Survival Endpoints Research Articles

Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial

BackgroundZotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor thought to inhibit tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma. MethodsEORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design in IDH wild-type newly diagnosed glioblastoma or anaplastic astrocytoma. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), according to O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry. ResultsThe MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B). Two dose-limiting toxicities were observed at 150 mg: one in group A (grade 3 seizure), one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders and hepatotoxicity. PFS-6 in group C was 6.7%. CDK-9, c-MYC and MCL-1 were confirmed to be expressed and their expression was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival. ConclusionsTG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.

Baseline C-reactive protein predicts efficacy of the first-line immune checkpoint inhibitors plus chemotherapy in advanced lung squamous cell carcinoma: a retrospective, multicenter study

AimsTo investigate the predictive value of baseline C-reactive protein (CRP) levels on the efficacy of chemotherapy plus immune checkpoint inhibitors (ICI) in patients with advanced lung squamous cell carcinoma (LSCC).Materials and methodsIn this retrospective multicenter study spanning from January 2016 to December 2020, advanced LSCC patients initially treated with chemotherapy or a combination of chemotherapy and ICI were categorized into normal and elevated CRP subgroups. The relationship between CRP levels and treatment outcomes was analyzed using multivariate Cox proportional hazards models and multivariate logistic regression, focusing primarily on the progression-free survival (PFS) endpoint, and secondarily on overall survival (OS) and objective response rate (ORR) endpoints. Survival curves were generated using the Kaplan-Meier method, with the log-rank test used for comparison between groups.ResultsOf the 245 patients evaluated, the 105 who received a combination of chemotherapy and ICI with elevated baseline CRP levels exhibited a significant reduction in PFS (median 6.5 months vs. 11.8 months, HR, 1.78; 95% CI: 1.12–2.81; p = 0.013) compared to those with normal CRP levels. Elevated CRP was identified as an independent risk factor for poor PFS through multivariate-adjusted analysis. However, among the 140 patients receiving chemotherapy alone, baseline CRP levels did not significantly influence PFS. Furthermore, within the combination therapy group, there was a notable decrease in the ORR (51% vs. 71%, p = 0.035), coupled with a significantly shorter OS (median 20.9 months vs. 31.5 months, HR, 2.24; 95% CI: 1.13–4.44; p = 0.033).ConclusionIn patients with advanced LSCC, elevated baseline CRP levels were identified as an independent predictive factor for the efficacy of combination therapy with chemotherapy and ICI, but not in chemotherapy alone. This suggests that CRP may be a valuable biomarker for guiding treatment strategies.

Dose and gender dependence of chlorine inhalation in a conscious ovine model

Characterization of the pathophysiology of ARDS following chlorine gas inhalation in clinically relevant translational large animal models is essential, as the opportunity for clinical trials in this type of trauma is extremely limited. To investigate Cl2 concentration and gender-dependent ARDS severity. Sheep (n = 54) were exposed to air or Cl2 premixed in air at a concentration of 50, 100, 200, and 300 ppm for 30 min under anesthesia/analgesia and monitored for an additional 48 h in a conscious state. Cardiopulmonary variables and survival endpoints were compared between male and female sheep. Overall there were no significant differences in the responses of female and male sheep except pulmonary oxygenation tended to be better in the male sheep (300 ppm group), and the pulmonary arterial pressure was lower (200 ppm group). The onset of mild ARDS (200 < PaO2/FiO2 ≤ 300) was observed at 36 h post exposure in the 50 ppm group, whereas the 100 ppm group developed mild and moderate (100 ≤ PaO2/FiO2 ≤ 200) ARDS by 12 and 36 h after injury, respectively. The 200 ppm and 300 ppm groups developed moderate ARDS within 6 and 3 h after injury, respectively. The 300 ppm group progressed to severe (PaO2/FiO2 ≤ 100) ARDS at 18 h after injury. Increases in pPeak and pPlateau were noted in all injured animals. Compared to sham, inhalation of 200 ppm and 300 ppm Cl2 significantly increased lung extravascular water content. The thoracic cavity fluid accumulation dose-dependently increased with the severity of trauma as compared to sham. At necropsy, the lungs were red, heavy, solidified, and fluid filled; the injury severity grew with increasing Cl2 concentration. The severity of ARDS and mortality rate directly correlated to inhaled Cl2 concentrations. No significant sex-dependent differences were found in measured endpoint variables.

Effect of histological breast cancer subtypes invasive lobular versus non-special type on survival in early intermediate-to-high-risk breast carcinoma: results from the SUCCESS trials

BackgroundInvasive lobular breast carcinomas (ILC) have different histological features compared to non-special type carcinomas (NST), but the effect of histological subtypes on survival is controversial. In this study, we compared clinicopathological characteristics and outcomes between ILC and NST based on a large pooled data set from three adjuvant breast cancer trials (SUCCESS A, B, and C) and investigated a potential differential effect of recurrence risk related to nodal stage on survival.MethodsFrom 2005 to 2017, the large randomized controlled SUCCESS A, B, and C trials enrolled 8190 patients with primary, intermediate-to-high-risk breast carcinoma. All patients received adjuvant chemotherapy, and endocrine and/or HER2-targeted treatment was given where appropriate. Survival outcomes in terms of disease-free survival (DFS), overall survival (OS), breast cancer-specific survival (BCSS), and distant disease-free survival (DDFS) were estimated using the Kaplan–Meier method and analyzed using log-rank tests as well as univariable and adjusted multivariable Cox regression models.ResultsIn the SUCCESS trials, 6284 patients had NST and 952 had ILC. The median follow-up time was 64 months. ILC patients were older, more likely to receive mastectomy, and more likely to have larger tumor sizes, lymph node infiltration, hormone receptor-positive, HER2neu-negative, and luminal A-like tumors than NST patients. In the overall cohort, no significant differences between ILC and NST were detectable regarding the four survival endpoints, with hazard ratios obtained in adjusted multivariable cox regressions of 0.96 (95% CI 0.77–1.21, p = 0.743) for DFS, 1.13 (95% CI 0.85–1.50, p = 0.414) for OS, 1.21 (95% CI 0.89–1.66, p = 0.229) for BCSS, and 0.95 (95% CI 0.73–1.24, p = 0.689) for DDFS. However, a differential effect of nodal stage on survival was observed, with better survival for ILC patients with pN0/pN1 tumors and worse survival for ILC patients with pN2/pN3 tumors compared to NST patients.ConclusionsOur results revealed that ILC was associated with worse survival compared to NST for patients at high risk of recurrence due to advanced lymph node infiltration. These findings should be taken into account for treatment decisions and monitoring.

Sample size calculation for multi-arm parallel design with restricted mean survival time.

With the recent advances in oncology treatment, restricted mean survival time (RMST) is increasingly being used to replace the routine approach based on hazard ratios in randomized controlled trials for time-to-event outcomes. While RMST has been widely applied in single-arm and two-arm designs, challenges still exist in comparing RMST in multi-arm trials with three or more groups. In particular, it is unclear in the literature how to compare more than one intervention simultaneously or perform multiple testing based on RMST, and sample size determination is a major obstacle to its penetration to practice. In this paper, we propose a novel method of designing multi-arm clinical trials with right-censored survival endpoint based on RMST that can be applied in both phase II/III settings using a global test as well as a modeling-based multiple comparison procedure. The framework provides a closed-form sample size formula built upon a multi-arm global test and a sample size determination procedure based on multiple-comparison in the phase II dose-finding study. The proposed method enjoys strong robustness and flexibility as it requires less a priori set-up than conventional work, and obtains a smaller sample size while achieving the target power. In the assessment of sample size, we also incorporate practical considerations, including the presence of non-proportional hazards and staggered patient entry. We evaluate the validity of our method through simulation studies under various scenarios. Finally, we demonstrate the accuracy and stability of our method by implementing it in the design of two real clinical trial examples.

Event-free survival as a predictor of overall survival and recurrence burden of patients with non–small cell lung cancer receiving neoadjuvant therapy

ObjectivesEvent-free survival has replaced overall survival as a primary end point in many recent and ongoing clinical trials. This study aims to examine the correlation between real-world event-free survival and overall survival and to assess the clinical and economic burden associated with disease recurrence among patients with resected stage II to III non–small cell lung cancer who received neoadjuvant therapy in the United States. MethodsThis retrospective study used the Surveillance, Epidemiology, and End Results Medicare database (2007–2019) to identify patients with newly diagnosed, resected, stage II to IIIB (N2) non–small cell lung cancer who received neoadjuvant therapy. The correlation between real-world event-free survival and overall survival was assessed using the normal scores rank correlation and landmark analysis. Overall survival, all-cause health care resource use and costs, and non–small cell lung cancer–related health care resource use and costs were compared between patients with and without recurrence. ResultsA total of 221 patients met the eligibility criteria (median follow-up time from neoadjuvant treatment initiation: 32.7 months). The mean age was 72.1 years, and 57.0% of patients were male. Real-world, event-free survival and overall survival are positively and significantly correlated (0.68; 95% CI, 0.52-0.79). Patients with recurrence had significantly shorter median overall survival (19.3 vs 116.9 months), 4.59 times increased risk of death (95% CI, 2.56-8.26), and significantly higher all-cause and non–small cell lung cancer–related health care resource use and costs (adjusted mean monthly costs per patient difference: $5758 and $3187, respectively [all P < .001]). ConclusionsThese findings help validate event-free survival as a clinically meaningful end point and strong predictor for overall survival and highlight the need for additional novel therapies that may delay or prevent recurrence in resectable stage II and III non–small cell lung cancer.

Atezolizumab monotherapy versus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis from a randomised, controlled, phase 3 study

The primary analysis of IMvigor130 showed a significant progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial cancer. However, this finding did not translate into significant overall survival benefit for group A versus group C at the final analysis, precluding formal statistical testing of outcomes with atezolizumab monotherapy (group B) versus group C. Here we report the final overall survival results for group B versus group C; this report is descriptive and should be considered exploratory due to the study's statistical design. In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) who had locally advanced or metastatic urothelial cancer previously untreated in the metastatic setting and Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), using a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin score, and investigator's choice of platinum-based chemotherapy, to receive either atezolizumab plus platinum-based chemotherapy (group A), atezolizumab alone (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo in group A and group C; atezolizumab monotherapy in group B was open label. For groups B and C, atezolizumab (1200 mg) or placebo was administered intravenously every 3 weeks. Chemotherapy involved 21-day cycles of gemcitabine (1000 mg/m2 body surface area on day 1 and day 8 of each cycle) plus the investigator's choice of carboplatin (area under the curve 4·5 mg/mL per min or 5 mg/mL per min) or cisplatin (70 mg/m2 body surface area), administered intravenously. Co-primary endpoints were progression-free survival and overall survival in group A versus group C, and overall survival in group B versus group C, tested hierarchically, in the intention-to-treat (ITT) population, and then the populations with high PD-L1 tumour expression (immune cell [IC] expression score of IC2/3) if the results from group A versus group C were significant. Here, we report the co-primary endpoint of overall survival for group B versus group C in the ITT and IC2/3 populations. The ITT population for this analysis comprised concurrently enrolled patients in groups B and C who were randomly assigned to treatment. For the safety analysis, all patients enrolled in group B and group C who received any study treatment were included. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting. Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 362 patients were assigned to group B and 400 to group C, of whom 360 and 359, respectively, were enrolled concurrently (ITT population). 543 (76%) of 719 patients were male, 176 (24%) were female, and 534 (74%) were White. As of data cutoff (Aug 31, 2022), after a median follow-up of 13·4 months (IQR 6·2-30·8), median overall survival was 15·2 months (95% CI 13·1-17·7; 271 deaths) in group B and 13·3 months (11·9-15·6; 275 deaths) in group C (stratified hazard ratio 0·98 [95% CI 0·82-1·16]). The most common grade 3-4 treatment-related adverse events were anaemia (two [1%] in patients who received atezolizumab monotherapy vs 133 [34%] in those who received placebo plus chemotherapy), neutropenia (one [<1%] vs 115 [30%]), decreased neutrophil count (0 vs 95 [24%]), and decreased platelet count (one [<1%] vs 92 [24%]). Serious adverse events occurred in 163 (46%) patients versus 196 (50%). Treatment-related deaths occurred in three (1%; n=1 each, pneumonia, interstitial lung disease, large intestinal obstruction) patients who received atezolizumab monotherapy and four (1%; n=1 each, diarrhoea, febrile neutropenia, unexplained death, toxic hepatitis) who received placebo plus chemotherapy. The final analysis from IMvigor130 did not show a significant improvement in overall survival with first-line atezolizumab monotherapy compared with platinum-based chemotherapy in the intention-to-treat population. The safety profile of atezolizumab monotherapy remained acceptable after extended follow-up, with no new safety signals. F Hoffmann-La Roche.

Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration-resistant prostate cancer

Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC. Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS was defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R2 ≥ 0.7 defined a priori as clinically relevant. A total of 15 164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. The median follow-up was 8.3 years and the median postmetastasis survival was 3.1 years in ICECaP-2, compared with 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient level, and R2 from weighted linear regression (WLR) of 8-year OS on 5-year MFS was 0.73 (95% confidence interval 0.53-0.82) at the trial level. For condition 2, R2 was 0.83 (95% confidence interval 0.64-0.89) from WLR of log[hazard ratio (HR)]-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81. MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa.

Plasma cell-free RNA PD-L1 or tissue PD-L1 protein expression and outcomes with first-line immunotherapy in metastatic non-small cell lung cancer

BackgroundTissue programmed death ligand-1 (PD-L1) protein expression is associated with immune checkpoint inhibitor (ICI) treatment benefit in metastatic non-small cell lung cancer (NSCLC). However, tissue PD-L1 protein testing is limited by sampling tumor heterogeneity and fraught with tissue acquisition difficulties. A liquid biopsy-based PD-L1 assay could overcome these limitations of tissue PD-L1 testing. MethodsAn observational cohort of patients with metastatic NSCLC treated with first-line ICI-based therapies were retrospectively assessed for a pre-planned endpoint of median and 3-year landmark overall survival (OS) based upon plasma cell-free RNA (cfRNA) PD-L1 expression by a commercial exosome-free real-time qPCR assay or tissue PD-L1 protein expression (Dako 22C3) performed in CLIA/CAP accredited laboratories. Results53 contemporaneous patients in 3 patient cohorts were compared with a median follow-up 34 months. 16 patients were cfRNA plasma PD-L1 positive, including 6 (37 %) tissue PD-L1 negative or tissue quantity not sufficient for testing; 16 were plasma PD-L1 negative but tissue PD-L1 positive; 21 were both plasma and tissue PD-L1 negative. OS was identical whether positive plasma cfRNA PD-L1 expression or positive tissue PD-L1 protein expression (median OS 15 months; 3-year landmark OS 30 %; hazard ratio (HR) 0.97; 95 % CI, 0.44–2.10; p-value = 0.93). Within the positive plasma PD-L1 cohort there was no differing OS whether tissue PD-L1 positive, negative, or unknown (median OS 15 months; 3-year landmark OS 30 %; HR 1.15; 95 % CI, 0.322–4.05; p-value = 0.81). Positive plasma cfRNA expression was associated with a numerically longer median and higher 3-year OS compared to patients lacking PD-L1 expression (median 15 months versus 8 months; 3-year landmark OS 30 % versus 15 %; HR 0.57, 95 % CI 0.26–1.20; p-value = 0.11). ConclusionsIn this retrospective study of real-world metastatic NSCLC patients, plasma cfRNA PD-L1 expression was similarly predictive of ICI benefit as tissue PD-L1 protein expression.

29P The impact of body mass index on survival endpoints among patients with metastatic urothelial carcinoma undergoing treatment with immune checkpoint inhibitors: A real-world multicenter analysis

29P The impact of body mass index on survival endpoints among patients with metastatic urothelial carcinoma undergoing treatment with immune checkpoint inhibitors: A real-world multicenter analysis

CO56 Radiographic Progression Free Survival as a Surrogate Endpoint for Overall Survival Among Men With Metastatic Castration-Resistant Prostate Cancer

CO56 Radiographic Progression Free Survival as a Surrogate Endpoint for Overall Survival Among Men With Metastatic Castration-Resistant Prostate Cancer

Similar Efficacy Observed for First-Line Immunotherapy in Racial/Ethnic Minority Patients With Metastatic NSCLC.

Limited data exist on the impact of immunotherapy use in ethnic minority patients with non-small cell lung cancer (NSCLC), because they have been underrepresented in immunotherapy trials. This study aims to evaluate race/ethnicity and other demographic, socioeconomic, and clinical factors of patients with metastatic NSCLC treated with first-line immunotherapy. A retrospective cohort study of 5,920 patients diagnosed with lung cancer treated at Montefiore Einstein Cancer Center from January 1, 2013, to June 1, 2022, was used to identify patients with metastatic NSCLC without EGFR, ALK, or ROS1 alterations who underwent first-line immunotherapy (n=248). The primary endpoint was overall survival (OS), with secondary endpoints of progression-free survival (PFS) and time to discontinuation (TTD) from the start of immunotherapy. Among the 248 patients, median follow-up time was 12.0 months, median age at start of treatment was 66 years, and 39.1% were non-Hispanic Black, 30.2% were Hispanic, and 30.7% were non-Hispanic White. OS (P=.39), PFS (P=.29), and TTD (P=.98) were similar among racial/ethnic groups. Patients with an ECOG performance status (PS) of <2 at the start of immunotherapy had longer OS compared with those with ECOG PS of ≥2 (P<.0001). PD-L1 expression (<50% vs ≥50%; P=.03) and body mass index (BMI) (P=.01) were also found to be associated with PFS, and ECOG PS (P<.0001) and BMI (P=.02) were associated with TTD. In a multivariate analysis of OS and PFS, ECOG PS was the only variable found to be significant. Our study observed similar benefits of immunotherapy in patients with metastatic NSCLC in different racial and ethnic groups. Furthermore, ECOG PS was associated with OS, and PD-L1 expression and BMI were associated with PFS and TTD. These findings help identify potential factors associated with outcomes and care while patients are undergoing immunotherapy.

CO54 Recurrence-Free Survival (RFS) as a Surrogate Endpoint (SE) for Overall Survival (OS) in Resected Stage II/III Melanoma: A Correlation Meta-Analysis of Randomized Controlled Trials (RCTs)

CO54 Recurrence-Free Survival (RFS) as a Surrogate Endpoint (SE) for Overall Survival (OS) in Resected Stage II/III Melanoma: A Correlation Meta-Analysis of Randomized Controlled Trials (RCTs)

Compared to Venetoclax Plus Hypomethylating Agents, High Dose Cytarabine Based Intensive Chemotherapy Induction for Newly Diagnosed Acute Myeloid Leukemia (AML) Leads to a Faster Remission Resulting in Better Survival

Hypomethylating agents plus venetoclax is a commonly used induction regimen for newly diagnosed AML patients who are not eligible for standard intensive chemotherapy (IC). Due to the high remission rates and the easier administration of Venetoclax plus hypomethylating agents in the outpatient settings and community practices, some patients receive such induction even if IC eligible. We retrospectively analyzed 206 newly diagnosed AML patients, age 56-80 years who received either Venetoclax plus hypomethylating agents (n=65) or high dose cytarabine based IC ( n=141) to assess the difference in remission rates, time to achieve remission and the impact of time to achieving remission on survival endpoints. Patients who received IC ( FLAG or CLAG +/- Idarubicin) were younger ( median age 66 (56,79) vs 73(56,79) years, p&amp;lt;0.001) but had similar race distribution, NCCN cytogenetics risk and distribution of primary versus secondary leukemia compared to patients with hypomethylating agents plus venetoclax. Patients who received IC has similar chance of achieving CR (89% vs 71%, p=0.89) and transplant rate compared to venetoclax/hypomethylating agents. Patients who received IC had better DFS (p=0.026), a trend towards better OS (p=0.06) and similar relapse risk (p=0.69) compared to venetoclax/hypomethylating agents (figure 1). In a logistic regression analysis, patients who received IC and patients with favorable/intermediate risk AML had higher likelihood of achieving CR in the first 60 days post induction ( HR 2.34, 95% CI 1.19-4.61; P=0.01 for IC versus Venetoclax/hypometh; and HR 0.24 , 95% CI 0.12-0.49, P&amp;lt;0.001 for NCCN adverse versus favorable/intermediate risk AML). A cox model for survival endpoints where age was factored into three equal size groups (56-63, 64-70 and 71-79) and NCCN risk fitted as strata, was performed on survival endpoints. Achieving CR1 within 60 days of induction treatment had significant impact on overall survival (HR 0.24, 95% CI 0.13-0.46, p&amp;lt;0.001). Our data shows that among patients aged 55-80 years with newly diagnosed AML, receiving high dose cytarabine based IC have similar rates but more likely to achieve CR within 60 days than venetoclax plus hypomethylating agents. Achieving CR within 60 days of induction is a predictor of better overall survival. Based on our analysis, high dose cytarabine based IC should remain the preferred choice for patients eligible for such treatment.

Association and Significance of Allostatic Load with Outcomes of Patients with Chronic Myeloid Leukemia (CML)

Introduction: Chronic psychosocial stress has been linked to cancer development and progression. Allostatic load (AL) has been proposed as a novel approach to measure the biological consequence of cumulative stress seeking to explain health disparities. As a multidimensional framework, AL delineates functioning across several physiologic networks including neuroendocrine, cardiovascular, metabolic, and inflammatory systems. Emerging evidence highlights the association between AL and cancer risk, yet little is known about its relevance in hematologic malignancies and its impact on treatment outcomes. Aim: To assess the influence of AL on the outcomes of CML patients (pts). Methods: We performed a retrospective analysis of a cohort of CML pts assessing sociodemographic, clinical, laboratory, and molecular data from 2003 to 2023. The AL was obtained from 23 biomarkers (peripheral pulse, systolic &amp; diastolic blood pressure, hemoglobin, red &amp; white blood cells, platelets, Na, K, Cl, CO2, Ca, urea, creatinine, glucose, total protein, albumin, AST, ALT, ALk, total bilirubin, body mass index, and estimated glomerular filtration rate). We calculated an AL index by summing the number of biomarkers that were out of normal range and categorizing the AL score as low (˂3) or high (≥3). The outcomes of interest were molecular response (MMR, MR 4, MR 4.5) and survival endpoints (freedom-free [FFS], event-free [EFS], transformation-free [TFS], and overall [OS]). Results: We included 132 CML pts; median age at diagnosis was 62 years (IQR, 46-72.5 years). Most pts were women (61.4%), more likely to identify as white (69.2%), then black (23.3%), and had multiple comorbidities (Median, Charlson Comorbidity Index 4, IQR 2-6). Reported healthy behaviors included regular exercise (76.8%), never smoking (64.8%), and not having history of substance abuse (85.4%). The mean AL index was 5.11 with 84.8% of pts allocated to high AL score (15.2% low). High AL was correlated with black race (OR= 3.527, CI 0.77-16.17), men (OR=1.73, CI 0.66-4.51), alcohol consumption (OR=0.55, CI 0.18-1.64), tobacco use (OR=0.48, CI 0.17-1.32), and substance abuse (OR=0.33, CI 0.093-1.17). AL was also associated with Social Determinants of Health, including living in metropolitan areas (OR=0.37, CI 0.10-1.318) or alone (OR=1.67, CI .46-6.23), and employment (OR=0.4, CI 0.1-1.3). Notably, pts with high AL presented a statistically significant lower probability of MMR (HR= 0.56, CI 0.31-0.98), and worse FFS (HR=2.76, CI 1.17-6.50). There was also a for pts with high AL not achieving MR4 (OR= 0.44, CI 0.17-1.15) or MR4.5 (OR=0.48, CI 0.18-1.28), having TKI failure (OR= 2.39, CI 0.90-6.34), transformation to accelerated or blast phase (OR=3.13, CI 0.39-25.06), and worse EFS (HR 1.15, CI 0.59-2.26) (illustrated in the figure). Conclusion: Pts with CML who have a high AL index showed an association with unfavorable treatment outcomes and deep molecular responses. AL, as a measurement of chronic stress, shows a potential ability to elucidate racial and socioeconomic disparities and predict molecular and clinical responses. Assessing AL through multiple time points could uncover help identify modifiable risk factors that could potential help improve outcomes.

A Phase I Study of Ruxolitinib in Combination with Abemaciclib for Patients with Primary or Post-Polycythemia Vera/Essential Thrombocythemia Myelofibrosis

Background and Significance: Patients (pts) with primary or secondary myelofibrosis (MF) experience variable degrees of constitutional symptoms, cytopenias and risk of progression to acute myeloid leukemia leading to a reduced life-expectancy compared to age-matched controls. Although several oral Janus Kinase (JAK) inhibitors such as ruxolitinib (RUX) have been approved by the US FDA based on improvements in symptom burden and spleen volume compared to physician's choice of best available therapy, the duration of response to these agents is generally time-limited and treatment with JAK inhibitors is not considered to have disease-modifying potential. Furthermore, the median overall survival after RUX discontinuation is only 11-14 months highlighting the need for novel mechanism-based therapies for pts with disease progression on RUX. JAK2 V617F mutations promote transition from the G1 to S-phase of the cell cycle via increased expression of CDC25A, which is also upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D have also been implicated in MF pathogenesis and contribute to myeloproliferation. Finally, we and others have shown synergistic effects of the combination of CDK4/6 inhibitors and RUX in murine models of MF (Rampal et al., CCR 2021) including improvement in bone marrow fibrosis suggesting the potential for disease-modifying activity. Several CDK4/6 inhibitors have been approved by the US FDA for the treatment of hormone receptor-positive metastatic breast cancer establishing a robust record of safety data. These preclinical data and known safety profile of CDK4/6 and RUX as single agents, provide rationale for combining CDK4/6 and JAK inhibition in pts with MF. Methods: This multicenter, phase I dose-escalation trial (NCT05714072) evaluates the safety of RUX + the CDK4/6 inhibitor abemaciclib in primary or secondary MF pts with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to RUX. Inadequate response to RUX is defined by (I) palpable splenomegaly ≥5 cm below the left costal margin at study entry AND/OR (II) active MPN symptoms, as defined by the presence of one symptom score ≥5 or two symptom scores ≥3 using the screening MPN-SAF TSS. Pts must have been on a stable dose of 10 mg or 15 mg BID of RUX for at least 4 weeks prior to enrollment with adequate platelet (≥75 x 10 9/L) and neutrophil counts (≥1.5 x 10 9/L). Key exclusion criteria include prior treatment with a CDK4/6 inhibitor, accelerated- or blast-phase MPN, platelet count &amp;lt;50 x 10 9/L in the 4 weeks before screening or platelet transfusion(s) within 8 weeks before screening, and absolute neutrophil count &amp;lt;0.5 x 10 9/L in the 4 weeks before screening. Among the currently FDA-approved CDK4/6 inhibitors, abemaciclib was chosen for combination therapy due to less myelosuppressive effects compared with other CDK4/6 inhibitors. This trial uses a conventional “3+3” dose-escalation design ( Figure), pts will be treated with increasing doses of abemaciclib added to a stable dose of RUX (10 mg or 15 mg BID). The pre-study dose of RUX will be maintained to determine the maximum tolerated dose of the combination of RUX and abemaciclib. The primary endpoint is to determine the maximum tolerated dose of RUX + abemaciclib. Secondary endpoints include measures of efficacy such as overall response rate, duration of response and survival endpoints. Exploratory endpoints include changes in allele fraction of driver mutations, gene expression profiling, and clonal architecture to identify biomarkers of response, mechanisms of resistance, and to assess for any disease-modifying effects of the combination therapy. At this time, 2 pts have been enrolled at dose level 0 without any dose-limiting toxicities observed. In line with the known adverse event profile of abemaciclib, grade 1 diarrhea occurred in one patient. One patient developed grade 3 neutropenia which promptly resolved with holding abemaciclib. No unexpected safety signal was noted and enrollment continues. This trial is open to enrollment at Memorial Sloan Kettering Cancer Center and will commence at MD Anderson Cancer Center later this year.

A Single Center Experience with Using Dose-Adjusted Repoch in Elderly Patients with Large B-Cell Lymphoma

Background: RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) has been the predominant regimen for treatment of aggressive large B-cell lymphomas (LBCL). In the CALGB 50303 trial, REPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) was associated with similar efficacy but increased toxicity compared to RCHOP, however pts with higher risk disease by International Prognostic Index (IPI) had longer progression-free survival (PFS) with REPOCH therapy in the subgroup analysis ( J Clin Oncol, 2019). Providers may be hesitant to use REPOCH therapy in older, frail patients (pts) with high-risk LBCL due to concern for increased toxicity. One study demonstrated that empirically dose-reduced REPOCH (30-50% dose reduction by age group) was effective and well-tolerated in an elderly population ( Ann Hematol, 2018).A separate study showed significantly reduced neuropathy rates without compromised efficacy when vincristine doses in the REPOCH regimen were capped at 0.5 mg/d compared to 0.4 mg/m 2/d ( Leukemia &amp; Lymphoma, 2019). At our institution, vincristine doses are capped at 0.4 mg/d for all pts, and REPOCH dosing is not empirically dose-reduced based for age alone. The aim of this study is to provide additional insights on the safety and efficacy of REPOCH in elderly pts diagnosed with LBCL with a routine vincristine dose cap of 0.4 mg/day (“REPOCH 0.4”). Methods: In this single cohort study, pts with newly diagnosed LBCL that received dose-adjusted REPOCH 0.4 at a single institution from August 2015 to October 2020 were retrospectively reviewed. Pts were excluded if they received fewer than 2 cycles, had CNS disease, transferred to another facility during treatment, or were lost-to-follow-up. Primary endpoints included adverse effects (AEs), overall response rates (ORR) via Lugano staging at end of treatment, 2y PFS, and overall survival (OS). Survival endpoints were estimated via Kaplan-Meier survival analysis. Secondary endpoints included CNS relapse rates and percentage of pts electing for hospice during therapy. Outcomes were descriptively compared to the historical cohort (N=241) in the CALGB 50303 trial receiving R-REPOCH without a vincristine dose cap ( J Clin Oncol, 2019) . Results: Forty-six pts were eligible for analysis (“entire cohort”), 19 of whom were 70 years or older (“70+ cohort”, figure 1). Median age in the entire and 70+ cohort was 67 and 75 years respectively. In the entire cohort, 23.9% of pts were double-hit, 43.5% had a non-germinal center phenotype, and 78.3% had stage III-IV disease. The median number of REPOCH 0.4 cycles received in both the entire and 70+ cohort was 6. In the 70+ cohort, 57.9% of pts were escalated to a dose level (DL) of 2 or 3 with no pts escalated beyond DL 3. Fifty-eight percent of pts in the entire cohort received intrathecal CNS prophylaxis and all pts received pegfilgrastim support. Pts in the entire cohort were older and higher-risk in comparison to the historical cohort as evidenced by IPI risk and double-expressor status. In the entire cohort, REPOCH 0.4 was well-tolerated (figure 2) with grade 3+ neuropathy rates of only 2.2% (5.2% in the 70+ cohort). Febrile neutropenia (all grades) occurred in 19.5% and 15.8% of the entire cohort and 70+ cohort respectively. Only 1 patient in the 70+ cohort experienced acute ejection fraction (EF) decline during therapy. ORR (complete and partial response) in the entire and 70+ cohort were 80% and 74% respectively. Complete response (CR) rates in the entire and 70+ cohort were both 63%. 2y PFS in the entire cohort was 68.3% (median not reached), and the 2y OS in the entire cohort was 82.9% (median not reached) which compares favorably to the 2y OS of 86.5% in the historical cohort. Overall, only 7% of pts elected for hospice and only 4% experienced CNS relapse. Conclusion: Pts with LBCL 70+ years tolerated dose-adjusted REPOCH 0.4 mg/d similarly to the entire cohort of all ages indicating that empiric dose reduction for age alone isn't necessary. CR rates were similar (63%) with pts 70+ years compared to pts in the entire cohort of all ages. REPOCH 0.4 mg/d was observed to have numerically lower rates of grade 3 or higher neuropathy (2.2%) compared to vincristine 0.4 mg/m 2/d (8.4%, J Clin Oncol 2019) and vincristine 0.5 mg/d dosing strategies (4.5%, Leukemia &amp; Lymphoma 2019) . To our knowledge, this is the first report of outcomes with REPOCH using a vincristine dose cap of 0.4 mg/d.

Azacitidine, Venetoclax and Allogeneic NK Cells in Newly Diagnosed Acute Myeloid Leukemia (ADVENT-AML): An Investigator-Initiated Multicenter Phase Ib Trial

BACKGROUND AND SIGNIFICANCE : Older/unfit patients with acute myeloid leukemia (AML) have limited treatment options. Outcomes in adverse-risk subgroups of AML are modest with CR/CRi rates of 45% to 60% and median overall survival (OS) of 5 to 12 months with current standard frontline therapy of hypomethylating agent with venetoclax (HMA-VEN).While allogeneic stem cell transplantation (allo-SCT) can significantly improve OS in AML, only 10 to 20% of older pts are able to undergo allo-SCT (Pratz et al. Blood 2019, Maiti et al. Blood 2022) Natural killer (NK) cells bridge the innate and adaptive immune system and play a major role in graft-vs-leukemia (GVL) effect responsible for the clinical benefit noted with allo-SCT. NK cell-based adoptive cellular therapies have shown good safety profiles and promising activity in AML with responses noted in 25% to 88% of patients. Furthermore, NK cells are less likely to induce graft-versus-host disease (GVHD), severe cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). We hypothesize that the combination of azacitidine, venetoclax and allogeneic NK cells will be safe and improve cure rates in AML compared to either Aza/Ven or NK cells alone. Improved clinical activity may be mediated through multiple synergistic mechanisms including reduction of disease burden by Aza/Ven, upregulation of epigenetically silenced NKG2D ligands, dual activation of extrinsic and intrinsic apoptotic cascades, mitochondrial priming of leukemia cells by venetoclax, and bypassing significant morbidity and mortality associated allo-SCT. Significance: This will be the first trial to evaluate 1) cellular therapy in the frontline setting in AML; 2) the synergy of venetoclax with adoptive NK cell therapy; and 3) Aza/Ven as a lymphodepletion strategy. The results will have significant impact on the development of cellular therapies for hematological and solid tumors. STUDY DESIGN AND METHODS: This investigator-initiated, multicenter, open-label, phase Ib study will evaluate the combination of azacitidine, venetoclax and ex vivo-expanded, off-the-shelf cryopreserved allogeneic NK cells in patients with AML (NCT05834244). Eligibility criteria: The dose escalation phase will enroll adults with relapsed or refractory AML or MDS/AML, and the dose expansion phase will enroll older/unfit pts with newly diagnosed adverse-risk AML. Eligible Pts will be ≥ 75 years, or ≥ 18 years with at least one protocol-defined comorbidity. Patients with favorable risk AML, poor end-organ function, needing immunosuppression, uncontrolled infection or CNS leukemia will be excluded. Trial design: The dose escalation phase will enroll a maximum of 12 patients at 2 dose levels to establish a recommended phase 2 dose (RP2D) using a BOIN design. The dose expansion will enroll up to 20 patients at the RP2D ( Fig. 1). Study treatment: Patients will receive Aza/Ven as standard. Two dose levels of NK cells including 0.5 x10 9 and 1 x10 9 flat dose on day 8 and 15 of the first 4 cycles will be evaluated. Subsequently, pts will continue Aza/Ven indefinitely. Objectives: The primary objective is to determine the safety of this novel triplet combination in terms of dose-limiting toxicities including acute GVHD, CRS or ICANS. Secondary objectives include overall response rate, CR/CRi by 4 cycles, rate of negative measurable residual disease, OS and relapse-free survival. Exploratory objectives include additional response and survival endpoints, the persistence of NK cells using SNP-NGS chimerism, kinetics of allorejection, remodeling of host immune microenvironment and impact on AML stem/progenitor cell hierarchies using single cell CyTOF to understand response/resistance mechanisms. Status: Trial approved by the FDA and institutional IRB. Activation planned for 2H 2023. Funding: Gateway for Cancer Research, MDACC PRIME Award, Chimeric Therapeutics, NCI Cancer Center Support Grant.

Patient-Reported Outcomes of BMT CTN 1703: A Randomized Phase III Study for Gvhd Prophylaxis - a Quality of Life Evaluation

Introduction A randomized phase III trial of post-transplantation cyclophosphamide (PTCy), tacrolimus, (Tac), and mycophenolate mofetil (MMF) versus tacrolimus/methotrexate (Tac/MTX) for graft-versus-host disease (GVHD) prophylaxis showed superior graft-versus-host disease-free, relapse-free survival (GRFS) in the PTCy-containing arm (NEJM, 2023). Here, we report the effect of GVHD prophylaxis on patient-reported outcomes and impact on quality of life (QOL). Methods The QOL study component of BMT CTN 1703 employed four primary endpoints: Lee Chronic GVHD Symptom Score and the PROMIS subscales of physical function, gastrointestinal symptoms, and satisfaction with participation in social roles. Secondary endpoints included hemorrhagic cystitis symptoms and Lee symptom subscale differences, with questionnaires to English and Spanish-speaking participants at enrollment and on Days 100, 180, and 365 post-transplant. Given the risk of missing assessments, an inverse probability weighted-independent estimating equations (IPW-IEE) model was applied for score comparison between arms, adjusting for baseline score, assessment time, age, donor type, disease risk index (DRI), planned conditioning regimen, and planned use of post-transplant maintenance therapy. Significance was declared at a 1.25% level for score comparisons between arms after Bonferroni correction for multiple testing. The analysis approach classified patients according to the intention-to-treat principle. Results QOL survey completion rates for patients at each timepoint were similar, exceeding 70% in each study arm. With the Lee Chronic GVHD Symptom Scale, higher scores indicate more severe symptoms. The IPW-IEE models indicated that the Lee Chronic GVHD Symptom Scale total scores were significantly lower in the PTCy arm compared to Tac/MTX at day 100 (mean difference [MD] -2.22, 99% confidence interval [CI] -5.05 to 0.61) and day 365 (MD -1.84, 99% CI -5.13 to 1.45, p=0.01 for overall treatment effect across all timepoints, Figure 1). Nutrition subscores were significantly better with PTCy at day 100 (MD -2.41, 99% CI -5.06 to 0.24, p=0.0014). Mouth scores were significantly better in the PTCy arm at day 365 (MD -7.09, 99% CI -13.21 to -0.98, p=0.0035). Patients over 65 years of age had better psychological subscores across the study population (MD -4.80, 99% CI -8.91 to -0.69, p=0.0026); no interaction was found between age and study treatment. Patient-reported hemorrhagic cystitis symptoms showed no significant difference between the study arms at any post-transplant time point. There was no significant treatment effect observed on the 3 PROMIS subscales. Across the entire study population, both relapse and acute GVHD were associated with worse scores on the Lee Symptom Scale, and PROMIS physical function, gastrointestinal symptoms, and social functions subscales. Chronic GVHD was associated with worse scores on the Lee Symptom Scale only, not the PROMIS subscales. No associations were found between patient-reported QOL at baseline and 1-year GRFS, disease-free survival, or overall survival. Conclusions The PTCy arm of BMT CTN 1703 showed superior GRFS, and this study confirms better patient-reported outcomes with PTCy. Patients who received PTCy showed better nutrition and mouth subscores on the Lee Chronic GVHD Symptom Scale compared to those who received Tac/MTX, possibly due to lower observed rates of severe acute and chronic GVHD in the PTCy arm. No association was found between patient-reported baseline quality of life and survival endpoints, suggesting the necessity of further research to elucidate the interplay of treatment strategies, patient factors, and their impact on long-term outcomes.

A Matching-Adjusted Indirect Comparison of the Efficacy of Elranatamab Versus Physician's Choice of Treatment in Patients with Triple-Class Exposed/Refractory Multiple Myeloma

BACKGROUND For patients with triple-class exposed/refractory multiple myeloma (TCE/R MM), prognosis is poor and limited effective treatment options are available. Elranatamab is a novel B-cell maturation antigen (BCMA)- and CD3-directed bispecific antibody that demonstrated safety and efficacy in patients with TCE/R MM in the phase 2, single-arm MagnetisMM-3 trial (NCT04649359). To compare the effectiveness of elranatamab vs physician's choice of treatment (PCT) in the absence of comparative data, an unanchored matching-adjusted indirect comparison (MAIC) was conducted. METHODS Individual patient data (IPD) from the 14.7-month follow-up of MagnetisMM-3 (Cohort A [BCMA-naïve] N=123) was matched to published summary data from two real-world studies of PCT: LocoMMotion ([NCT04035226]), an ongoing, prospective, non-interventional study of PCT in patients with TCE MM (N=248); and MAMMOTH, a multicenter, retrospective study investigating the history and outcomes of patients with TCE MM who received subsequent therapies (N=177). To adjust for differences in baseline characteristics, patients from MagnetisMM-3 were reweighted to match those in LocoMMotion reported in Mateos et al (2022) and MAMMOTH reported in Bal et al (2022). The base-case adjustment variables were selected based on univariate Cox regressions using the MagnetisMM-3 IPD, a systematic literature review of prognostic variables and effect modifiers in RRMM, a review of the prognostic variables identified in clinical studies for TCE/R MM, a review of the recent analogous indirect comparisons, and confirmation by clinical experts. Weights were determined using a propensity score-type logistic regression via the method of moments (Signorovitch et al. 2012) based on age, median time since diagnosis, International Staging System disease stage, high-risk cytogenetics, extramedullary disease, number of prior lines of therapy, Eastern Cooperative Oncology Group performance status, creatinine clearance, and penta-exposed and penta-refractory status (where available). In the analysis for the endpoint of overall survival (OS), sex was also included in the analysis. A sensitivity analysis was conducted in which missing values of the adjusted baseline characteristics for elranatamab were imputed by a random sample of the observations in MagnetisMM-3 to potentially increase the effective sample size (ESS). Unanchored MAIC analyses used the R Studio statistical code provided in the National Institute for Health and Care Excellence Decision Support Unit 18 by Phillippo et al (2016) . In the MAIC vs LocoMMotion &amp; MAMMOTH, adjusted objective response rate (ORR), complete response rate or better (≥CR), progression-free survival (PFS), and OS at 15 months for elranatamab were compared with PCT. Results were reported as rate differences, which is the difference between the ORR or ≥CR rates of elranatamab and PCT, and odds ratios (ORs) for binary endpoints and hazard ratios (HRs) for time-to-event endpoints, with two-sided 95% confidence intervals (CIs). RESULTS In the MAIC for elranatamab vs PCT in LocoMMotion, the post-matching ESS was 68 for all endpoints in the base case. Compared with PCT in LocoMMotion, elranatamab was associated with a significantly higher ORR (rate difference: 37.52; 95% CI 26.20-48.83; OR: 4.85; 95% CI 2.85-8.23), higher ≥CR (rate difference: 42.29; 95% CI 31.84-52.74; OR: 184.01; 95% CI 24.66-1372.86), and longer PFS (HR 0.32; 95% CI 0.20-0.49) and OS (HR 0.62; 95% CI 0.40-0.94) (Table 1). In the MAIC vs PCT in MAMMOTH, the base-case post-matching ESSs were 100 for all endpoints. Compared with PCT in MAMMOTH, elranatamab was associated with a significantly higher ORR (rate difference: 28.14; 95% CI 16.77-39.52; OR: 3.24; 95% CI 1.98-5.32) and ≥CR (rate difference: 26.22; 95% CI 16.40-36.05; OR: 5.48; 95% CI 2.88-10.44). Elranatamab also had longer PFS (HR 0.25; 95% CI 0.17-0.37) and OS (HR 0.49; 95% CI 0.33-0.71) than PCT (Table 2). Sensitivity analysis results were consistent with the base case. CONCLUSIONS In this MAIC, elranatamab demonstrated significantly higher ORR, higher ≥CR rate, longer PFS, and longer OS compared with PCT in the real-world. These results suggest that elranatamab offers significantly improved outcomes versus standard treatments used in patients with TCE/R MM in clinical practice.