median follow up of 45.1 months for surviving patients, overall survival (OS) for auto HCT was 12.9 (95%CI: 0-27.8) years. At the time analysis, 8 patients were relapse-free. Allogeneic HCT Cohort: A total of 10 patients received allo HCT with a median age of 46 (range, 22-56) years at HCT. Disease status at allo HCT was CR2 in 2, CR3 in 6, and two had refractory disease. Two patients had prior auto HCT. Donor type was HLA-identical sibling=5; one antigen-mismatched sibling=1; HLA-matched unrelated donor=3; related haploidentical=1. Seven patients received peripheral blood graft and 3 received bone marrow graft. Conditioning regimen intensity was myeloablative in 7 (fludarabine/busulfan +/- anti-thymocyte globulin=3; Bu/Cy=3; cyclophosphamide/total body irradiation=1), and reduced intensity in 3 (fludarabine/melphalan=2; fludarabine/cyclophosphamide/total body irradiation=1). Seven patients received tacrolimus-based graft-versus-host disease (GVHD) prophylaxis. Median time of neutrophil engraftment was 15 (range, 12-22) days, and platelet engraftment was 22 (range, 15-28) days. The median PFS for allo HCT was 11.9 (95%CI: 2.1-21.6) months. With a median follow up of 48.2 months for surviving patients, median OS for allo HCT was 12.4 (95%CI: 4.8-19.9) months. At the time of analysis 4 patients were relapse-free. CONCLUSIONS: In our single center analysis, auto HCT for APL resulted in a durable remission and prolonged survival. Outcomes after allo HCT were suboptimal primarily due to their heavily pretreated condition and chemotherapy resistant disease. Further research on novel conditioning regimen and relapse prevention is needed to improve the outcomes of allo HCT in APL. Figure Disclosures Lancet: Jazz Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Consultancy; Daiichi-Sankyo: Consultancy; Pfizer: Consultancy. Sweet:Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Stemline: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; Agios: Consultancy; JAZZ: Consultancy; Incyte: Consultancy; pfizer: Consultancy; DSI: Consultancy; celgene: Consultancy. Bejanyan:Kiadis Pharma: Other: advisory board. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding.


2004 ◽  
Vol 18 (2) ◽  
pp. 75-80 ◽  
Author(s):  
Sophie Vallet ◽  
Arnaud Gagneur ◽  
Pierre J Talbot ◽  
Marie-Christine Legrand ◽  
Jacques Sizun ◽  
...  

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11008
Author(s):  
Chu-Wen Yang ◽  
Mei-Fang Chen

Background The innate immune system especially Toll-like receptor (TLR) 7/8 and the interferon pathway, constitutes an important first line of defense against single-stranded RNA viruses. However, large-scale, systematic comparisons of the TLR 7/8-stimulating potential of genomic RNAs of single-stranded RNA viruses are rare. In this study, a computational method to evaluate the human TLR 7/8-stimulating ability of single-stranded RNA virus genomes based on their human TLR 7/8-stimulating trimer compositions was used to analyze 1,002 human coronavirus genomes. Results The human TLR 7/8-stimulating potential of coronavirus genomic (positive strand) RNAs followed the order of NL63-CoV > HKU1-CoV >229E-CoV ≅ OC63-CoV > SARS-CoV-2 > MERS-CoV > SARS-CoV. These results suggest that among these coronaviruses, MERS-CoV, SARS-CoV and SARS-CoV-2 may have a higher ability to evade the human TLR 7/8-mediated innate immune response. Analysis with a logistic regression equation derived from human coronavirus data revealed that most of the 1,762 coronavirus genomic (positive strand) RNAs isolated from bats, camels, cats, civets, dogs and birds exhibited weak human TLR 7/8-stimulating potential equivalent to that of the MERS-CoV, SARS-CoV and SARS-CoV-2 genomic RNAs. Conclusions Prediction of the human TLR 7/8-stimulating potential of viral genomic RNAs may be useful for surveillance of emerging coronaviruses from nonhuman mammalian hosts.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 616-616 ◽  
Author(s):  
Mohamed Sorror ◽  
B. Storer ◽  
A. Gopal ◽  
L. Holmberg ◽  
B.M. Sandmaier ◽  
...  

Abstract An HCT-comorbidity index (HCT-CI) was modeled to capture comorbidities and predict outcomes among pts given allogeneic HCT (Blood 2005). Here, we asked whether the HCT-CI could provide prognostic information among pts given autologous HCT. We retrospectively collected and analyzed comorbidities and other pretransplant variables among 273 pts with lymphoma transplanted between 2000 and 2005. Pts were conditioned with cyclophosphamide + total body irradiation or radio-labeled monoclonal antibody (n=127), busulfan/melphalan/thiotepa (n=86), melphalan/cytarabine/BCNU/etoposide (n=37), or other regimens (n=17). Diagnoses were indolent (n=36) or aggressive non-Hodgkin lymphoma (n=169) and Hodgkin lymphoma (n=68). At HCT, 16%, 37%, and 34% of pts had disease transformed from follicular lymphoma, chemosensitive disease, and elevated LDH, respectively. Median age was 49 (range:13–76) years. Median number of prior regimens was 3 and 58% and 26% had prior rituximab and radiotherapy, respectively. HCT-CI comorbidities (score >0, Table 1) were found among 65% of pts, of whom 16% had score 1, 19% score 2, 26% scores 3–4, and 4% scores ≥5. Among pts with scores ≥3 (n=82), 20 had a single comorbidity while 62 had ≥2 comorbidities. In univariate analyses, number of prior regimens, prior rituximab, prior radiotherapy, histology, transformed disease, conditioning regimen, CD34+ cell dose, and time between diagnosis and HCT were not statistically significant in predicting outcomes. Factors which were significant in univariate analyses, were tested in multivariate models (Table 2), where HCT-CI scores independently predicted non-relapse mortality (NRM) and together with LDH and chemosensitive disease predicted overall (OS) and relapse-free survivals (RFS). Pts with HCT-CI scores of 0 vs 1–2 vs ≥3 had 2-year NRM of 3%, 8%, and 19% and OS of 80%, 78%, and 52% respectively (Figure). Further, pts with scores of 3–4 vs ≥5 had NRM and OS of 15% and 57% vs 42% and 25%, respectively. In conclusion, Pts with HCT-CI scores of 0 and 1–2 tolerated high-dose conditioning equally well, while scores ≥3 were associated with increasing mortality. The HCT-CI is an informative tool to assess pts given autologous HCT, and it could provide valuable independent prognostic information when used prospectively. Table 1: HCT-CI Comorbidities % Score Pulmonary Moderate 30 2 Severe 9 3 Cardiac EF ≤ 50% 7.3 1 Arrhythmia 2.9 1 CAD 1.8 1 Valvular 0.7 3 Hepatic Mild 6.6 1 Moderate 1 3 Prior malignancy 5.5 3 Ulcer 2.6 2 Rheumatologic 1 2 Renal 0.4 2 Diabetes 4.8 1 Psychiatric 14 1 Infection 3.7 1 Obesity 8.8 1 Others 1.8 1 Table 2: Multivariate analyses NRM Mortality RFS HR P HR P HR P *Age was included but was not statistically significabt HCT-CI scores 0 1 1 1 1–2 1.6 0.5 1.1 0.8 1.1 0.6 ≥3 6.6 0.0009 2.9 <0.0001 2.4 0.0001 LDH Normal 1 1 1 Abnormal 1.6 0.27 2.0 0.001 1.6 0.01 Chemosensitivity Yes 1 1 1 No 1.2 0.7 1.6 0.02 1.7 0.005 Figure Figure


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3506-3506
Author(s):  
James Tracey ◽  
Mei-Jie Zhang ◽  
Kathleen A Sobocinski ◽  
Elizabeth L. Thiel ◽  
Michael J. Eckrich ◽  
...  

Abstract Abstract 3506 Recurrent disease is the most important cause of treatment failure after HCT. Total body irradiation (TBI)-containing conditioning regimens are associated with fewer relapses and longer leukemia-free survival (LFS) in children and adolescents with ALL. While TBI <13 Gy + cyclophosphamide (Cy) is considered standard, attempts to lower relapse rates have led to addition of a second chemotherapeutic agent (etoposide) or higher dose TBI (≥13 Gy) with or without addition of etoposide. TBI dosing (<13 Gy vs. ≥13 Gy) or the addition of etoposide to TBI + Cy regimen has not been examined in children. We report on 765 patients aged <18 years, who received either an HLA-matched sibling (n=160) or an unrelated donor (URD, n=605) HCT between 1998 and 2007. Seventy percent of patients were in 2nd complete remission (CR), 20% were in 3rd CR, and the remaining 10%, in relapse at HCT. The median age of the study population is 9 years and the median follow-up of surviving patients is 4 years. Transplant outcomes were examined in four treatment groups: 1) TBI <13 Gy + Cy (n=304), 2) TBI <13 Gy + Cy + etoposide (n=108), 3) TBI ≥13 Gy + Cy (n=327), and 4) TBI ≥13 Gy + Cy + etoposide (n=26). Ninety-six percent of patients in the TBI <13 Gy group received 12 Gy and 4%, 10 Gy. Irradiation doses in the TBI ≥13 Gy group were 13.2 Gy (24%), 13.5 Gy (41%) and 14 Gy (35%). Patient and disease characteristics (performance score, disease status, NCI-risk score, duration of first remission and cytogenetic risk) were similar among the treatment groups. The 3-year probabilities (95% confidence interval) of treatment-related mortality (TRM), relapse, and LFS in the four treatment groups are shown in the Table below. Neither higher dose TBI (≥13 Gy) nor the addition of etoposide regardless of TBI dose was associated with lower risks of leukemia recurrence or longer LFS after HCT. In the absence of an advantage for leukemia control, further intensification of the conditioning regimen TBI <13 Gy + Cy is not recommended. TRM Relapse LFS 1) TBI dose <13 Gy + Cy 25 (21–31)% 30 (24–35)% 45 (39–51)% 2) TBI dose <13 Gy + Cy + etoposide 29 (21–38)% 26 (18–34)% 45 (35–54)% 3) TBI dose ≥13 Gy + Cy 23 (19–28)% 33 (28–39)% 43 (38–49)% 4) TBI dose ≥13 Gy + Cy + etoposide 35 (17–52)% 31 (15–69)% 35 (17–52)% Disclosures: No relevant conflicts of interest to declare.


2021 ◽  
Author(s):  
Lisa Forrest ◽  
John Fechner ◽  
Jennifer Post ◽  
Nathaniel Van Asselt ◽  
Kevin Kvasnica ◽  
...  

Development of a new methodology to induce immunological chimerism after allogeneic hematopoietic cell (HC) transplantation in a rhesus macaque model is described. The chimeric state was achieved using a non-myeloablative, helical tomotherapy-based total lymphoid irradiation (TomoTLI) conditioning regimen followed by donor HC infusions between 1-haplotype matched donor/recipient pairs. The technique was tested as a feasibility study in an experimental group of seven rhesus macaques that received the novel TomoTLI tolerance protocol and HC allo-transplants. Two tomotherapy protocols were compared: TomoTLI (n = 5) and TomoTLI/total-body irradiation (TBI) (n = 2). Five of seven animals developed mixed chimerism. Three of five animals given the TomoTLI protocol generated transient mixed chimerism with no graft-versus-host disease (GVHD) with survival of 33, 152 and &gt;180 days. However, the inclusion of belatacept in addition to a single fraction of TBI resulted in total chimerism and fatal GVHD in both animals, indicating an unacceptable conditioning regimen.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4101-4101
Author(s):  
Johnnie J. Orozco ◽  
Aimee Kenoyer ◽  
Ethan R. Balkin ◽  
Donald K. Hamlin ◽  
D Scott Wilbur ◽  
...  

Abstract Abstract 4101 Background: Despite the curative promise of hematopoietic cell transplantation (HCT), many patients with hematologic malignancies relapse and others may not proceed to HCT due to the unavailability of a matched donor. Toxicities remain high with HCT, due in part to the administration of non-specific therapies such as total body irradiation (TBI) as part of preparative regimens. We aim to overcome these limitations by replacing TBI with anti-CD45 radioimmunotherapy (RIT) for haploidentical HCT to deliver radiation directly to leukemic cells while sparing normal organs and minimizing non-specific toxicities. Methods: We established an initial TBI HCT regimen in B6SJLF1/J mice (H-2Db haplotype) conditioned with fludarabine (FLU, days -6 to -2), followed by TBI (250, 500, 750 cGy; day -1). The mice then received 15 million donor (CB6F1/J, H-2Dd) BM cells (day 0), followed by cyclophosphamide (CY) for graft-versus-host disease (GvHD) prophylaxis (day +2). Subsequent RIT HCT studies involved B6SJLF1/J mice conditioned with and without fludarabine (FLU) and escalating doses (200–400 μCi) of 90Y-anti-CD45 Ab (30F11) RIT without TBI, followed by infusion of haploidentical BM cells from CB6F1/J mice and a single dose of cyclophosphamide (CY) 2 days after HCT. Chimerism studies were performed using flow cytometric analysis to assay for engraftment of donor CD8+ cells. Therapeutic studies were performed in B6SJLF1/J mice given 105 syngeneic leukemia cells via tail vein (day -5), followed by 200 or 400 μCi 90Y-30F11 (day -3), and 1.5 × 107 BM donor cells (day 0) and two doses of CY (days -2 and +2) without FLU. Results: Using this model we have demonstrated that mixed chimerism was established in mice transplanted with TBI or escalating doses (200–400 μCi) of 90Y-30F11 RIT followed by injection of haploidentical BM donor rescue cells. TBI-based HCT showed that chimerism as determined by flow cytometric analysis for donor CD8+ cells was TBI dose-dependent; mice receiving ≥500 cGy were fully chimeric 4 weeks post-HCT, and persisted ≥12 months. RIT-based HCT also revealed mice with mixed chimerism, with up to 89% of donor CD8+ cells 1 month after HCT. Elimination of FLU from the conditioning regimen did not significantly decrease chimerism, as mice transplanted without FLU showed up to 70% donor CD8+ cells 1 month after HCT. Subsequent RIT experiments in B6SJLF1/J mice harboring AML were treated with escalating doses of 90Y-30F11 prior to HCT without FLU. Mice treated with anti-CD45 RIT using 200 μCi and 400 μCi of 90Y-30F11 had a median overall survival (OS) of 73 (p<0.001) and 107.5 (p=0.0015) days, respectively, compared to untreated leukemic control mice which had a median OS of 34 days after HCT (p values by Log rank (Mantel-Cox) testing)(Figure). Two mice in the 400 μCi-90Y-30F11 group were euthanized on day 3 for excessive weight loss, without gross histology abnormality in kidneys or liver. Conclusion: These studies suggest that anti-CD45 RIT in the absence of TBI and FLU prior to haploidentical HCT can lead to establishment of mixed chimerism. Moreover, this anti-CD45 RIT in combination with haploidentical HCT can lead to improvement in survival for mice with AML. These results suggest that clinical studies with anti-CD45 RIT in lieu of TBI and FLU in a haploidentical HCT regimen should be considered for further investigation. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5847-5847
Author(s):  
Jan Vydra ◽  
Veronika Válková ◽  
Markéta Šťastná Marková ◽  
Ludmila Nováková ◽  
Jiří Schwarz ◽  
...  

Abstract Introduction Combination of total body irradiation, fludarabine, cytarabine and idarubicine (TBI/Flu/AraC/Ida) is a disease-specific myeloablative conditioning regimen used in patients with acute myeloid leukemia. We report a single centre retrospective analysis of outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in patients with AML treated with TBI/Flu/AraC/Ida in comparison to TBI/Cy. Methods Patients in the TBI/Flu/AraC/Ida arm received 12 Gy total body irradiation in 6 fractions on days -3 to -1, fludarabine 25mg/m2 on days -7 to -1, cytarabine 2000mg/m2 on days -7 to -3 and idarubicine 10mg/m2 on days -7,-5 and -3. Patients in TBI/Cy arm received 12Gy TBI in 6 fractions on days -3 to -1 and cyclophosphamide 60mg/kg on days -7 and -6. GvHD prophylaxis consisted of cyclosporine and methothrexate prior to year 2004. Since 2004, GvHD prophylaxis included cyclosporine with mycophenolate mofetil and ATG-Fressenius 20 – 40mg/kg was given to patients with unrelated donors. Results Sixty four patients with AML received allo-HCT using TBI/Flu/Ida/AraC conditioning regimen between 2004 and 2012. Fifty three patients received TBI/Cy conditioning between 1987 and 1998 and between 2009 and 2014. Median age was 46 (range: 19-60) and 42 (range: 14-59) TBI/Flu/Ida/AraC and TBI/Cy, respectively. In the TBI/Flu/Ida/AraC group, 19 (30%) of patients received transplant from a HLA matched sibling donor, 16 (25%) from a HLA matched unrelated donor and 29 (45%) from HLA mismatched unrelated donor. In the TBI/Cy group, 24 (45%) of patients received transplant from a HLA matched sibling donor, 20 (38%) from a HLA matched unrelated donor and 9 (17%) from HLA mismatched unrelated donor (p = 0.0049). Other baseline patient and donor characteristics (patient/donor gender, CMV serology, AB0 matching, cytogenetic risk group, disease status and HCT-CI comorbidity score, ATG use) were not significantly different between the groups. Median time to neutrophil engraftment was 18 days (range 10 - 31) and 21 days (range 12 – 32) in TBI/Flu/AraC/Ida a TBI/Cy groups, respectively. Median time to platelet engraftment to more then 20G/l was 21 (range 12 – 103) and 22.5 (range 9 – 54) days, respectively. Among patients who survived more than 100 days, 2/45 patients did not engraft platelets in the TBI/Flu/AraC/Ida group and 3/35 in the TBI/Cy group. Overall survival (OS) at 2 years was 35% (95% CI: 25 – 49%) in TBI/Flu/Ida/AraC group and 47.5% (95% CI: 35 – 65%) in TBI/Cy group. Two years disease free survival (DFS) was 35% (95% CI: 25 - 49) in TBI/Flu/Ida/AraC group and 40% (95% CI: 27 - 58) in TBI/Cy group. Cumulative incidence of relapse at 2 years after transplant was 12.5% and 25% (p = 0,08), and the cumulative incidence of non-relapse mortality was 53% and 36% (p = 0.059) in the TBI/Flu/Ida/AraC and TBI/Cy groups, respectively. Survival curves and relapse incidence curves are presented in Figure 1. In multivariate analysis of the influence of baseline characteristics and conditioning regimen on OS and DFS, only HLA mismatch was significantly associated with increased risk of mortality with HR 2,22 (95% CI: 1,25 – 3,95). HR of death was 1.11 (95% CI: 0.62 – 1.98) and HR of death or relapse was 0.87 (95% CI: 0.50 - 1.52) in patients who recieved TBI/Flu/Ida/AraC. There was a trend towards increased incidence of acute graft versus host disease (aGVHD) grade II-IV in the TBI/Flu/AraC/Ida group (p = 0,09). The cumulative incidence of aGVHD was 46% and 34% in the TBI/Flu/AraC/Ida and TBI/Cy groups, respectively. Estimates of the cumulative incidence of aGVHD in the presence of competing risk of relapse or death are shown in Figure 2. Conclusion TBI/Flu/Ida/AraC regimen led to similar OS and DFS as TBI/Cy. There was a trend towards decreased rate of relapse, but increased non-relapse mortality with the TBI/Flu/Ida/AraC conditioning. In multivariate analysis, only HLA mismatch had significant effect on patient outcome. The retrospective nature of the study and inequalities in baseline transplant characteristics, mainly more frequent use of mismatched unrelated donors in the TBI/Flu/Ida/AraC group, are main limitations of the study. Figure 1 Figure 1. Disclosures Off Label Use: Fludarabine, Cytarabine and Idarubicine as part of conditioning regimen.


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