Yates, Samuel J.

Hematologic malignancies, including leukemias, lymphomas, and multiple myeloma, are diseases of older adults (age ≥ 60 years). Treatment decisions in older adults with cancer are heavily influenced by patient fitness: the ability of an individual patient to tolerate the off-target effects of anti-cancer therapy. Sarcopenia, defined as low muscle mass and strength, is increasingly recognized as an important marker of fitness. Furthermore, sarcopenia is known to be modifiable with nutrition and exercise interventions in older adults without cancer, but such evidence is limited for patients with cancer. Much of the literature on sarcopenia in older adults with cancer has focused on patients with solid tumors. However, there is an increasing body of literature on the impact of sarcopenia in older adults with hematologic malignancies. In this comprehensive review, we attempt to (i) describe the most up-to-date diagnostic criteria and diagnostic approach to sarcopenia, (ii) summarize the prognostic impact of sarcopenia among older adults with hematologic malignancies, (iii) discuss the proposed mechanisms of sarcopenia and its pathogenesis, (iv) review the evidence for interventions targeting sarcopenia, and (v) provide future directions for the advancement of sarcopenia management among older adults with hematologic malignancies.

ABSTRACT Patients with newly diagnosed acute myeloid leukemia (ND‐AML) derive variable survival benefit from venetoclax + hypomethylating agent (Ven‐HMA) therapy. The primary objective in the current study was to develop genetic risk models that are predictive of survival and are applicable at the time of diagnosis and after establishing treatment response. Among 400 ND‐AML patients treated with Ven‐HMA at the Mayo Clinic, 247 (62%) achieved complete remission with (CR) or without (CRi) count recovery. Multivariable analysis–derived hazard ratios (HR), including 1.8 for European LeukemiaNet (ELN) adverse karyotype, 4.7 for KMT2Ar , 1.7 for TP53 MUT , 2.6 for KRAS MUT , and 2.1 for IDH2 WT were applied to develop an HR‐weighted risk model: low, intermediate, and high; respective median survival censored for allogeneic stem cell transplant (ASCT) (3‐year survival) were “not reached” (67%), 19.1 (33%), and 7.1 months (0%). In patients achieving CR/CRi, adverse karyotype, KMT2Ar , KRAS MUT , IDH2 WT predicted inferior survival, allowing for a complementary response‐stratified risk model. The model was externally validated and was shown to be superior to the ELN 2024 risk model (AIC 179 vs. 195 and AUC 0.77 vs. 0.69). Survival was inferior with failure to achieve CR/CRi or not receiving ASCT; 3‐year survival for high‐risk with or without ASCT was 42% versus 0% ( p < 0.01); intermediate 72% versus 43% ( p = 0.06); and low‐risk 88% versus 78% ( p = 0.53). The Mayo genetic risk models offer pre‐treatment and response‐based prognostic tools for ND‐AML treated with Ven‐HMA. The current study underscores the prognostically indispensable role of achieving CR/CRi and ASCT.

Background: Hypomethylating agent (HMA) and venetoclax (VEN) therapy is a standard of care frontline treatment of acute myeloid leukemia (AML) amongst patients (pts) ineligible for intensive therapy. Despite its convenient flat dose, oral nature, and static excretion irrespective of body weight (wt), VEN has a large, variable volume of distribution and extensive protein binding (Yang, Molecules, 2022). Body mass index (BMI) is a more accurate, albeit imperfect, indicator of body fat that has not been evaluated as an independent predictor of differential VEN exposures and clinical outcomes. We sought to evaluate this possibility amongst pts treated with frontline HMA+VEN in a multi-center, real-world, retrospective study. Methods: We conducted a multi-center, retrospective study through four US academic centers in the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND). 368 pts treated with frontline HMA+VEN from 6/2016-8/2023were evaluated based on BMI within 30 days of induction. Responses were defined by European LeukemiaNet (ELN) 2022 criteria. Pearson's chi-squared test and Wilcoxon rank-sum test were used for comparison between groups. The Kaplan-Meier method and multivariable Cox regression model were applied to overall survival (OS). Continuous variables were summarized as a median with interquartile range (IQR), and categorical variables were reported as a frequency (percentage). Results: The median age was 75 (IQR: 70-79) years, 58% were male, and 76% were white. 107 (29%) had a normal BMI of 18-25 kg/m2, 141 (38%) were overweight (BMI 25-30 kg/m2), and 120 (33%) were obese (BMI &gt;30 kg/m2). There were no significant differences in baseline pt-, disease-, and treatment-specific factors when comparing pts with normal wt to BMI &gt;25.The cohort was enriched for complex karyotype and TP53-mutated disease (27% and 32%, respectively), with 73% categorized as adverse risk by ELN 2022. There was no difference in 30-, 60-, and 90-day mortality rates (6-8%, 14-18%, 19-29%, respectively) by BMI group. Complete remission (CR/CRi) rate was 50% overall and was not impacted by BMI (41%, normal wt; 55%, overweight; 52%, obese) (p=0.10). Overall response rate (ORR) (CR/CRi/MLFS) was 59% overall and differed by BMI groups (50%, normal wt; 66%, overweight; 58%, obese) (p= 0.047). The median OS was 6.6 months for normal wt, 13.7 months for overweight, and 8.3 months for obese pts, and not significantly different when comparing normal to overweight (p=0.052) or obese pts (p=0.756). In multivariable analysis, the effect of BMI varied by the composite remission rate used. Overweight was borderline significantly associated with higher likelihood of achieving CR compared to normal wt (odds ratio [OR] 1.98, 95% confidence interval [CI] 0.99-4.03; p=.056), whereas obesity was not (OR 1.78, CI 0.86-3.74; p=.13). Other co-variates with a significant association with achieving CR included diagnosis of secondary AML (sAML) (OR 0.37, CI 0.18-0.74; p=.006) and presence of IDH (OR 2.81, CI 1.30-6.15; p=.009), ASXL (OR 0.39, CI 0.15-0.96; p=.046), TET2 (OR 2.43, CI 1.17-5.09; p=.02), and DNMT3A (OR 2.37, CI 1.19-4.78; p=.02) mutations. There was a trend towards higher likelihood of achieving CR/CRi for both overweight (OR 1.74, CI 0.92-3.32; p=.09) and obese pts (OR 1.88, CI 0.96-3.74; p=.07). Diagnosis of sAML and presence of TET2, ASXL, and DNMT3A mutations no longer had a significant association with achieving CR/CRi, while IDH mutations maintained an association (p=.01). None of these variables demonstrated a significant impact on ORR (inclusive of MLFS) except overweight (OR: 1.99, CI 1.06-3.80; p=.03) and sAML vs de novo (OR: 0.53, CI 0.29-0.99; p=.047). In multivariable logistic regression, higher ECOG score was associated with risk of early mortality within 60 (p=.01) and 90 (p=.01) days, but not 30 days. sAML vs de novo associated with higher 90-day mortality, presence of NPM and TP53 mutation associated with higher 30-day mortality, and cytogenetic risk associated with higher 60- and 90-day mortality. Conclusions: This multi-center, real-world study demonstrates that BMI may not have a linear effect on response to frontline HMA+VEN, with some indication of negative impact at both lower and higher BMI categories. However, additional dedicated studies are needed to determine if differences in BMI is associated with altered drug exposure as an explanation for these differences.

Introduction: Acute myeloid leukemia (AML) has been considered by many to be an oncologic emergency often leading to hospital admission for expeditious evaluation and treatment. Previous studies reported that time from diagnosis to treatment (TDT) does not impact outcomes (Sekeres, Blood, 2009), (Bertoli, Blood, 2013), (Rollig, Blood, 2020), however these analyses were restricted to intensively treated and/or non-United States (US) patients (pts). We report on a multi-center, retrospective analysis of TDT in adults with newly diagnosed AML receiving Hypomethylating agent (HMA) + venetoclax (Ven) using real-world data from the COMMAND. Methods: Eight US academic medical centers with AML expertise performed a review of adult pts within their center treated with HMA+Ven for newly diagnosed AML. TDT was defined as days from diagnosis of AML to initiation of treatment with HMA+Ven. Cytoreduction with hydroxyurea or leukapheresis was included to control for the effects of severity of presentation on TDT. The primary outcome was impact of TDT on overall survival (OS) (defined as date of diagnosis to date of death). TDT was treated continuously for time-to-event analyses. Secondary outcomes included measurable residual disease (MRD) by flow cytometric analysis (sensitivity &lt;0.1%), complete response (CR), complete response with incomplete count recovery (CRi), defined by European LeukemiaNet (ELN) 2022 Guidelines (Dohner, Blood,2022), and early mortality (death within 30 and 60 days of initiation of HMA+Ven). Pre-planned subgroup analyses included those based on disease biology (FLT3 ITD, IDH1/2, TP53 mutation, ELN 2022 risk), HMA used (azacitidine vs decitabine) and age (&lt;75 vs ≥75 years). For those analyses where TDT was significant in univariable analysis (P=0.1), multivariable analysis was conducted controlling for the following: ECOG performance status (PS), age, receipt of cytoreduction, ELN 2022 risk, and presence of individual pathogenic variants detected on broad myeloid gene next generation sequencing panels used at each institution. All analyses were conducted by a central statistician using RStudio statistical package. Results: 488 pts were included in the analysis. Median age was 76 (interquartile range: 70-80) and the majority of pts had an ECOG PS of 0 or 1 (56%). Most pts (67.6%) had adverse risk with 9.4% and 18.6% of pts having favorable and intermediate risk disease by ELN 2022, respectfully. The most common mutations identified were TP53 (27.5%), IDH1/2 (19.3%), NPM1 (16.4%), DNMT3A (16.8%), ASXL1 (15.4%), and FLT3-ITD (13.7%). Twenty-eight percent of pts received cytoreduction prior to initiation of HMA+Ven. Azacitidine+Ven was the most common regimen utilized (53.9%). Median number of cycles of HMA+Ven was 3 (IQR: 1-6). MRD (-) CR, MRD (+) CR, and CRi was achieved in 21.5%, 10.5%, and 16.4% of pts after one cycle of HMA+Ven. Median OS for the cohort was 10.4 months (95% CI: 9.4-12.6). Median TDT for the cohort was 9 days (IQR: 5-17). In univariate Cox model, longer TDT was associated with improved OS (HR: 0.989, 95% CI: 0.981 to 0.998; p = 0.013). In multivariable analysis, longer TDT was still associated with improved OS (HR: 0.987; 95% CI: 0.973-0.999; p=0.049). TDT and presence of bZIP in-frame CEBPA mutations were the only factors associated with improved OS, while ECOG PS of 2 or 3-4, when compared to ECOG PS=0 (p=0.035 and 0.0002, respectively) and therapy-related AML (p=0.002), were associated with worse OS. Notably, ELN 2022 risk and IDH1/2 or NPM1 mutation status did not impact OS. Discussion: In this real-world, multi-center, US-based analysis of pts with newly diagnosed AML treated with HMA+Ven we show that longer TDT is associated with improved OS even when controlling for severity of presentation, ELN 2022 risk score, ECOG PS, and age. This finding is consistent with data in pts treated with 7+3. Similar to results published in an electronic medical record-based analysis out of Germany (Baden, Haemotologica, 2024) in pts treated with lower-intensity Ven regimens, our results show that pts with newly diagnosed AML eventually treated with HMA+Ven are best served with a complete appraisal of disease biology and treatment planning before initiation of induction therapy. Given the consistent negative impact of ECOG PS and the findings of our study, future consideration for potential patient optimization strategies to improve ECOG PS prior to therapy initiation are warranted.

Prostate cancer is a disease of older adults that has undergone a significant therapeutic paradigm shift in the last decade with the emergence of novel androgen receptor pathway inhibitors (ARPis). One of the more commonly used ARPis is enzalutamide. This drug, along with darolutamide and apalutamide, initially received approvals in the metastatic castrate-resistant prostate cancer setting but is now utilized frequently in the metastatic castrate-sensitive and non-metastatic castration-resistant settings. Landmark phase III data illustrating ARPi efficacy in older adults are limited to those with excellent performance status. However, its role in unfit older prostate cancer patients remains to be explored in the context of a narrative review. This first-of-its-kind drug review aims to shed light on the most up-to-date evidence behind the unique toxicity profile of ARPis in the context of geriatric vulnerabilities such as cognitive and functional impairment, along with potential solutions and supporting evidence that exists to circumvent these issues in the vulnerable older adult.