12-month Cumulative Incidence Research Articles

Developing and validating prediction models for severe exacerbations and readmissions in patients hospitalised for COPD exacerbation (SERCO) in China: a prospective observational study

BackgroundThere is a lack of individualised prediction models for patients hospitalised with chronic obstructive pulmonary disease (COPD) for clinical practice. We developed and validated prediction models of severe exacerbations and...

Salvage Ablative Radiotherapy for Isolated Local Recurrence of Pancreatic Adenocarcinoma following Definitive Surgery.

Introduction: The rate of isolated locoregional recurrence after surgery for pancreatic adenocarcinoma (PDAC) approaches 25%. Ablative radiation therapy (A-RT) has improved outcomes for locally advanced disease in the primary setting. We sought to evaluate the outcomes of salvage A-RT for isolated locoregional recurrence and examine the relationship between subsequent patterns of failure, radiation dose, and treatment volume. Methods: We conducted a retrospective analysis of all consecutive participants who underwent A-RT for an isolated locoregional recurrence of PDAC after prior surgery at our institution between 2016 and 2021. Treatment consisted of ablative dose (BED10 98-100 Gy) to the gross disease with an additional prophylactic low dose (BED10 < 50 Gy), with the elective volume covering a 1.5 cm isotropic expansion around the gross disease and the circumference of the involved vessels. Local and locoregional failure (LF and LRF, respectively) estimated by the cumulative incidence function with competing risks, distant metastasis-free and overall survival (DMFS and OS, respectively) estimated by the Kaplan-Meier method, and toxicities scored by CTCAE v5.0 are reported. Location of recurrence was mapped to the dose region on the initial radiation plan. Results: Among 65 participants (of whom two had two A-RT courses), the median age was 67 (range 37-87) years, 36 (55%) were male, and 53 (82%) had undergone pancreaticoduodenectomy with a median disease-free interval to locoregional recurrence of 16 (range, 6-71) months. Twenty-seven participants (42%) received chemotherapy prior to A-RT. With a median follow-up of 35 months (95%CI, 26-56 months) from diagnosis of recurrence, 24-month OS and DMFS were 57% (95%CI, 46-72%) and 22% (95%CI, 14-37%), respectively, while 24-month cumulative incidence of in-field LF and total LRF were 28% (95%CI, 17-40%) and 36% (95%CI 24-48%), respectively. First failure after A-RT was distant in 35 patients (53.8%), locoregional in 12 patients (18.5%), and synchronous distant and locoregional in 10 patients (15.4%). Most locoregional failures occurred in elective low-dose volumes. Acute and chronic grade 3-4 toxicities were noted in 1 (1.5%) and 5 patients (7.5%), respectively. Conclusions: Salvage A-RT achieves favorable OS and local control outcomes in participants with an isolated locoregional recurrence of PDAC after surgical resection. Consideration should be given to extending high-dose fields to include adjacent segments of at-risk vessels beyond direct contact with the gross disease.

Edoxaban for 12 Versus 3 Months in Cancer-associated Isolated Distal Deep Vein Thrombosis According to Different Doses: Insights from the ONCO DVT study.

The ONCO DVT study revealed the superiority of 12-month relative to 3-month edoxaban treatment for cancer-associated isolated distal deep vein thrombosis (DVT) regarding the thrombotic risk. In this pre-specified subgroup analysis of the ONCO DVT study, we stratified the patients into those with a standard edoxaban dose (60 mg/day; N=151) and those with a reduced edoxaban dose (30 mg/day; N=450) and evaluated the clinical outcomes for the 12-month and 3-month treatments. The cumulative 12-month incidence of symptomatic recurrent venous thromboembolism was lower in the 12-month than 3-month group for both the 60 mg (1.3% vs. 11.6%, P=0.02; odds ratio [OR], 0.12; 95% CI, 0.01-0.97) and 30 mg (1.1% vs. 7.6%, P=0.002; OR, 0.14; 95% CI, 0.03-0.60) edoxaban subgroups, which was consistent across the edoxaban doses without a significant interaction (P =0.90). The 12-month cumulative incidence of major bleeding was higher in the 12-month group than 3-month group for the 60 mg edoxaban subgroup (14.3% vs. 4.4%, P=0.046; OR, 3.61; 95% CI, 0.97-13.52), whereas it did not significantly differ between the two groups for the 30 mg edoxaban subgroup (8.7% vs. 8.6%, P=0.89; OR, 0.97; 95% CI, 0.49-1.91), signaling there was a potential interaction (P=0.07). A 12-month edoxaban regimen for cancer-associated isolated distal DVT was consistently superior to a 3-month regimen, across the edoxaban doses for the thrombotic risk. However, caution was suggested for the standard dose of edoxaban due to the potential for an increased risk of bleeding with prolonged anticoagulation therapy.

Prognostic Implications of Small Cell Lung Cancer Transcriptional Subtyping for CNS Metastases.

Small cell lung cancer (SCLC) often metastasizes to the brain and has poor prognosis. SCLC subtypes distinguished by expressing transcriptional factors ASCL1 or NEUROD1 have been identified. This study investigates the impact of transcription factor-defined SCLC subtype on incidence and outcomes of brain metastases (BMs). Patients with SCLC with ASCL1 (A) and NEUROD1 (N) immunohistochemical expression status were identified and classified: (1) A+/N-, (2) A+/N+, (3) A-/N+, and (4) A-/N-. Cumulative incidence competing risk analyses were used to assess incidence of CNS progression. Cox proportional hazards models were used for multivariable analyses of overall survival (OS) and CNS progression-free survival (CNS-PFS). Of 164 patients, most were either A+/N- or A+/N+ (n = 62, n = 63, respectively). BMs were present at diagnosis in 24 patients (15%). Among them, the 12-month cumulative incidence of subsequent CNS progression was numerically highest for A+/N- (50% [95% CI, 10.5 to 74.7]; P = .47). Among those BM-free at diagnosis, the 12-month cumulative incidence of CNS progression was numerically the highest for A+/N- (16% [95% CI, 7.5 to 27.9]) and A-/N+ (9.1% [95% CI, 0.0 to 34.8]; P = .20). Both subtypes, A+/N- and A-/N+, had worse OS compared with A+/N+ (A+/N-: hazard ratio [HR], 1.62 [95% CI, 1.01 to 2.51]; P < .05; A-/N+: HR, 3.02 [95% CI, 1.35 to 6.76]; P = .007). Excellent response rates (28, 65% CR/PR) across subtypes were seen in patients who had CNS-directed radiotherapy versus systemic therapy alone (9, 36% CR/PR). To our knowledge, this report is the first to investigate CNS-specific outcomes based on transcription factor subtypes in patients with SCLC. BM-free patients at diagnosis with A+/N- or A-/N+ subtypes had worse outcomes compared with those with transcriptional factor coexpression. Further investigation into the mechanisms and implications of SCLC subtyping on CNS-specific outcomes is warranted to ultimately guide personalized care.

Development and Validation of Staging Systems for AA Amyloidosis.

The kidney is involved in almost 100% of cases of AA amyloidosis, a rare disease caused by persistent inflammation with long overall survival but frequent progression to end-stage kidney failure . Identification of patients with advanced disease at diagnosis is difficult, given the absence of validated staging systems. Newly diagnosed patients with AA amyloidosis from the Pavia (n=233, testing cohort) and Heidelberg (n=243, validation cohort) centers were included in the study. Cut-offs of continuous variables were determined by ROC analysis predicting death or dialysis at 24 months. Prognostic factors included in staging systems were identified by multivariable models in the testing cohort. Age ≥65 years, estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2 and elevated natriuretic peptides (type-B natriuretic peptide [BNP] >130 ng/L and/or N-terminal BNP [NT-proBNP] >1000 ng/L) were predictors of overall survival and included in the staging system (all with simplified coefficients 1). Mean 36-months overall survival was lower with higher staging system scores (score 0-1: 92%; score 2: 72%; score 3: 32%). These results were confirmed in the validation cohort. For kidney failure, variables selected to enter in the staging system model were proteinuria >3 g/24h and eGFR <35 mL/min/1.73m2 (both with simplified coefficients 1). The 36-month cumulative incidence of kidney failure was higher with higher staging system scores (score 0: 0%; score 1: 24%; score 2: 51%). Again, similar results were obtained in validation cohort. We identified and validated biomarker-based staging systems for overall survival and kidney failure in AA amyloidosis.

40 Gray in 5 Fractions for Salvage Reirradiation of Spine Lesions Previously Treated With Stereotactic Body Radiotherapy.

A retrospective single-center analysis of the safety and efficacy of reirradiation to 40 Gy in 5 fractions (reSBRT) in patients previously treated with stereotactic body radiotherapy to the spine was performed. We identified 102 consecutive patients treated with reSBRT for 105 lesions between 3/2013 and 8/2021. Sixty-three patients (61.8%) were treated to the same vertebral level, and 39 (38.2%) to overlapping immediately adjacent levels. Local control was defined as the absence of progression within the treated target volume. The probability of local progression was estimated using a cumulative incidence curve. Death without local progression was considered a competing risk. Most patients had extensive metastatic disease (54.9%) and were treated to the thoracic spine (53.8%). The most common regimen in the first course of stereotactic body radiotherapy was 27 Gy in 3 fractions, and the median time to reSBRT was 16.4 months. At the time of simulation, 44% of lesions had advanced epidural disease. Accordingly, 80% had myelogram simulations. Both the vertebral body and posterior elements were treated in 86% of lesions. At a median follow-up time of 13.2 months, local failure occurred in 10 lesions (9.5%). The 6- and 12-month cumulative incidences of local failure were 4.8% and 6%, respectively. Seven patients developed radiation-related neuropathy, and 1 patient developed myelopathy. The vertebral compression fracture rate was 16.7%. In patients with extensive disease involvement, reSBRT of spine metastases with 40 Gy in 5 fractions seems to be safe and effective. Prospective trials are needed to determine the optimal dose and fractionation in this clinical scenario.

Validation of the IMPEDE VTE score for prediction of venous thromboembolism in Chinese patients with multiple myeloma: A single-center retrospective cohort study

Multiple myeloma (MM) significantly increases the risk of venous thromboembolism (VTE) within 6 months of treatment initiation. The IMPEDE VTE score is a VTE risk prediction model which is recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, but it lacks validation among Asians, including Chinese MM patients. We performed a retrospective chart review of 405 Chinese with newly diagnosed MM who started therapy at Beijing Jishuitan Hospital between April 2013 to October 2022. The 6-month cumulative incidence of VTE was 3.8 % (95 % CI:1.6–7.6), 8.6 % (95 % CI: 5.3–21.9) and 40.5 % (95 % CI: 24.9–55.7) in the low-, intermediate- and high-risk groups (P < 0.001), respectively. The C-statistic of the IMPEDE VTE scores for predicting VTE within 6 months of treatment initiation was 0.74 (95 % CI: 0.65–0.83). Of note, in this single-center cohort study, we propose that the anticoagulant LMWH may be more effective than the antiplatelet aspirin in potentially preventing VTE in newly diagnosed MM patients. Our findings suggest that the IMPEDE VTE score is a valid evidence-based risk stratification tool in Chinese patients with newly diagnosed MM.

Real-world Data on Treatment Patterns and Bleeding in Cancer-associated Thrombosis: Data from the TROLL Registry.

Background International guidelines are increasingly recommending direct oral anticoagulants (DOACs) as the first-line treatment for cancer-associated thrombosis (CAT). However, data regarding treatment patterns and adherence to guidelines in patients with CAT are scarce. Objectives This study aimed to explore anticoagulant treatment patterns in patients with CAT and to calculate the incidence rates of bleeding events. Methods Patients ≥18 years with active cancer and a first-time venous thromboembolism between 2005 and 2020 were identified through the Venous T hrombosis R egistry in Østf OL d Hospita L . Outcome measures were patterns of anticoagulant treatment during the study period and bleeding events. We calculated overall incidence rates per 100 person-years and 6- and 12-month cumulative incidence of major and clinically relevant nonmajor bleeding (CRNMB) during anticoagulant treatment. Results Median age of 842 CAT patients at the time of thrombosis was 69 years (interquartile range 61-77), and 443 (52.6%) were men. In total, 526 patients (62.5%) had pulmonary embolism and 255 (30.3%) had deep vein thrombosis. Low molecular weight heparin (LMWH) was prescribed to 713 (85.8%) patients, whereas 64 (7.7%) received DOACs and 54 (6.5%) received vitamin K antagonists as the initial anticoagulant treatment. Prescription of DOACs as initial treatment increased from 3.0% in 2013/2014 to 18.0% in 2019/2020. The incidence rate of major bleeding was 6.9 (95% confidence interval [CI] 5.2-9.2) and 10.1 (95% CI 8.0-12.9) in CRNMB. Conclusion Most patients were treated with LMWH. However, a gradual shift in treatment toward DOACs was observed. Overall, bleeding complications were rare and comparable to those reported in randomized trials.

Incidence of thromboembolism and associated factors in multiple myeloma patients treated with immunomodulatory drugs: a retrospective analysis in Belo Horizonte, Brazil.

The use of immunomodulators in the treatment of multiple myeloma (MM) patients has been associated with venous thromboembolism (VTE). Due to the increase in mortality of cancer patients, venous thromboembolism is an important concern for newly diagnosed multiple myeloma (NDMM) patients. The aim of this study was to determine the incidence of thromboembolic events and evaluate associated risk factors among Brazilian NDMM patients using immunomodulators. Real-life retrospective cohort study in two Brazilian institutions with newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulators from January 2009 to December 2019. Data was collected from patients' medical records for the period of 1 year, and Cox regression was performed to identify risk factors on the development of VTE. We included 131 patients of which there was a mean age of 61.5 years (SD 11.3), 51.9% female, and predominantly using thalidomide (97.7%) as immunomodulator. We found 9 VTE episodes among our patients, with a 12-month cumulative incidence of 6.97% (95% CI 3.41-12.24). Associated factors after multivariate analysis were recent sepsis, recent traumatic injury, previous VTE, and thromboprophylaxis. Our real-life retrospective cohort presented a low incidence of VTE among Brazilian NDMM patients treated with immunomodulators.

Clinical and economic impact of ventricular assist device infections: a real-world claims analysis

Background VAD therapy has revolutionized the treatment of end-stage heart failure, but infections remain an important complication. The objective of this study was to characterize the clinical and economic impacts of VAD-specific infections. Methods A retrospective analysis of a United States claims database identified members ≥ 18 years with a claim for a VAD implant procedure, at least 6 months of pre-implant baseline data, and 12 months of follow-up between 1 June 2016 and 31 December 2019. Cumulative incidence of infection was calculated. Infection and non-infection cohorts were compared regarding mortality, healthcare utilization, and total cost. Regression models were used to identify risk factors associated with infections and mortality. Results A total of 2,259 patients with a VAD implant were included, with 369 experiencing infection (12-month cumulative incidence 16.1%). Patients with infection were 2.1 times more likely to die (p < 0.001, 95% CI [1.5–2.9]). The mean 12-month total cost per US patient was $354,339 for the non-infection cohort and $397,546 for the infection cohort, a difference of $43,207 (p < 0.0001). Conclusions VAD infections were associated with higher mortality, more healthcare utilization, and higher total cost. Strategies to minimize VAD-specific infections could lead to improved clinical and economic outcomes.

Long-Term Intracranial Outcomes With Combination Dual Immune-Checkpoint Blockade and Stereotactic Radiosurgery in Patients With Melanoma and Non-Small Cell Lung Cancer Brain Metastases

The intracranial benefit of offering dual immune-checkpoint inhibition (D-ICPI) with ipilimumab and nivolumab to patients with melanoma or non-small cell lung cancer (NSCLC) receiving stereotactic radiosurgery (SRS) for brain metastases (BMs) is unknown. We hypothesized that D-ICPI improves local control compared with SRS alone. Patients with melanoma or NSCLC treated with SRS from 2014 to 2022 were evaluated. Patients were stratified by treatment with D-ICPI, single ICPI (S-ICPI), or SRS alone. Local recurrence, intracranial progression (IP), and overall survival were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence. Two hundred eighty-eight patients (44% melanoma, 56% NSCLC) with 1,704 BMs were included. Fifty-three percent of patients had symptomatic BMs. The median follow-up was 58.8 months. Twelve-month local control rates with D-ICPI, S-ICPI, and SRS alone were 94.73% (95% CI, 91.11%-96.90%), 91.74% (95% CI, 89.30%-93.64%), and 88.26% (95% CI, 84.07%-91.41%). On Kaplan-Meier analysis, only D-ICPI was significantly associated with reduced local recurrence (P = .0032). On multivariate Cox regression, D-ICPI (hazard ratio [HR], 0.4003; 95% CI, 0.1781-0.8728; P = .0239) and planning target volume (HR, 1.022; 95% CI, 1.004-1.035; P = .0059) correlated with local control. One hundred seventy-three (60%) patients developed IP. The 12-month cumulative incidence of IP was 41.27% (95% CI, 30.27%-51.92%), 51.86% (95% CI, 42.78%-60.19%), and 57.15% (95% CI, 44.98%-67.59%) after D-ICPI, S-ICPI, and SRS alone. On competing risk analysis, only D-ICPI was significantly associated with reduced IP (P = .0408). On multivariate Cox regression, D-ICPI (HR, 0.595; 95% CI, 0.373-0.951; P = .0300) and presentation with >10 BMs (HR, 2.492; 95% CI, 1.668-3.725; P < .0001) remained significantly correlated with IP. The median overall survival after D-ICPI, S-ICPI, and SRS alone was 26.1 (95% CI, 15.5-40.7), 21.5 (16.5-29.6), and 17.5 (11.3-23.8) months. S-ICPI, fractionation, and histology were not associated with clinical outcomes. There was no difference in hospitalizations or neurologic adverse events between cohorts. The addition of D-ICPI for patients with melanoma and NSCLC undergoing SRS is associated with improved local and intracranial control. This appears to be an effective strategy, including for patients with symptomatic or multiple BMs.

Risk Factors Associated with Anticoagulant-Related Bleeding in Patients with Cancer-Associated Thrombosis

Background: Patients with cancer-associated thrombosis (CAT) have a high risk of recurrent venous thromboembolism as well as anticoagulant-related major bleeding. Thus, initiation and maintenance of anticoagulant therapy requires careful consideration of the risk versus benefit of therapy. Prior literature demonstrates that existing bleeding risk models have mediocre to moderate predictive performance for anticoagulant-related bleeding in patients with cancer. Patients with cancer have unique risk factors for bleeding that are absent in many of these models. Thus, we aimed to evaluate the association candidate traditional and cancer-specific risk factors with anticoagulant-related bleeding in a large cohort of patients with CAT. Methods : Using a nationwide cohort of US Veterans, we identified patients diagnosed with CAT with a new prescription for anticoagulant therapy between 2012 and 2020. Eligible anticoagulant therapy included a prescription for at least 30 days of: direct oral anticoagulants (DOACs), direct selective factor Xa inhibitors, low molecular-weight-heparin (LMWH), or vitamin K antagonists (VKA). Patients with outpatient prescriptions for anticoagulation within the six months preceding CAT were excluded. We further identified a subgroup of patients on chemotherapy around the time of CAT diagnosis, chemotherapy cohort. Using the methods of Fine and Gray, we assessed the association between candidate risk factors and clinically significant anticoagulant-related bleeding using competing risk analyses to account for the competing risk of death. Anticoagulant related bleeding was identified using previously validated international classification of disease (ICD) coding, with position dependent on site of bleed. Results : We identified a cohort of 11,731 patients with CAT, of whom 4,298 patients received anti-cancer systemic therapy within 6 months before to 12 months after CAT diagnosis. The most common malignancies represented in the full cohort included lung (23%), gastrointestinal (14%), and prostate (11%). Most patients received anticoagulant therapy with LMWH (47.7%), followed by DOACs (26.8%), VKAs (24.5%), and fondaparinux (1%). When assessing anticoagulant trends over time, DOACs were the treatment of choice by 2018 with 45.3% of patients receiving initial therapy with a DOAC and further increased to 78.1% by 2020. The 6-month and 12-month cumulative incidence of bleeding in the full cohort was 7% (CI 6.5-7.5) and 9.5% (CI 8.9-10.1), respectively. In the chemotherapy cohort, 6-month and 12-month cumulative incidence of bleeding was 7.9% (CI 7.1-8.8) and 12% (CI 10.8-13.2). In both the chemotherapy and full cohorts, the most frequent sites of clinically significant bleeding included gastrointestinal (GI) tract (57.2%, 54.5%), genitourinary (GU) tract (excluding microscopic hematuria) (20.2%, 21.2%), and intracranial hemorrhage (10.4%, 11.4%) respectively. Of the traditional candidate variables assessed in the full cohort, history of bleeding, estimated glomerular filtration rate (eGFR), uncontrolled hypertension, predisposition to falling, history of ischemic stroke, alcohol abuse, anemia (defines as hemoglobin &amp;lt; 13g/dL in men and &amp;lt; 12 g/dL in women), and liver disease had the highest association with anticoagulant-related bleeding. In addition, use of chemotherapy was associated with an increased risk of bleeding. Findings were similar in the chemotherapy cohort, history of ischemic stroke, alcohol abuse, and anemia were no longer associated with bleeding risk. Of cancer specific candidate variables, GI cancer, GU cancer and metastatic cancer was most predictive. Full results of the analyses are in Table 1 for both the full and chemotherapy cohorts. Conclusions : In this study, many candidate variables in available risk prediction models for anticoagulant-related bleeding were not associated with bleeding risk. This may explain the performance of these models in patients with cancer on anticoagulant therapy. We identified cancer-specific candidate variables that were associated with risk of anticoagulant-related bleeding. Incorporation of these cancer-specific variables into available models could improve predictive performance.

Incidence, characteristics, and associated factors of pressure injuries acquired in intensive care units over a 12-month period: A secondary analysis of a quality improvement project

ObjectivesTo determine the 12-month cumulative incidence, characteristics, and associated factors of pressure injuries acquired in Intensive Care Units. SettingFour intensive care units in a Norwegian University Hospital. Research methodologyA prospective observational cohort study using data from daily skin inspections during a quality improvement project. We used descriptive statistics and logistic regression. Variables associated with the development of intensive care unit-acquired pressure injuries are presented with odds ratios (OR), and 95% confidence intervals. ResultsThe 12-month cumulative incidence of patients (N = 594) developing intensive care unit-acquired pressure injuries was 29 % (172/594) for all categories and 16 % (95/594) when excluding category I pressure injuries (no skin loss). Cumulative incidence for patients acquiring medical device-related pressure injuries was 15 % (91/594) and 11 % (64/594) for category II or worse. Compression stockings (n = 51) and nasogastric tubes (n = 22) were the most frequent documented medical devices related to pressure injuries. Development of pressure injuries category II or worse was significantly associated with vasoactive drug infusions (OR 11.84, 95 % CI [1.59; 88.13]) and longer intensive care unit length of stay (OR 1.06, 95 % CI [1.04; 1.08]). ConclusionThe 12-month cumulative incidence of intensive care unit-acquired pressure injuries was relatively high when category I pressure injuries were included, but comparable to other studies when category I was excluded. Some medical device-related pressure injuries were surprisingly frequent, and these may be prevented. However, associated factors of developing pressure injuries were present and deemed non-modifiable. Implications for clinical practiceAwareness about pressure injury prevention is needed in the intensive care unit considering high incidences. Nurses can detect category I pressure injuries early, which may be reversed. Our findings show several factors that clinicians can control to reduce the risk of pressure injuries in the intensive care unit.

CDKN2C Deletion on 1p32 Locus As Part of Irwazh Score, a New Risk Assessment Model for Venous Thromboembolism Occurring within 6-12 Months of Treatment Initiation in Newly Diagnosed Multiple Myeloma

Background Adequate risk-stratification of venous thromboembolism (VTE) in multiple myeloma (MM) is an unmet need. Methods This is a retrospective study of 320 newly diagnosed MM (NDMM) patients treated from 2011 to 2023. All gave their informed consent. Required minimal follow-up (FU) length was 12 months or lower if VTE or death occurred. We aimed to evaluate VTE incidence at 6 and 12 months of first line treatment (L1) initiation, identify risk predictors and assess VTE impact on overall survival (OS). Comorbidities, baseline demographic (excluding race), clinical, biological (including FISH) and imaging data, treatment exposures, response profile and OS were all analyzed. Total scores for 4 existing risk assessment models (RAM) (IMPEDE-VTE, SAVED, PRISM, IFM/DFCI-related) were also calculated from L1 start. VTE events (VTEe) were adjudicated to exclude superficial ones and restrict analysis to documented deep vein thrombosis (DVT) and pulmonary embolism (PE). Predictors validated by Cox model were weighted based on their hazard ratios (HR). Results The cohort comprised 147 (45.9%) women and 111 (34.7%) transplant-eligible patients. Overall median age was 70.1 (36.6-98.4) years and 205 (64.1%) subjects were &amp;gt;65. Two hundred and twenty-five (70.3%) received standard-of-care regimens containing immunomodulatory drugs (IMID) (Thalidomide in 98: 30.6%; Revlimid in 127: 39.7%), while 130 (40.6%) received high-dose (≥160 mg) Dexamethasone (HDD) per L1 cycle. VTE prophylaxis was omitted in 32 (10%) or consisted of NSAID in 97 (30.3%), prophylactic low molecular weight heparin (LMWHp) in 115 (36%) and direct oral anticoagulant (DOA) in 55 (17.2%), while 10 (3.1%), 9 (2.8%) and 2 (0.6%) were previously receiving curative LMWH (LMWHc), vitamin K antagonist (VKA) or a mixed regimen, respectively, for prior VTE or other indications. In 33 (10.3%) patients, 34 VTEe occurred (31 [91.2%] within the first 6 months): 4 (11.8%) as both PE and DVT; 3 (8.8%) as PE; 27 (79.4%) as isolated proximal (12 [35.3%]) or distal (15 [44.1%]) DVT of the upper (2 [5.9%]) or lower (25 [73.5%]) limbs, including 3 (8.8%) with both proximal and distal and 3 (8.8%) close to central venous catheter. Based on Cox univariate analysis, VTEe were not related to usual parameters such as past VTE history, IMID, HDD or EPO exposure, prophylaxis omission or modality or recent surgery. A 6-parameter RAM, named Irwazh score, was built from multivariate Cox model, including: age &amp;lt;55 years (HR 0.34; 95% confidence interval [CI]: 0.0-0.8; p=0.014), prior diabetes (HR 3.41; 95% CI: 1.48-7.85; p=0.004), creatinine clearance (Cr-Cl) using MDRD &amp;lt;40 ml/mn (HR 2.64; 95% CI: 1.26-5.51; p=0.009), CRP ≥10 mg/dl (HR 2.65; 95% CI: 1.27-5.48; p=0.009), ≥50% 1p32 deletion (HR 3.44; 95% CI: 1.17-10.09; p=0.024) and minimal response (MR) to L1 (HR 4.67; 95% CI: 1.71-12.73; p=0.003). Area under the curve (AUC) was 0.718 (95% CI: 0.624-0.811; p&amp;lt;0.0001) at 12 months and 0.731 (95% CI: 0.636-0.825; p&amp;lt;0.0001) at 6. In comparison, AUC was 0.649 (95% CI: 0.546-0.751; p=0.004) for IMPEDE-VTE, 0.597 (95% CI: 0.505-0.689; p=0.039) for PRISM, 0.584 (95% CI: 0.486-0.682: p=0.091) for IFM/DFCI-related and 0.580 (95% CI: 0.473-0.687; p=0.141) for SAVED (Figure 1). Based on points attributed to each parameter (age &amp;lt;55 years: 1; prior diabetes: 9; Cr-Cl&amp;lt;40 ml/mn: 6; CRP≥10 mg/dl: 6; ≥50% 1p32 deletion: 9; MR: 11), patients were stratified into low (&amp;lt;6 points), intermediate (6-15) and high risk (≥16), with 12-month cumulative VTE incidence of 4,51% (6/133), 10,45% (16/153) and 35,29% (12/34), respectively. Of low-risk patients, 2 were receiving NSAID and 4 LMWHp; of intermediate-risk ones, 2 had no prophylaxis, 9 were under NSAID and 5 LMWHp; of high-risk ones, 2 had no prophylaxis, 5 were receiving NSAID, 2 LMWHp, 1 VKA, 1 LMWHc and 1 DOA. Using Kaplan-Meier analysis for VTE-free survival, statistical difference was found significant between low- and intermediate-risk ( p=0.043), low- and high-risk ( p&amp;lt;0.0001) and intermediate- and high-risk groups ( p=0.000) (Figure 2). Median total FU was 33.2 (0.2-147) months; OS assessment using Cox model did not find a significant statistical impact of VTE neither at 6 ( p=0.491) and 12 ( p=0.199) months nor during the whole FU length ( p=0.438). Conclusion The Irwazh score, with an unprecedented FISH feature, a statistically significant risk-stratifying power and a better AUC than existing VTE RAMs is worth validating in a larger clinical study.

Validation of ELN 2022 Risk Classification in Patients Diagnosed with AML Undergoing Allogeneic Hematopoietic Cell Transplantation

Background: In 2022, the European LeukemiaNet (ELN) updated their guidelines (Döhner H et al., Blood 2022) for risk allocation of patients with acute myeloid leukemia (AML) based on essential genetic features at diagnosis as defined in the newest classifications (Arber D et al., Blood 2022, Khoury JD et al., Leukemia 2022). Methods: Retrospective analysis of the 147 consecutive patients diagnosed with AML and available genetic information who underwent alloHCT in a complete morphological response (CR) between 2011 and 2021 in a single institution (HCB). Data was collected retrospectively and updated in July 2023. G-banding karyotype, FISH, qualitative and quantitative PCR and targeted Next Generation Sequencing were assessed at diagnosis to classify patients according to ELN 2022 risk classification. Our primary goal was to validate the ELN 2022 risk classification in patients undergoing alloHCT analyzing overall survival (OS). Secondary objectives were analyzing leukemia-free survival (LFS), 24-month cumulative incidence of relapse (CIR) and in the different molecular subgroups within the ELN2022 risk groups. Results: The main patient, disease-related and transplant characteristics are displayed in Figure 1. Overall, the median age was 52 years (range 18-70), 53.7% of the patients males, with 88% of the patients undergoing alloHCT in CR1. Twenty-two patients could not be classified through NGS assessment between 2011 and 2016 and included in the intermediate risk category due to normal karyotype and wildtype recurrent abnormalities measured by PCR. Patients in the adverse-risk group were older (p &amp;lt;0.001) and underwent alloHCT less often with undetectable measurable residual disease (p = 0.006). Moreover, patients in the favorable or intermediate risk group underwent alloHCT more often in CR2 or CR3 (p = 0.02). In addition, alloHCT characteristics were similar for all the patients included. With a 67-month median follow-up for LFS (95CI: 55-76), the median OS and LFS in patients classified into the favorable and intermediate risk groups were not reached (5-year OS and LFS rate in favorable risk group: 81% (95CI: 73-89) and 72% (95CI: 63-81). 5-year OS and LFS rate in intermediate risk group: 62% (95CI: 56-68) and 64% (95CI: 58-70). Patients included in the adverse risk group had an OS and LFS of 23.7 months (15.3-NR, p &amp;lt;0.001 between intermediate and adverse risk. Figure 1B) and 15.2 months (5.79-NR, p=0.015) respectively, with a significant lower 5-year OS rate (40%, 95CI: 34-46), LFS rate (38%, 95CI: 32-44) and a higher CIR (18% in the favorable risk group (95%CI: 11-26) vs. 20% in the intermediate risk group (95%CI: 18-23) vs. 40% in the adverse risk group (95%CI: 38-44), p = 0.024). Based on these results, a subanalysis was conducted in the patients classified into the adverse group. Those patients diagnosed with complex karyotype, inv(3), t(3;3), del(17p) and/or TP53 mutated were reassessed into a new risk category group called: Adverse-Plus (AdvP).No different baseline characteristics between the AdvP patients and the other subgroups were found. AdvP patients presented a shorter OS (NR in the rest of subgroups vs. 8.73 months in AdvP, p &amp;lt; 0.001 for AdvP vs. adverse risk. Figure 1C), LFS (NR in the rest of subgroups vs. 5.2 months, p &amp;lt; 0.001), and a higher CIR (62.5% in the AdvP group, p &amp;lt;0.001 between adverse risk and AdvP). Interestingly, using this four-group classification including AdvP, the other risk groups presented similar OS, LFS, and CIR without statistical differences in between them Summary/Conclussion: ELN2022 risk classification discriminates properly accurate in patients undergoing alloHCT. Reclassifying AML adverse risk patients diagnosed with complex karyotype, inv(3), t(3;3), del(17p) and/or TP53 mutated in a different subgroup should be considered due to a much worse prognosis after alloHCT, although it remains mandatory in first complete response.

Phase I/II Study of Reduced Dosing of Post-Transplantation Cyclophosphamide (PTCy) after HLA-Identical Peripheral Blood Hematopoietic Stem Cell Transplantation

Introduction Post-transplant cyclophosphamide (PTCy)-based prophylaxis for acute graft versus host disease (aGvHD) has become a standard protocol in HLA haploidentical bone marrow transplantation. Preliminary evidence indicates that compared to the standard dosage (50 mg/kg on days +3 and +4 post-transplantation), a regimen of half the typical cyclophosphamide dosage is both feasible and effective. However, the optimal dosage and timing of PTCy for aGvHD prophylaxis in a HLA identical setting, using peripheral stem cells as the graft, remain unknown. This study aims to investigate the efficacy and safety of a reduced PTCy dosage regimen in patients undergoing peripheral blood stem cell transplants (PBSCT) with HLA indentical donors. Methods This prospective, single-center phase I/II study enrolled patients scheduled for PBSCT with HLA identical donors. The aGVHD prophylaxis regimen comprised PTCy on days +3 and +4, followed by cyclosporine initiation from day 5 post-transplant. In the phase I stage, an initial cohort of five patients received PTCy at a dosage of 50 mg/kg/day on days +3 and +4 (designated as dose level 1, DL1). This was followed by a 3+3 dose de-escalation design with subsequent dose levels as follows: DL2, 50 mg/kg on day +3 and 25 mg/kg on day +4; and DL3, 25 mg/kg on both day +3 and +4. The dose-limiting toxicity for this de-escalation was defined as the occurrence of grade III-IV aGVHD within the first 100 days post-transplantation. The phase II stage comprised an expansion cohort, which was based on the optimal dose identified during phase I. aGvHD classification was established using the Mount Sinai Acute GVHD International Consortium (MAGIC) criteria, while chronic GvHD (cGvHD) was assessed per the latest National Institutes of Health Consensus on cGvHD. Patients were closely followed-up at +1, +2, +3, +4, +6, +9, +12, +18, and +24 months post-transplant. Results In the first stage, a total of 11 patients (5 in DL1, 3 in DL2, and 3 in DL3) were included, and no patient developed grade III-IV aGVHD. Based on this, DL3 was selected as the PTCy dose for phase II, which comprised 18 patients. Overall, 29 patients (17 females, 12 males) with a median age of 39 years (range 17-65) were included, and the median follow-up duration was 12.7 months (range 2.2-22.1). Patient and disease characteristics are summarized in Table 1. By day +30 post-ASCT, all patients achieved complete remission (CR) and minimal residual disease (MRD) clearance. No patient developed grade III-IV aGVHD within 100 days post-transplantation. There was no significant difference in the neutrophil and platelet engraftment interval among the three groups (Figure 1A, B). Among the 21 patients who received the DL3 dose of PTCy, the estimated cumulative incidence of grade II to IV aGVHD at day +100 was recorded at 28.6%, and the incidence of aGVHD at day +100 presented no difference among the three DL groups (Figure 1C). In addition, 1 patient in DL3 developed grade IV intestinal aGVHD on day +141 and died one month later. The estimated 1-year cumulative incidence of hemorrhagic cystitis (HC) and cytomegalovirus (CMV) reactivation was 19.3% and 19%, respectively (Figure 1D). Five patients (all in DL3) experienced relapse, with a median interval of 6.7 months and an estimated 1-year cumulative incidence of 10.6%. A total of 5 fatalities occurred during our study (1 in DL1, and 4 in DL3), 1 due to relapse, 2 from COVID-19-associated pulmonary aspergillosis, 1 from severe septicemia and 1 due to grade IV aGVHD as mentioned above. The estimated 6-month cumulative incidence of NRM was 9.5%, presenting no difference among the three DL groups (Figure 1E). Among the 20 evaluable patients, the estimated 1-year cumulative incidence of chronic GVHD (cGVHD) and moderate cGVHD was 37.3% and 16% (Figure 1F), respectively, with no severe cGVHD observed. No cases of patient relapse were reported. The estimated 1-year progression-free survival (PFS) and overall survival (OS) were 61.2% and 80.4%, respectively (Figure 1G). Conclusion The findings of this study substantiate that a two-day regimen of PTCy at 25 mg/kg/day serves as an effective and safe prophylactic measure against aGVHD, comparable to the standard dosing protocol. However, to definitively establish whether the de-escalated PTCy dosage provides superior outcomes to the standard regimen, longer-term follow-up and comparative studies are warranted.

Low Mortality from COVID-19 Infection in Patients with B-Cell Lymphoma after Bispecific CD20xCD3 Therapy

Introduction: Patients with hematological malignancies are at an increased risk of morbidity and mortality after COVID-19 infection.Especially patients treated with chimeric antigen receptor T-cell (CAR-T) therapy for B-cell malignancies have shown poor outcomes after COVID-19, resulting in reported COVID-19 attributable mortality rates between 41%-50%.Outcomes after COVID-19 infection in patients treated with CD20xCD3 bispecific antibodies have not been reported. We investigated the impact and clinical course of COVID-19 in 130 Danish patients with B-NHL who have received bispecific antibodies. Methods: Using clinical data from electronic health charts, the national Danish database of microbiology (MiBA), and the national drug- and vaccination registry (SharedMedicineCard), we collected data on date of positive COVID-19 test, quantitative PCR-determined COVID-19 variant, symptoms, reactivations, resolution of disease (either clinical, confirmed by negative PCR test or death), vaccination status and treatment. Disease duration was defined as the time from diagnosis of COVID-19 to clinical resolution. Results: A total of 130 patients who received bispecific CD20xCD3 antibodies (glofitamab or epcoritamab) as part of clinical trials in Denmark were assessed. Of the 130 patients, 109 were alive after March 8, 2020. We identified 43 patients infected with COVID-19, 34 of whom were during CD20xCD3 specific treatment or after end-of-treatment (Table 1). A total of 26 patients (79%) were in complete remission at the time of COVID-19 diagnosis, 5 patients (15%) had progressive disease, 2 patients (6%) had stable disease and 1 patient had no data on lymphoma status at COVID-19 diagnosis. With regards to COVID-19 symptom burden, 4 patients (12%) were asymptomatic during infection. The most common symptoms included fever (n=15), cough (n=12), and dyspnea (n=6). There were 16 patients (48%) admitted to the hospital for the treatment of COVID-19. Of these, 2 patients required oxygen support. Twelve patients (35%) received no specific treatment for COVID-19, while the most commonly prescribed treatments were sotrovimab in 13 patients (42%) and remdesivir in 9 patients (29%). At six months after COVID-19 infection, 3 patients had died, two before recovering from COVID-19. The two cases, where COVID-19 presumably was a cause of death, had a combination of multiple bacterial infections and progression of malignant disease. The 6-month cumulative incidence of death related to COVID-19 was 6.4% (95% CI 0% to 14.9%, Figure 1), while the cumulative incidence of death overall was 9.6% (95%CI 0% to 19.9 %). Of the 25 patients who were alive and had data available at 6 months follow-up after COVID-19 infection, 20 were in complete remission, while the rest (n=5) had refractory/relapsed lymphoma. Of the patients with COVID-19 during CD20xCD3 specific treatment or after end-of-treatment, 13 out of 34 had at least one reactivation. The mean number of COVID-19 reactivations was 1.2 (95%CI 0.44 to 2.03), ranging from 0 up to 9. An additional patient had a reactivation 20 days after first infection and 4 days after first treatment with bispecific antibodies. Only 9% (1 out of 11) of the patients who tested positive for SARS-CoV-2 before bispecific antibody treatment had a reactivation compared to 38% of those testing positive after or during bispecific antibody treatment. In an adjusted multivariable regression for age and sex only hospitalization during the first COVID-19 infection was significantly associated to reactivations (OR: 18.9, 95%CI 2.84-238, p=0.007). Conclusions: To our knowledge, this study presents the first data on COVID-19 incidence and severity in patients with relapsed/refractory lymphoma who have received CD3xCD20 bispecific antibodies. The COVID-19 attributable mortality after bispecific CD20xCD3 antibody therapy, when compared to CAR-T cell therapy, was much lower and comparable to the mortality reported in other cohorts of less heavily treated hematological malignancies infected with omicron variants. However, these patients present with considerable number of COVID-19 reactivations. In conclusion, it seems relatively safe to prescribe bispecific CD20xCD3 antibodies for lymphoma for patients who have been vaccinated for COVID-19 with the currently circulating virus variants.

Maintenance Ruxolitinib Is Associated with Low Rates of Chronic Gvhd Requiring Systemic Treatment in Older Adults with AML/MDS Undergoing Allogeneic HCT: Results of a Phase II Multicenter Trial

Introduction: Despite recent advances in graft-versus-host disease (GVHD) prophylaxis, novel approaches to effective prevention of chronic GVHD remain of utmost importance. This is particularly true for older transplant recipients,for whom high-dose cyclophosphamide or prolonged treatment with corticosteroids is challenging. Ruxolitinib, an oral selective inhibitor of JAK1/2, is FDA-approved for the treatment of refractory acute and chronic GVHD. However, the clinical efficacy of JAK inhibition in preventing severe chronic GVHD is not well characterized. Methods: In this prospective, multicenter phase II trial (NCT03286530), older adult subjects (age 60-80) with AML in CR1 or MDS undergoing RIC allogeneic HCT were enrolled. Transplants could be conducted from HLA-matched related donors or 7/8 or 8/8 HLA-matched unrelated donors. Transplants were required to use busulfan- or melphalan-based reduced intensity conditioning and peripheral blood stem cells. Standard GVHD prophylaxis consisted of tacrolimus and methotrexate (5-10 mg/m 2 on Days +1, +3, and +6 ± +11). Subjects were enrolled prior to transplant. Ruxolitinib therapy could begin between Day +30 and Day +100, after meeting pre-treatment criteria, which included: donor engraftment, ongoing remission confirmed by biopsy, adequate hematopoietic recovery (Hgb ≥8 g/dL, PLT ≥50K/uL), and the absence of progressive acute GVHD. Ruxolitinib was administered at 10 mg BID continuously in 28-day cycles (allowing for dose reductions due to drug interactions or cytopenias), for up to 24 cycles. The primary objective was to evaluate the GRFS at 1-year after HCT. Key secondary objectives included the cumulative incidence of chronic GVHD, acute GVHD, and relapse, as well as overall survival. Results: Seventy-eight subjects were enrolled, and 63 subjects received ruxolitinib on trial. The reasons for not initiating ruxolitinib were acute GVHD (n=4), physician discretion (n=3), disease relapse (n=2), low chimerism (n=2), death (n=2), primary graft failure (n=1), and subject withdrawal (n=1). In the treated subjects, the median age was 68 years (range, 61-79). Fifty-five (87.3%) subjects had AML and 8 (12.7%) had MDS. Transplants were performed from HLA-matched related (n=16, 25.4%) or unrelated (n=47, 74.6%) donors with either Fludarabine/Melphalan (n=34, 54%) or Fludarabine/Busulfan (n=29, 46%). The median start date of ruxolitinib after HCT was day 45 (range, 32-93). The median follow-up of survivors was 19 months (range, 3-64) at last cutoff (2/14/23). At the time of analysis, the median number of cycles on treatment is 14 (range, 1-24). 17 subjects remain on therapy; the reasons for discontinuation include completed treatment (n=21), disease relapse (n=13), adverse events (n=7), and physician discretion (n=5). The most common (severe grade ≥3) adverse events experienced while on ruxolitinib were neutropenia (n=18, 29% of subjects), thrombocytopenia (n=17, 27% of subjects), and anemia (n=16, 25% of subjects). Seven subjects experienced grade ≥3 infectious events; no fungal infections have occurred. In subjects receiving ruxolitinib, the 6-month cumulative incidence of Grade II-IV acute GVHD was 14% (95%CI, 7-24) and Grade III-IV acute GVHD was 4.8% (95%CI, 1.3-12), with three cases of grade II-IV GVHD occurring prior to initiation of ruxolitinib. While the 12-month incidence of all cases of chronic GVHD is 27% (95%CI, 17-39), the 12-month incidence of chronic GVHD requiring systemic therapy is 8.4% (95%CI, 3.1-17). The 18-month cumulative incidence of NRM is 5.6% (95%CI, 1.4-14); with only one death attributed to GVHD and one death due to infection (COVID-19), thus far. The 18-month cumulative incidence of disease relapse is 27% (95%CI, 16-39). The 12-month GRFS (primary endpoint) is 70% (95%CI, 56-80). The 18-month OS, PFS, and CRFS are 78% (95%CI, 64-88), 68% (95%CI, 53-78) and 64% (95%CI, 50-76), respectively ( Figure 1). Conclusion: Prolonged administration of ruxolitinib following allogeneic HCT is associated with low rates of chronic GVHD requiring systemic treatment. The incidence of relapse is comparable to historical rates, suggesting no compromise of GVL effect. Despite the anticipated cytopenias with therapy, most subjects were able to remain on treatment. The incorporation of JAK inhibition into GVHD prevention approaches warrants further investigation.

Hospitalization for Infection in Patients with Primary Autoimmune Hemolytic Anemia Treated with Rituximab. a Prospective, Nationwide Cohort Study in France

Introduction Autoimmune hemolytic anemia (AIHA) is a rare disease caused by the production of autoantibodies directed against red blood cells. Infections are frequent and severe in patients with primary AIHA. Rituximab is the reference second-line treatment for warm AIHA and the basis of the treatment of symptomatic cold agglutinin disease. However, the risk of infection after rituximab is not known in these patients with primary AIHA the real-world. Opportunistic infections had been described and the use of specific prophylaxis is debated. Consequently, this cohort study aimed to: (i) measure the incidence of hospitalization for infection after the exposure to rituximab in adult patients with primary AIHA; (ii) describe the types of these infections; (iii) measure the 30-day overall mortality after the first hospitalization for infection; (iv) determine the factors associated with hospitalization for infection; and (v) assess the effectiveness of pneumocystis prophylaxis. Methods Patients were selected from the AHEAD cohort (Autoimmune HEmolytic Anemia: a population-baseD study) between January 2012 and July 2018. This cohort consists in all adult patients with incident AIHA, selected in the French National Health Database. This database covers virtually the entire French population (67 million individuals). It links socio-demographic, outpatient, and hospitalization data. Patients with AIHA were identified using the International Classification of Diseases, tenth version (ICD-10) D59.1 code as hospital discharge or long-term disease diagnosis (the latter being coded by general practitioners). Incident cases were selected using a prior observation period of at least 2 years without the D59.1 diagnosis code. This code yielded a positive predictive value of 90.0% (95% CI: 79.5 to 96.2) in a previous validation study. We restricted the study population to adult patients exposed to rituximab. The first infusion of rituximab defined the index date. Patients with causes of secondary AIHA before the index date were excluded. We assessed the cumulative incidence of hospitalizations with a discharge diagnosis of infection during the six months after the index date (median duration of B-cell depletion). The overall mortality was measured during the 30 days after hospitalization for infection. We assessed the association of age, sex, comorbidities, red blood cell transfusions before the index date (as indicator of AIHA severity), exposure to corticosteroids, to other immunosuppressive drugs, splenectomy (time-varying exposures) as well as pneumococcal and influenza vaccinations before the index date on the occurrence of hospitalization for infection using Cox regression models. A sensitivity analysis was performed using Fine and Gray's models with death as competitive risk. Pneumocystis pneumonia was identified using the B48.5 and B59 discharge diagnosis codes. The association with specific prophylaxis was assessed. Results Between 2012 and 2018, we identified 959 adult patients with incident primary AIHA who received rituximab. The mean age was 67 years and 61% of the patients were women. The 6-month cumulative incidence of hospitalization with a discharge diagnosis of infection was 18.3% (95% CI: 15.9 to 20.9). The most frequently characterized infections were pulmonary, urogenital, and gastrointestinal. Opportunistic infections were observed in 28 (16.6%) patients. The 30-day overall mortality after the first hospitalization for infection was 12.5% (95% CI: 8.0 to 18.0). The risk factors associated with hospitalization for infection in multivariable analysis were an age ≥70 years (HR: 2.7; 95% CI: 1.6-4.6) and current exposure to corticosteroids (HR: 1.6; IC 95%: 1.2-2.2). The results of the sensitivity analysis were concordant. In total, 189 (19.7%) patients were exposed to pneumocystis prophylaxis and 14 pneumocystis pneumonia occurred. All cases occurred during the exposure to corticosteroids and in patients with no specific prophylaxis. All but 2 were aged ≥70 years. Conclusion The incidence of hospitalizations for infection and mortality after hospitalization for infection were high in adult patients with primary AIHA treated with rituximab. Opportunistic infections were not uncommon. Concomitant exposure to corticosteroids and an older age are the main risk factors for infection. Pneumocystis prophylaxis should be discussed for these patients.

Dacomitinib in EGFR-mutant non-small-cell lung cancer with brain metastasis: a single-arm, phase II study

Dacomitinib showed superior progression-free survival (PFS) and overall survival compared to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations in the ARCHER1050 study. However, because that study did not include patients with brain metastases, the efficacy of dacomitinib in patients with brain metastases has not been clarified. This single-arm phase II study enrolled 30 patients with treatment-naïve advanced NSCLC harboring activating EGFR mutations from January 2021 to June 2021 and started them on dacomitinib (45 mg/day). All patients had non-irradiated brain metastases with a diameter of ≥5 mm. The primary endpoint was confirmed intracranial objective response rate (iORR). Patients had exon 19 deletions (46.7%) and L858R mutations in exon 21 (55.3%). The confirmed iORR was 96.7% (29/30), with an intracranial complete response of 63.3%. Median intracranial PFS (iPFS) was not reached, with 12- and 18-month iPFS rates of 78.6% [95% confidence interval (CI) 64.8% to 95.4%] and 70.4% (95% CI 54.9% to 90.1%), respectively. In the competing risk analysis, the 12-month cumulative incidence of intracranial progression was 16.7%. Regarding the overall efficacy for intracranial and extracranial lesions, the overall ORR was 96.7%, and the median PFS was 17.5 months (95% CI 15.2 months-not reached). Grade 3 or higher treatment-related adverse events were reported in 16.7% of patients, and 83.3% required a reduced dacomitinib dose to manage adverse events. However, none permanently discontinued dacomitinib treatment due to treatment-related adverse events. Dacomitinib has outstanding intracranial efficacy in patients with EGFR-mutant NSCLC with brain metastases.