Cumulative Incidence Of Grade Research Articles

Effect of blood pressure control on the risk of proteinuria during bevacizumab treatment in patients with colorectal cancer: a single-center retrospective cohort study

PurposePre-existing hypertension is reportedly a major risk factor for bevacizumab-induced proteinuria. However, few studies have focused on the effects of blood pressure (BP) control on proteinuria during bevacizumab treatment. We report a retrospective study of the association between poor BP control and the risk of developing proteinuria in patients with colorectal cancer (CRC).MethodsData for CRC patients who received bevacizumab between April 2015 and March 2022 were retrospectively collected. Patients were categorized into two groups based on average systolic blood pressure (SBP) during treatment: normal SBP (< 140 mmHg) and high SBP (≥ 140 mmHg). To evaluate the association between average SBP and grade ≥ 2 proteinuria, we used a 3 month landmark analysis and a Cox regression model.ResultsOf the 279 patients analyzed, 109 had high SBP and 170 had normal SBP. The cumulative incidence of grade ≥ 2 and severe proteinuria was significantly higher in the high compared to the normal SBP group (p < 0.001 and p = 0.028, respectively). Landmark analysis indicated significant differences in proteinuria between patients with and without high average SBP during the first 3 months of treatment (p = 0.002 and p = 0.015, respectively). Multivariate analysis showed that average SBP ≥ 140 mmHg was a significant independent risk factor for proteinuria (p = 0.008).ConclusionLandmark analysis showed that BP status during the first 3 months of bevacizumab treatment influences the risk of subsequent proteinuria. Therefore, timely diagnosis and stricter BP control are recommended for at least the first 3 months to avoid severe proteinuria.

Safety of combined ablative radiotherapy and immune checkpoint inhibitors in three phase I trials

BackgroundStereotactic body radiotherapy (SBRT) is safe and effective for treatment of extracranial metastatic disease, but its safety when combined with immune checkpoint inhibitors (ICI) has not yet been comprehensively reported. Here we report adverse events (AEs) associated with combined SBRT and ICI using prospectively-collected data on patients in three trials investigating multi-site SBRT combined with ICI. MethodsPatients were included from three prospective trials of ICI (pembrolizumab; nivolumab/urelumab or nivolumab/cabiralizumab; nivolumab/ipilimumab) with SBRT to 1–4 sites. AEs were recorded prospectively using the CTCAE v4.0. Survival was analyzed using Kaplan-Meier method with a 90-day landmark. Association of patient characteristics with cumulative incidence of AEs was assessed using Fine-Gray regression. Results213 patients were included, with a median follow-up of 10 months. Over the follow-up period, 50 % and 27 % of patients experienced at least one grade ≥ 2 or grade ≥ 3 AE, respectively. Cumulative incidences of grade ≥ 2 and grade ≥ 3 AEs at 6 months were 47 % and 23 %, respectively. Three grade 5 AEs rated “possibly” related to treatment occurred outside the 90-day dose-limiting toxicity window. Landmarked survival analysis of patients with or without grade ≥ 3 AEs showed no significant difference in progression-free or overall survival. Dual-agent ICI was significantly associated with grade ≥ 3 AE. ConclusionThis analysis features the largest prospectively evaluated cohort of patients treated with combination ablative SBRT and ICI to date and provides context for future trial design. We conclude that multi-site SBRT and ICI can be safely co-administered when SBRT is delivered with prioritization of normal tissue constraints.

Comparison of Cyclophosphamide-Based Graft Versus Host Disease Prophylaxis after "Allogeneic Stem Cell Transplantation from 9/10 HLA Matched Unrelated Donor'' with Standard Graft Versus Host Disease Prophylaxis after "10/10 HLA Matched Relative Donor'' Transplant.

Background: Graft Versus Host Disease (GvHD), which can be observed at a rate of 30-80% after allogeneicstem cell transplantation (ASCT) is an important complication that adversely affects the survival and quality of the life of patients.Posttransplant cyclophosphamide (PTCy) effectively prevents GvHD after HLA-haploidentical ASCT. In our study, the use of PTCy in 1-antigen HLA-mismatched unrelated donor (9/10MMUD) ASCT was compared with standard GvHD prophylaxis in HLA-identical related donor (MRD) ASCT. Materials and Methods: We conducted a retrospective study of the comparison of 42 patients with 9/10 MMUD ASCT receiving PTCy+Methotrexate (MTX)+Calcineurin Inhibitor (CNI) and 37 patients with HLA-identical MRD who received MTX+CNI in 3 bone marrow transplantation centers. Results: Cumulative incidences of grade I-II (64.6% vs 45.4%, p=0.187) or grade III to IV acute GvHD (35.4% vs54.6%,p=0.187)and chronic GvHD (11.9% vs 29.7%, p=0.096) were similar in the PTCy group and control group. No statistically significant differences were observed between PTCy and the control group in overall survival rate (52.4% vs 62.2%, p=0.381), progression-free survival (1483.97 vs 1200.70 days, p=0.502), relapsed-related mortality rate (21.4% vs 16.2%, p=0.556) and treatment-related mortality rate (16.7% vs 21.6%, p=0.575). Conclusion: With the addition of PTCy to standard GvHD prophylaxis in 9/10MMUD ASCT, the risk of GvHD due to incompatibility and unrelated transplantation is eliminated, and transplantation success is achieved with MRD ASCT. PTCy-based prophylaxis is an effective and safe strategy to prevent GvHD in 9/10 MMUD ASCT without increasing the risk of relapse and treatment-related mortality.

Outcomes of hematopoietic stem cell transplantation in 813 pediatric patients with Fanconi anemia

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative option for Fanconi anemia (FA)–associated bone marrow failure (BMF)/aplastic anemia (AA) and acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS). We performed a retrospective multicenter study on 813 children with FA undergoing first HSCT between 2010 and 2018. Median duration of follow-up was 3.7 years. Median age at transplant was 8.8 years (IQR, 6.5-18.1). Five-year overall survival (OS), event-free survival (EFS), and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) were 83% (95% confidence interval [CI], 80-86), 78% (95% CI, 75-81), and 70% (95% CI, 67-74), respectively. OS was comparable between matched family donor (MFD; n = 441, 88%) and matched unrelated donor (MUD; n = 162, 86%) and was superior to that of mismatched family donor (MMFD) or mismatched unrelated donor (MMUD; n = 144, 72%) and haploidentical donor (HID; n = 66, 70%; P < .001). In multivariable analysis, a transplant indication of AML/MDS (vs AA/BMF), use of MMFD/MMUD and HID (vs MFD), and fludarabine-cyclophosphamide (FluCy) plus other conditioning (vs FluCy) independently predicted inferior OS, whereas alemtuzumab vs antithymocyte globulin was associated with better OS. Age ≥10 years was associated with worse EFS and GRFS. Cumulative incidences (CINs) of primary and secondary graft failure were 2% and 3% respectively. CINs of grade 3 to 4 acute GVHD and chronic GVHD were 12% and 8% respectively. The 5-year CIN of secondary malignancy was 2%. These data suggest that HSCT should be offered to patients with FA with AA/BMF at a younger age in the presence of a well-matched donor.

Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS.

Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment. Patients with nmCRPC were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval-specific new and cumulative event rates were determined during the first 24 months of the double-blind period. Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months. Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment-related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment. ClinicalTrials.gov identifier NCT02200614.

Single non-blood-related umbilical cord blood transplantation using a reduced-intensity conditioning regimen for the treatment of severe aplastic anemia

Objective: To evaluated the clinical efficacy of a reduced-intensity preconditioning regimen for single non-blood-related umbilical cord blood transplantation (sUCBT) in the treatment of severe aplastic anemia (SAA) . Methods: The clinical data of 63 patients with SAA who underwent sUCBT from January 2021 to July 2023 at the Department of Hematology of the First Affiliated Hospital of USTC were retrospectively analyzed. Fifty-two patients received total body irradiation/total bone marrow irradiation (TMI) combined with fludarabine or a cyclophosphamide- conditioning regimen (non-rATG group) , while 11 patients received rabbit anti-human thymocyte immunoglobulin (rATG) combined with TMI, fludarabine, or the cyclophosphamide-conditioning regimen (rATG group) . All patients received cyclosporine A and mycophenolate mofetil for graft-versus-host disease (GVHD) prophylaxis. Complications post-transplantation and long-term survival were compared between the two groups. Results: The baseline parameters were balanced between the two groups (P>0.05) . In the rATG group, all patients achieved stem cell engraftment, and in the non-rATG group, five patients had primary graft failure. There was no significant difference in the cumulative incidence of neutrophil engraftment at 42 days after transplantation or platelet engraftment at 60 days between the two groups. The incidence of grade Ⅱ-Ⅳ acute GVHD in the rATG group was significantly lower than in the non-rATG group (10.0% vs. 46.2% , P=0.032) , and the differences in the cumulative incidences of grade Ⅲ/Ⅳ acute GVHD and 1-year chronic GVHD were not statistically significant (P=0.367 and P=0.053, respectively) . There were no significant differences in the incidences of pre-engraftment syndrome, bacterial bloodstream infections, cytomegalovirus viremia, or hemorrhagic cystitis between the two groups (P>0.05 for all) . The median follow-up time for surviving patients was 536 (61-993) days, and the 1-year transplantation related mortality (TRM) of all patients after transplantation was 13.0% (95% CI 6.7% -24.3% ) . Among the patients in the non-rATG and rATG groups, 15.5% (95% CI 8.1% -28.6% ) and 0% (P=0.189) , respectively, had mutations. The 1-year overall survival (OS) rate of all patients after transplantation was 87.0% (95% CI 75.7% -93.3% ) . The 1-year OS rates in the rATG group and non-rATG group after transplantation were 100% and 84.5% , respectively (95% CI 71.4% -91.9% ) (P=0.198) . Conclusion: The preliminary results of sUCBT with a low-dose irradiation-based reduced-intensity conditioning regimen with fludarabine/cyclophosphamide for the treatment of patients with SAA showed good efficacy. Early application of low-dose rATG can reduce the incidence of acute GVHD after transplantation without increasing the risk of implantation failure or infection.

Acute Leukemia and MDS Patients Older Than 70 Years Have Inferior Survival Following Allogeneic Stem Cell Transplant Compared to Those with 60-69 Years of Age

Introduction: Increasing number of older patients are undergoing allogeneic stem cell transplants (alloSCT) for acute leukemia and MDS. We and others have previously reported alloSCT outcomes of older patients. However, majority of these studies included very few patients older than 70 years. In addition, the information on the influence of donor source on alloSCT outcomes among older patients is limited. In this study, we aim to answer two questions: Is there any difference in long-term survival between patients 60-69 years and those older than 70 years? Does donor source affect alloSCT outcomes of these two groups? Methods: We retrospectively evaluated alloSCT outcomes of 467 patients older than 60 years with acute leukemia (AML and ALL) and MDS. We compared outcomes between two groups: 60-69 years of age and those older than 70 years. The primary objective was to evaluate long-term overall survival (OS). Multivariable analyses included age, comorbidity index, KPS, disease risk index, donor relation, CMV serotype, conditioning regimen, GVD prophylaxis, and thymoglobulin use as variables. Results: Between January 2010 and December 2022, 335 patients with 60-69 years and 132 older than 70 years underwent alloSCT. Median age of the population was 66 years (range, 60-80); 6% (N=30) were African American and 22% (N=101) were of ethnic minority; 53% (N=249) had AML, 39% (N=184) had MDS, and 7% (N=34) had ALL; donor was matched unrelated in 60% (N=279), matched related and haploidentical in 14% each, and mismatched unrelated in 12% (N=55). Source of allograft was peripheral blood stem cells in all patients. Higher proportion of patients older than 70 years received matched unrelated donor compared to those with 60-69 years (69% vs 56%; p=0.004). Reduced intensity conditioning (RIC) regimen was frequently used among patients older than 70 years compared to 60-69 years (97% vs 79%, p&amp;lt;0.001). Neutrophil and platelet engraftment time was similar in both groups. Graft failure rate was higher for patients older than 70 years compared to 60-69 years (5.3% vs. 1.2%; p=0.014). The cumulative incidence of grade 3-4 acute GVHD was similar (13.5% vs 7.6%, p=0.2), while severe chronic GVHD was higher for the 60-69 group compared to the 70+ group (20.1% vs 10%, p=0.009). Median follow up for OS was 4.46 years. At 3 years, OS was 48% for the 60-69 group and 38.23% for the 70+ group (HR 1.34, p=0.02); RFS was 44% for the 60-69 group and 36.3% for the 70+ group (HR 1.32, p=0.02); relapse rate was 26.2% for the 60-69 group and 27.2% for the 70+ group (HR 1.13, p=0.51); and NRM was 30% for the 60-69 group and 37% for the 70+ group (sHR 1.26, p=0.19). In the multivariable analyses, patients older than 70 years experienced poor survival (HR 1.41, p=0.01) and relapse-free survival (RFS) (HR 1.4, p=0.01), and numerically higher non-relapse mortality (NRM) (sHR 1.38, p=0.08) compared to those with 60-69 years. Compared to haploidentical donors, matched related (sHR 0.39, p=0.04) and unrelated donors (sHR 0.28, p=0.005) were associated with lower NRM, while a trend for increased relapse rate and NRM was associated with the use of thymoglobulin and post-transplant cyclophosphamide (PTCy) containing GVHD prophylaxis, respectively. Conclusion: Our results indicate that although rates of acute GVHD and relapse were similar between both groups, patients older than 70 had worse OS and RFS compared to patients between 60-69. The NRM was numerically higher in patients older than 70 years of age. Haploidentical donor was associated with increased NRM, most likely secondary to toxicity associated with PTCy based GVHD prophylaxis. Detailed analysis of toxicity will be presented at the conference.

HLA 1 Allele-Mismatched Unrelated Vs Haploidentical Donor Transplants in Acute Myeloid Leukemia

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the curative treatment for acute Myeloid Leukemia (AML) patients. When there is no HLA-identical sibling or unrelated donor, alternative donors such as 1 allele-mismatched unrelated donors (1-MMUD) or haploidentical donors (HID) may be considered. While there have been reports that the outcomes of these two donors are comparable with those of HLA-matched unrelated donors, there is limited data directly comparing the outcomes between 1-MMUD and HID transplantation. Therefore, we conducted an analysis of the outcomes of allo-HSCT from 1-MMUD and HID in AML patients. This study is a retrospective cohort study at a single institution, including patients with AML who underwent first allo-HSCT in complete remission (CR) or CR with incomplete hematologic recovery between 2002 and 2022, from 1-MMUD or HID. For HID transplantation, patients were administered fludarabine 30mg/BSA for 4 days, intravenous busulfan 3.2mg/kg for 2 days, and depending on the condition, they received either total body irradiation (TBI) at 400cGy or fractionated TBI at 800cGy (400cGy for 2 days). Graft-versus-host disease (GVHD) prophylaxis for HID transplantation consisted of antithymocyte globulin total 5.0mg/kg, methotrexate 5mg/BSA 3 or 4 times, and calcineurin inhibitors. In 1-MMUD transplantation, various myeloablative or reduced-intensity conditioning regimens were used. All patients received T-cell replete peripheral blood stem cells. A total of 108 patients who underwent 1-MMUD transplantation and 447 patients who underwent HID transplantation were included. The 1-MMUD group showed a tendency to be younger (median 42 years vs. 51 years, Wilcox rank-sum test p &amp;lt; 0.01) and had a lower proportion of ABO-matched transplantations (28.7% vs. 51.7%, Chi-square test p &amp;lt; 0.01). Other patient characteristics were similar between the two groups. In terms of survival, the median OS in the 1-MMUD group was 60.1 months, and in the HID group was 58.7 months, showing no significant difference between the two groups (Log rank test p = 0.81). Similarly, the median RFS was 54.8 months in the 1-MMUD group and 40.9 months in the HID group, with no statistically significant difference (Log rank test p = 0.96). The cumulative incidence of relapse and NRM at 60 months after allo-HSCT showed no significant difference between the two groups, with 26.1% and 25.7% for relapse and 23.9% and 26.3% for NRM in the 1-MMUD and HID groups, respectively (Gray's test p for relapse: 0.81, p for NRM: 0.82). Although the cumulative incidence of grade 2 or higher acute GVHD did not show a significant difference between the two groups (38.0% in 1-MMUD, 45.4% in HID, Gray's test p = 0.41), the incidence of chronic GVHD was significantly higher in the HID transplantation group (63.6%) compared to the 1-MMUD transplantation group (52.0%) (Gray's test p &amp;lt; 0.01). Finally, in a multivariate Cox model In conclusion, both 1-MMUD and HID can be considered equivalent alternative donors, and caution should be exercised regarding the occurrence of chronic GVHD in HID transplantation. Further comparisons between the two donors, including in different settings such as post-transplantation cyclophosphamide, warranted.

New Aplastic Anemia Preconditioned with Fludarabine, Thiotepa, Cyclophosphamide, and Anti-Thymocyte Globulin

Aplastic anemia (AA) is one of life-threatening hematological disorder that can be cured by hematopoietic stem cell transplantation. When the absence of a matched sibling donor, haploidentical stem cell transplantation (haplo-HSCT) becomes an alternative choice for AA patients. We used a prospective study aimed to confirm the feasibility of Thiotepa-based modified post-transplantation cyclophosphamide (PTCY) strategy in haplo-HSCT for AA patients. We analyzed the outcomes of 15 patients who had undergone haplo-HSCT between October 2021-May 2023 in our clinical center. The modified condition regimen consisted of anti-thymoglobulin/antilymphocyte globulin, fludarabine, thiotepa, busulfan and modified low and high-dose cyclophosphamide, mycophenolate mofetil (MMF) and tacrolimus (FK-506)/cyclosporin (CsA) were administered as graft versus host disease (GVHD) prophylaxis after transplantation. The median follow-up time was 267 (range 97-532) days. All 15 patients were successfully implanted (100%), the median times for neutrophil and platelet engraftment were 14 (range 12-19) days and 12 (range 8-25) days, respectively. But one patient developed secondary graft failure because of infected with COVID-19、cytomegalovirus and H1N1. Fortunately, she subsequently underwent a successful secondary haplo-HSCT. The most common regimen-related toxicity was canker sore, hemorrhagic cystitis occurred in 3 patients during transplantation. The cumulative incidence of grade Ⅰ-Ⅱ aGVHD and cGVHD were 13.3% and 6.7% respectively, whereas the incidence of grade Ⅲ-Ⅳ aGVHD was not found so far. All 15 patients are alive, with a failure-free survival rate of 100% and GVHD relapse-free survival rate of 100%. The efficacy evaluation of haplo-HSCT, 14 patients achieved CR and 1 patient achieved PR. Because of 7 patients received the prevention strategy of Letermovir since August 2022, the reactivation rate of cytomegalovirus (CMV) was only 20% and 60% of Epstein-Barr virus (EBV) reactivation, but the CMV diseases and post-transplantation lymphoproliferative disorder (PTLD) were rare. Our study using Thiotepa-based modified haplo-HSCT demonstrated an encouraging result with prolonged survival and reduced complications for aplastic anemia patients.

TKI Dose Optimization Based on Therapeutic Drug Monitoring（TDM) with Encouraging Outcomes and Well-Tolerated for Chronic Myeloid Leukaemia Patients

Background Imatinib, nilotinib, and dasatinib are tyrosine kinase inhibitors (TKIs) that have become first-line treatments for Philadelphia chromosome-positive chronic myeloid leukemia (CML). Series studies indicated TKIs had a high therapeutic index, which led to the registration of these medications at fixed doses. Therapeutic drug monitoring (TDM) is a strategy for dosage optimization to provide individual treatment through dose adjustment to improve efficacy or avoid TKI-related adverse events (AEs). Objective We prospectively analyzed the outcome based on trough plasma concentrations (Cmin) to manage TKI dosage optimization during imatinib, nilotinib, and dasatinib therapy in patients with CML by 12 months. The primary efficacy endpoint was the rate of MMR at 12 months, the secondary endpoints included the cumulative rate of significant AEs defined as grade 3/4 fluid retention, all grade pleural effusion and pulmonary hypertension, grade 3/4 bilirubin increased, and grade 3/4 hematological toxicity related to TKIs within the first 12 months of therapy. Methods We examined 204 CML patients treated with imatinib, nilotinib, or dasatinib in the first line for CML-CP. We used high-performance liquid chromatography-tandem mass spectrometry (UPLC/MS-MS) to detect the Cmin of TKIs. Dasatinib or imatinib Cmin (24±3h post-dose) and nilotinib Cmin (12±3 h post-dose) were assessed after 7~10 days of therapy. We set the Cmin of imatinib at 1000~1500 ng/mL and that of nilotinib at 600~800 ng/mL, dasatinib at 1~3 ng/ml, respectively. Results Imatinib group (n = 67), Nilotinib group (n = 72), and Dasatinib group (n = 65), respectively. The initial dose of imatinib was 400mg qd, based on Cmin of imatinib was 900~1100ng/mL, there were 17 patients with dose reduction(1 case with 100mg qd, 5 cases with 200mg qd, 11 cases with 300mg qd) and 2 patients increased dose to 500mg qd; The initial dose of nilotinib was 300mg bid, based on Cmin of imatinib was 600~800ng/mL, there were 21 patients with dose reduction( 4 cases with 150mg bid, 16 cases with 450mg daily, 1 cases with 150mg qd) and 1 patients increased to 400mg bid; the initial dose of dasatinib was 100mg qd, based on Cmin of dasatinib was1~3 ng/ml, there were 32 patients with dose reduction(1 case with 20mg qd, 4 cases with 40mg qd, 20 cases with 50mg qd, 7 cases with 70mg qd ). Among the patients treated with imatinib, dasatinib, and nilotinib, no statistically significant associations were observed between gender, age, ELT scores, and plasma trough concentration (p&amp;gt;0.05). Early molecular reaction (EMR BCR: ABL(IS) &amp;lt;10%) was achieved by 83.6% (95% confidence interval [CI], 74.6%-92.5%) in the imatinib group, 87.7% (95% CI, 80.0%-95.4%) in the nilotinib group, and 83.3% (95% CI, 75.0%-91.7%) in the dasatinib group of patients at 3 months. The incidence of MMR at 12 months was 82.1% (95% CI, 73.1%-93.0%) in the imatinib group, 73.8% (95% CI, 64.6%-84.6%) in the nilotinib group, and 75.0% (95% CI, 65.3%-84.7%) in the dasatinib group, respectively. The cumulative incidence of grade 3/4 hematological toxicity was 7.8% (16/204), all-grade pleural effusion was 23.1% (15/65) in the dasatinib group, grade 3/4 bilirubin increased was 6.9% (5/72) in the nilotinib group, and there were no patients with pulmonary hypertension. Conclusion There are large individual differences in plasma trough concentrations in CML patients taking TKIs, the TKI dosage should be adjusted based on target plasma concentrations to maximize efficacy and minimize the incidence of adverse events.

Stereotactic reirradiation in the treatment of head and neck cancers: A retrospective study on the long-term experience of the Oscar Lambret Center

Background and purposeStereotactic radiotherapy potentially treats unresectable recurrences of previously irradiated head and neck (H&N) cancer. This study aimed to assess its efficacy and safety and evaluate prognostic factors. Materials and methodsWe conducted a large retrospective series that included 110 patients who had undergone 36-Gy, six-fraction stereotactic reirradiation (CyberKnife®) for recurrent/secondary H&N cancer between 2007 and 2020 at the Oscar Lambret Center. Patient characteristics and toxicities were assessed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. ResultsMedian follow-up time was 106.3 months. The 2-year OS rate was 43.8 % (95 % confidence interval, 95 % CI, 34.3–52.9) and the median survival was 20.8 months (95 % CI, 16.5–26.3). The cumulative 2-year local-recurrence, regional-recurrence, and distant-metastasis rates were 52.2 % (95 % CI, 42.4–61.1 %), 12.8 % (95 % CI, 7.4–19.8 %), and 11 % (95 % CI, 6.0–17.6 %), respectively. 73 patients received concomitant cetuximab, and it was not significantly beneficial (HR = 1.34; 95 % CI, 0.80–2.26; p = 0.26). The cumulative incidences of grade ≥ 2 late toxicity was 42 % (CI95%: 33–51) at 24 months. Two grade 4 bleedings and no treatment-related deaths were reported. ConclusionIn a large retrospective series of SBRT reirradiation for recurrent or second primary H&N cancers, we observed a median OS of 20.8 months, with a cumulative incidence of grade ≥ 2 late toxicity of 42 % at 24 months. Such a treatment is feasible. However, local recurrence rates remain non-negligible, warranting further research. Radiosensitizer use is currently under study. Therefore, establishing a balance between therapeutic modifications and toxicity is essential.

Impact of SARS-CoV-2 infection on graft composition and early transplant outcomes following allogeneic hematopoietic stem cell transplantation

Objective: To assess the feasibility of using donors with novel coronavirus disease 2019 (COVID-19) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) when there are no other available donors and allo-HSCT cannot be delayed or discontinued. Methods: Seventy-one patients with malignant hematological diseases undergoing allo-HSCT between December 8, 2022, and January 10, 2023, were included. Of these, 16 received grafts from donors with mild COVID-19 (D-COVID(+) group) and 55 received grafts from donors without COVID-19 (D-COVID(-) group). The graft compositions were compared between the two groups. Engraftment, acute graft-versus-host disease (aGVHD), overall survival (OS), and relapse were also evaluated. Results: There were no serious side effects or adverse events in the D-COVID(+) group. The mononuclear cell dose and CD34(+) cell dose were comparable between the two groups, and no additional apheresis was required. There were no significant differences in the lymphocyte, monocyte, and T-cell subset doses between the two groups. The median natural killer cell dose in the D-COVID(+) group was significantly higher than that in the D-COVID(-) group (0.69×10(8)/kg vs. 0.53×10(8)/kg, P=0.031). The median follow-up time was 72 (33-104) days. All patients achieved primary engraftment. The 60-day platelet engraftment rates in the D-COVID(+) and D-COVID(-) groups were 100% and (96.4±0.2) %, respectively (P=0.568). There were no significant differences in neutrophil (P=0.309) and platelet (P=0.544) engraftment times. The cumulative incidence of grade 2-4 aGVHD was (37.5±1.6) % vs. (16.4±0.3) % (P=0.062), and of grade 3-4 aGVHD was 25.0% ±1.3% vs. 9.1% ±0.2% (P=0.095) in the D-COVID(+) and D-COVID(-) groups, respectively. The probabilities of 60-day OS were 100% and 98.1% ±1.8% (P=0.522) in the D-COVID(+) and D-COVID(-) groups, respectively. There was no relapse of primary disease during the study period. Conclusion: When allo-HSCT cannot be delayed or discontinued and no other donor is available, a donor with mild COVID-19 should be considered if tolerable. Larger sample sizes and longer follow-up periods are required to validate these results.

Multiparametric Magnetic Resonance Imaging– Guided Dose-Escalated Radiation Therapy for Localized Prostate Cancer: A Prospective Phase 2 Trial

Purpose: To determine the late toxicity associated with dose escalation to PI-RADS III-V lesions on multiparametric MRI with an image-guided combined IMRT-SBRT approach in men with localized prostate cancer.Materials and Methods: In this phase II trial patients with localized prostate cancer with clinical tumor stage T1-T3bN0 and at least one PIRADS III-V lesion were recruited to receive 45 Gy in 25 fractions to the prostate and seminal vesicles followed by a boost of 18 Gy in 3 fractions to the prostate with a simultaneous integrated boost 21 Gy in 3 fractions to the PI-RADS lesion(s). The primary endpoint was the cumulative incidence of late grade ≥3 genitourinary and gastrointestinal toxicity by 18 months (NCI CTAE v4.0).Results: Overall, 50 patients were enrolled in this study. Overall, 43 patients completed at least 18 months of follow-up. The cumulative incidence of grade 1, 2, and 3 late genitourinary toxicity at 18 months was 18%, 53%, and 2%. One patient was noted to have grade 3 hematuria and needed cystoscopy guided cauterization. No acute grade 3 gastrointestinal or genitourinary toxicities were observed. The cumulative incidence of grade 1, 2, and 3 late gastrointestinal toxicity at 18 months was 31%, 4%, and 0%, respectively. At a median follow-up of 43.5 months, 3 patients developed biochemical recurrence, each with distant bone metastases without local or nodal recurrence. At 3-year, freedom from biochemical failure rate was 95.3% (95% confidence interval: 89.2 to 100).Conclusions: Multiparametric MRI-guided dose escalation to PI-RADS III-V lesions using a combined image guided IMRT-SBRT approach is associated with an acceptable risk of late gastrointestinal and genitourinary toxicity. The results should be interpreted with caution considering single institutional nature, small sample size, and short follow-up and should be validated in a larger study.

Treosulfan Compared to Busulfan in Allogeneic Haematopoietic Stem Cell Transplantation for Myelofibrosis: A Registry-Based Study from the Chronic Malignancies Working Party of the EBMT

Background The optimal conditioning prior to allogeneic stem cell transplantation (HSCT) for myelofibrosis (MF) remains an ongoing matter of debate. There is a paucity of randomized trials robustly showing superiority of one over another. Registry studies comparing reduced intensity conditioning (RIC) versus myeloablative conditioning (MAC) regimens did not show significant differences in overall survival (OS). Recently, a multi-center phase 3 trial in MDS-AML reported an advantage of fludarabine-treosulfan (TREO) over fludarabine-busuflan (BU) RIC (Lancet Haematol Beelen et al 2020). The role of this large EBMT registry study was to compare outcomes of MF HSCT following TREO and BU based MAC or RIC regimens. Methods Patients with MF transplanted from a T-cell replete graft between 2010-2018 following BUMAC, BURIC or TREO were identified in the EBMT registry. Patients who were transformed into AML were excluded. Centers were contacted to participate in additional data collection. 63 centers included a total of 536 patients of whom 6 patients were excluded due to missing data for major endpoints (relapse or regimen). The role of TREO was tested in multi-variable models adjusted on major prognostic factors especially those who were not well balanced between groups and using multiple imputation for missing values. Results Most TREO (n=73) patients received it in combination with FLUDARABINE (95%) and most BU (n=457) received FLUDARABINE +/- other (93%). Median total dose received of TREO was 42 g/m2 and median dose of BU was 8mg/kg. Main differences between the 3 groups were: 1) Recipient age; patients were the oldest in the RIC group (median age 61 years, (IQR: 55-65), the youngest in BUMAC (56 years, (IQR: 51-62)), and intermediate in the TREO group (59 years, (IQR: 54-64); 2) Performance status; Karnofsky score was &amp;lt; 80 in 20%, 30%, 42% in the TREO, BUMAC and BURIC groups, respectively; 3) Comorbidity score (HCT-CI) was lowest in the MAC group (HCT-CT ‘low’ in 56%, 45% and 37% of BUMAC, BURIC and TREO groups); 4) Disease status; patients in the TREO group were more often transplanted with progressive disease (58% vs 30% in BUMAC and 34% in BURIC); 5) JAK inhibitor prior to HSCT; a higher proportion of patients in the TREO group were treated with a JAK inhibitor before HSCT (61% vs 50% in BUMAC and 42% in BURIC); 6) Cytomegalovirus (CMV) donor/ recipient status; CMV combinations were more frequently donor recipient -/- in the TREO cohort (41% vs 28% in MAC and 36% in RIC); 7) an HLA matched sibling donor was less frequently used in TREO group (18% vs. 28% in BURIC and 36% in BUMAC). The 3 groups were well balanced regarding period of transplantation, MF classification (primary versus secondary), splenomegaly at time of transplantation, chromosome abnormalities, MF related symptoms, DIPSS score, GVHD prophylaxis and use of ATG. Median time to neutrophil recovery was 17 days (range: 6-54), with no differences between the 3 groups. Cumulative incidence of engraftment at day 30 was 91.5% (95%CI: 89.1-93.9), with no differences between the 3 groups. Cumulative incidence of grade 2-4 acute GVHD at 120 days for the entire cohort was 23% (95%CI: 19-26%); similar in the 3 groups. Three-year OS was 62% (95% CI 58 -66), 3-year PFS was 49% (45-53). At 3 years, cumulative incidence of relapse was 26% (22-29) and NRM was 25% (21-29). Figure 1 shows OS, PFS, NRM and cumulative incidence of relapse (CIR) according to regimen. Multiple variables Cox models after selection are shown in Table 1. TREO group had a significantly better OS than BUMAC (HR: 0.61, 95%CI: 0.39-0.93), BURIC had similar OS to BUMAC (HR: 0.92, 95%CI: 0.68-1.26) and there was a trend for a better OS with TREO over BURIC (HR: 0.66, 95%CI: 0.41-1.05). The same trend was also observed for PFS with a significant advantage of TREO over BUMAC (HR: 0.57, 95%CI: 0.38-0.84) and BURIC (HR: 0.60, 95%CI: 0.39-0.91) while BURIC had a similar risk to BUMAC (HR: 1.05, 95%CI: 0.80-1.39). The improvement of OS and PFS was related to a lower NRM (HR: 0.44, 95%CI: 0.24-0.80 TREO vs BUMAC; HR: 0.54, 95%CI: 0.28-1.04 TREO vs BURIC) and same relapse risk with TREO over BU (TREO vs BUMAC, HR: 0.71, 95%CI: 0.42-1.20; TREO vs BURIC, HR: 0.63, 95%CI: 0.36-1.11). Conclusion TREO based regimens compared to BU based shows better PFS in MF HSCT. This advantage was also confirmed for OS and NRM when compared to BUMAC. More specific prospective studies are needed to confirm findings from this registry based study.

Allogeneic Hematopoietic Stem Cell Transplantation in Adolescents and Young Adults with Acute Lymphoblastic Leukemia - Retrospective Dual-Center Study

Background: Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are treated with various chemotherapy regimens. Some patients undergo allogeneic hematopoietic stem cell transplantation (HCT) due to high-risk genetic characteristics, chemo-resistant disease (failure to achieve timely measurable residual disease (MRD) negative remissions, or relapse or refractory disease. There is paucity of data on outcomes of AYA ALL patients receiving HCT. Methods: We performed a dual-center analysis of data from MD Anderson Cancer Center (MDACC) and Dana-Farber Cancer Institute (DFCI) to evaluate outcomes of AYA patients who received HCT for Philadelphia-negative (Ph neg) ALL and examined variables that might have an impact on these outcomes. We included all patients who received their first HCT between the ages of 15-40 years between the years 2010-2022. MRD status was evaluated using flow cytometry with a sensitivity of 0.01%. Acute and chronic graft versus host disease (GvHD) were classified according to consensus criteria. The primary endpoint was overall survival (OS), and secondary endpoints included progression rate and non-relapse mortality (NRM). Cox proportional hazards regression analysis was used to evaluate predictors of OS, and Fine and Gray regression for predictors of relapse and NRM. Competing risks were accounted for in analyses pertaining to progression and NRM. Results: A total of 376 Ph neg ALL AYA patients were included in the analysis, 247 from MDACC and 129 from DFCI. The median age at transplant was 25 (range 15-40) years, 39 patients (10%) were aged ≤18 years at time of HCT and 251 (67%) were males.The majority had B-ALL (n=282, 75%), 42 (11%) had complex karyotype and 28 patients (7%) had translocation (4:11). Most patients received either pediatric-inspired (48%) or hyper- cyclophosphamide, vincristine sulfate, doxorubicin, dexamethasone (CVAD) based (42%) frontline induction regimens, and the median time from diagnosis to HCT was 11 (range 2-283) months. At transplant, most patients were in CR1 or CR2 (44% each); 63% of patients achieved MRD negativity prior to HCT. Most patients received an HCT from a matched unrelated donor (MUD) (33%) or a matched sibling donor (MSD) (32%), and most patients received myeloablative conditioning (MAC) (79%) ( Table 1). The cumulative incidence of grade 2-4 acute GvHD and grade 3-4 acute GvHD at 6 months was 37% (95% CI 33%-42%) and 13% (95% CI 10%-17%), respectively. The cumulative incidence of chronic GvHD at 3 years was 28% (95% CI 23%-33%), with most patients experiencing either mild (39%) or moderate (36%) chronic GvHD, and 25% had severe chronic GvHD. For patients transplanted in CR1, CR2 and CR3/PD the estimated 3-year OS was 69% (95% CI 61%-77%), 53% (95% CI 44%-61%) and 29% (95% CI 16%-43%), respectively; the 3-year NRM rate was 9% (95% CI 5%-15%), 18% (95% CI 13%-25%) and 27% (95% CI 16%-43%), respectively; and the 3-year progression rate was 27% (95% CI 20%-35%), 36% (95% CI 29%-45%) and 48% (95% CI 36%-65%), respectively. In multivariate analysis, HCT in CR3/PD was associated with inferior OS (HR 4.3, p&amp;lt;0.001) and higher NRM (HR 2.3, p=0.04, Table 2), however there was no difference in survival between HCT at CR1 vs. CR2 (p=0.3); &amp;gt;2 lines of therapy prior to HCT was associated with inferior OS (HR 1.8, p=0.004) and higher rate of progression (HR 1.9, p=0.008); HCT-CI&amp;gt;3 was associated with inferior OS (HR 1.6, p=0.01) and higher NRM (2.3, p=0.004); positive MRD status prior to HCT was associated with inferior OS (HR 1.9, p=0.004) and higher rate of progression (HR 3.3, p&amp;lt;0.001); use of bone marrow graft was associated with lower rate of progression (HR 0.6, p=0.02) and use of a matched donor (MSD/MUD) was associated with lower NRM (HR 0.5, p=0.01). Conclusions: In this analysis of a large dual-center cohort of AYA Ph -ALL patients that received HCT, we found that patients transplanted in CR1 had the most favorable outcomes with 69% 3-year OS. Patients not in CR1/CR2, patients who received HCT after &amp;gt;2 lines of therapy and those with positive MRD pre-HCT had inferior OS on MVA. Although patients who received HCT at CR3/PD had inferior OS, an estimated one-third of patients were still alive at 3 years after HCT.

Long-Term Outcomes Following Fairly Brief Androgen Suppression and Stereotactic Radiation Therapy in High-Risk Prostate Cancer: Update from the FASTR/FASTR-2 Trials.

There has been emerging interest in the role of ultra-hypofractionated radiotherapy for high-risk prostate cancer, especially given its low α/β ratio. However, there is limited data on the long-term outcomes of this treatment strategy. The FASTR and FASTR-2 clinical trials were designed to assess the tolerability of stereotactic ablative body radiotherapy (SABR) in high-risk prostate cancer. FASTR was discontinued early due to unacceptable acute toxicity, whereas the acute toxicities in FASTR-2 were minimal. Herein, the long-term results from these trials are reported. Eligible patients had at least 1 high-risk feature as per the National Comprehensive Cancer Network criteria for high-risk prostate cancer, no evidence of metastatic disease, and either a score of 3+ on the Vulnerable Elderly Scale or declined standard therapy. A total of 19 patients from a single institution were enrolled on FASTR between 2011 and 2015. They received 40 Gy to the prostate and 25 Gy to the pelvic lymph nodes in 5 fractions delivered once weekly for 5 weeks, along with 1 year of androgen deprivation therapy (ADT). The excessive acute toxicity in FASTR prompted several modifications in FASTR-2, including the omission of nodal irradiation. A total of 30 patients from the same institution were enrolled on FASTR-2 between 2015 and 2017. They received 35 Gy to the prostate alone in 5 fractions delivered once weekly for 5 weeks, along with 18 months of ADT. A total of 44 patients were eligible for analysis, 16 from FASTR and 28 from FASTR-2. Most patients were >70 years old (77%). High-risk features included Gleason score ≥8 (46%), T3-T4 disease (27%) and baseline PSA >20 (50%). With a median follow-up of 6.4 years, the cumulative incidence of grade ≥3 genitourinary/gastrointestinal toxicity was 50% among FASTR patients and 7% among FASTR-2 patients. At 5 years, the combined rates of biochemical failure-free survival, freedom from distant metastases, prostate cancer-specific survival and overall survival were 72%, 90%, 92% and 83%, respectively. A total of 12 patients (27%) required further treatment. No significant differences in clinical outcomes were noted between the FASTR and FASTR-2 cohorts. SABR for high-risk prostate cancer is an attractive option for reducing treatment burden. Clinical outcomes and toxicity with the FASTR-2 protocol were comparable to conventionally-fractionated radiotherapy plus ADT. Larger prospective, randomized trials exploring the role of SABR with ADT in high-risk disease are necessary to better understand the efficacy and tolerability of this approach.

Symptomatic Pneumonitis Rates Among Patients with Stage III Non-Small Cell Lung Cancer Receiving Adjuvant Durvalumab

Adjuvant durvalumab after definitive chemoradiation for stage III non-small cell lung cancer (NSCLC) has improved overall survival with low reported pneumonitis rates in clinical trials. However, real-world rates of treatment-associated pneumonitis remain poorly defined. We sought to describe pneumonitis rates among a largest-to-date real-world cohort of stage III NSCLC patients receiving adjuvant durvalumab. We performed a retrospective cohort study of patients with stage III NSCLC in the national Veterans Health Administration who received concurrent chemoradiation alone from 2015-2016 or concurrent chemoradiation followed by at least one dose of adjuvant durvalumab from 2017-2021. Incident pneumonitis was defined as new or worsening symptoms, radiographic changes on CT chest, at least one steroid prescription, and a likely diagnosis of pneumonitis by the treating physician within 2 years of the final radiation treatment; severity was graded by CTCAE v4.03 criteria. Pneumonitis events were ascertained by manual chart review assisted by keyword searches and steroid prescription data. Cox regression was used to identify baseline clinical factors associated with Grade 2+ pneumonitis. Our cohort included 1,994 patients with stage IIII NSCLC, 989 of whom received concurrent chemoradiation alone and 1005 of whom received adjuvant durvalumab. The overall incidence of symptomatic pneumonitis among patients receiving concurrent chemoradiation alone vs those receiving adjuvant immunotherapy was 6.8% vs 11% (Grade 2, p = 0.0005), 6% vs 8.4% (Grade 3, p = 0.007) and 1.1% vs 1.6% (Grade 5, p = 0.292), respectively. The cumulative incidence of Grade 2-5 pneumonitis at 2 years was 13.8% among patients treated with chemoradiation alone versus 22.1% for patients treated with chemoradiation followed by durvalumab (p ≤0.0001). Of those with Grade 2 pneumonitis, pneumonitis occurred in 85% of patients within one year of receiving radiation, and 84% of those with Grade 3-5 pneumonitis developed pneumonitis within one year. Patients prescribed outpatient steroids for pneumonitis had active prescriptions lasting a mean of 153 days, and among those hospitalized for pneumonitis, ¾ needed supplemental oxygen support. On multivariate analysis, the use of durvalumab is associated with higher risk of Grade 2-5 pneumonitis (HR 1.4, p = 0.004). Current smokers have a 50% risk reduction for Grade 2+ pneumonitis relative to never smokers (p≤0.001). In this largest-to-date cohort, we found that adjuvant immunotherapy is associated with higher risk of Grade 2+ pneumonitis. The increase in symptomatic pneumonitis associated with durvalumab should spur future work to refine patient selection, balance the risk/benefit of adjuvant immunotherapy, and potentially modify radiation dosimetric constraints to decrease pneumonitis rates.

Dosimetric correlates of toxicities and quality of life following two-fraction stereotactic ablative radiotherapy (SABR) for prostate cancer

PurposeThere is no evidence-based data to guide dose constraints in two-fraction prostate stereotactic ablative radiotherapy (SABR). Using individual patient-data from two prospective trials, we aimed to correlate dosimetric parameters with toxicities and quality of life (QoL) outcomes. Materials and methodsWe included 60 patients who had two-fraction prostate SABR in the 2STAR (NCT02031328) and 2SMART (NCT03588819) trials. The prescribed dose was 26 Gy to the prostate+/–32 Gy boost to the dominant intraprostatic lesions. Toxicities and QoL data were prospectively collected using CTCAEv4 and EPIC-26 questionnaire. The outcomes evaluated were acute and late grade ≥ 2 toxicities, and late minimal clinical important changes (MCIC) in QoL domains. Dosimetric parameters for bladder, urethra, rectum, and penile bulb were evaluated. ResultsThe median follow-up was 56 months (range: 39–78 months). The cumulative incidence of grade ≥ 2 genitourinary (GU), gastrointestinal (GI), and sexual toxicities were 62%, 3%, and 17% respectively in the acute setting (<3 months), and 57%, 15%, and 52% respectively in late setting (>6 months). There were 36%, 28%, and 29% patients who had late MCIC in urinary, bowel and sexual QoL outcomes respectively. Bladder 0.5 cc was significant predictor for late grade ≥ 2 GU toxicities, with optimal cut-off of 25.5 Gy. Penile bulb D5cc was associated of late grade ≥ 2 sexual toxicities (no optimal cut-off was identified). No dosimetric parameters were identified to be associated with other outcomes. ConclusionUsing real-life patient data from prospective trials with medium-term follow-up, we identified additional dose constraints that may mitigate the risk of late treatment-related toxicities for two-fraction prostate SABR.

PTCy, abatacept, and a short course of tacrolimus for GVHD prevention after haploidentical transplantation.

Reducing the incidence of graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell transplantation (HSCT) is warranted. Posttransplant cyclophosphamide (PTCy) is the main agent used for GVHD prevention in this setting. It remains unknown whether costimulation blockade can be safely combined with PTCy and enhance its efficacy. We performed a phase 1b-2 clinical trial to examine the combination of PTCy, abatacept, and a short course of tacrolimus (CAST) after peripheral blood haploidentical HSCT. The primary end point was the incidence of grades 2-4 acute GVHD by day+120. The study enrolled 46 patients with a median age of 60 years (range, 18-74 years). The cumulative incidences of grades 2-4 and 3 or 4 acute GVHD were 17.4% (95% confidence interval [CI], 9.2-32.9) and 4.4% (95%CI, 1.1-17.1), respectively. With a median follow-up of 15.3months, the cumulative incidence of 1-year treatment-related mortality was 4.4% (95%CI, 1.1-17.1). The estimated 1-year moderate-to-severe chronic GVHD rate, relapse rate, progression-free survival, overall survival, and GVHD- and relapse-free survival were 15.9% (95%CI, 8-31.7), 11.7% (95%CI, 5-27.2), 84.1% (95%CI, 73.8-95.7), 85.9% (95%CI, 75.9-97.2), and 66.1% (95%CI, 53.4-81.8), respectively. Toxicities were similar to those expected in patients receiving haploidentical HSCT. This clinical trial showed that the CAST regimen is safe and effective in reducing the rate of grades 2-4 acute GVHD after haploidentical peripheral blood HSCT. This trial was registered at www.clinicaltrials.gov as #NCT04503616.

Pneumonitis After Concurrent Chemoradiation and Immune Checkpoint Inhibition in Patients with Locally Advanced Non-small Cell Lung Cancer

AimsPneumonitis is a common and potentially deadly complication of combined chemoradiation and immune checkpoint inhibition (CRT-ICI) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). In this study we sought to identify the risk factors for pneumonitis with CRT-ICI therapy in LA-NSCLC cases and determine its impact on survival. Materials and methodsWe conducted a retrospective chart review of 140 patients with LA-NSCLC who underwent curative-intent CRT-ICI with durvalumab between 2018 and 2021. Pneumonitis was diagnosed by a multidisciplinary team of clinical experts. We used multivariable cause-specific hazard models to identify risk factors associated with grade ≥2 pneumonitis. We constructed multivariable Cox proportional hazard models to investigate the impact of pneumonitis on all-cause mortality. ResultsThe median age of the cohort was 67 years; most patients were current or former smokers (86%). The cumulative incidence of grade ≥2 pneumonitis was 23%. Among survivors, 25/28 patients had persistent parenchymal scarring. In multivariable analyses, the mean lung dose (hazard ratio 1.14 per Gy, 95% confidence interval 1.03–1.25) and interstitial lung disease (hazard ratio 3.8, 95% confidence interval 1.3–11.0) increased the risk for pneumonitis. In adjusted models, grade ≥2 pneumonitis (hazard ratio 2.5, 95% confidence interval 1.0–6.2, P = 0.049) and high-grade (≥3) pneumonitis (hazard ratio 8.3, 95% confidence interval 3.0–23.0, P < 0.001) were associated with higher all-cause mortality. ConclusionsRisk factors for pneumonitis in LA-NSCLC patients undergoing CRT-ICI include the mean radiation dose to the lung and pre-treatment interstitial lung disease. Although most cases are not fatal, pneumonitis in this setting is associated with markedly increased mortality.