Rina Li Welkie

Chemotherapy-induced nausea and vomiting (CINV) remains a clinically significant and challenging adverse effect of treatment for patients with classical Hodgkin lymphoma (cHL), with substantial neg...

Frameshift mutations in exon 12 of nucleophosmin 1 ( NPM1 ^mut ) are among the most common mutations in acute myeloid leukemia (AML) and have historically been considered favorable‐risk in the absence of FLT3 ‐ITD. In the European LeukemiaNet (ELN) 2024 risk‐classification for patients treated with hypomethylating agents plus venetoclax (HMA + VEN), NPM1 ^mut is not considered favorable when co‐occurring with signaling gene (SG) mutations (i.e., FLT3 ‐ITD, NRAS , KRAS ). However, due to limited numbers in the original analysis, the prognostic impact of SG mutations in NPM1 ‐mutant AML remains unclear. We evaluated the prognostic significance of NPM1 ^mut with and without SG mutations in two independent cohorts of patients ≥ 60 years with ELN 2024 favorable‐ or intermediate‐risk AML treated with HMA + VEN. Cohort 1 included 322 patients treated in the academic setting. NPM1 ^mut ( n = 61) was associated with a nonsignificantly longer overall survival (OS) compared to NPM1 wild‐type ( NPM1 ^wt ) (median, 53.05 vs. 17.03 months, p = 0.10). In multivariable analysis (MVA), SG mutations were not independently prognostic within the NPM1 ^mut subgroup. Cohort 2 included 816 patients from a real‐world community‐treated cohort. NPM1 ^mut ( n = 124) had a longer OS compared with NPM1 ^wt (median, 15.3 vs. 14.4 months, p = 0.03). In MVA, NRAS, KRAS , and FLT3 ‐ITD were independent unfavorable prognostic factors; NPM1 ^mut with, compared to without, SG co‐mutation had a shorter OS (median, 9.4 vs. 31.6 months, p = 0.001). These findings suggest SG mutations negate the favorable impact of NPM1 ^mut in older patients treated with HMA + VEN. Prospective clinical trials are needed to investigate the use of combination therapies to improve outcomes in this high‐risk subgroup.

Adults with sickle cell disease (SCD) experience fragmented access to primary and preventive care, which leads to poor adherence to general and SCD‑specific clinical practice guidelines. To address this gap, we implemented an embedded primary care model where a board‑certified internist/pediatric primary care provider (PCP) was embedded as a full member of the adult SCD care team, attending operational and educational meetings and practicing alongside hematologists in a comprehensive SCD clinic. Our primary aim was to test the hypothesis that an embedded primary care model was associated with improved guideline‑based preventive care and changes in acute healthcare utilization (e.g., emergency room visits and hospitalizations). We conducted a retrospective cohort study of adults with SCD seen at a single tertiary care center between July 2020 and June 2025. Of the 388 adults with SCD seen at the center, 174 received care from the embedded PCP. Patients in the embedded PCP model demonstrated significantly higher adherence to general preventive care including cervical cancer screening ((Odds Ratio) OR: 4.49; 95% (Confidence Interval) CI: 2.46, 8.23), depression screening (OR: 7.97; 95% CI: 1.78, 35.69), and diphtheria-tetanus-pertussis (Tdap) immunization (OR: 2.88; 95% CI:1.72, 4.84), and SCD‑specific guidelines, including annual eye examinations (OR: 2.59; 95% CI: 1.66, 4.04), pneumococcal immunization (OR: 3.58; 95% CI: 2.16, 5.92), urine protein screening (OR: 3.36; 95% CI: 1.89, 6.00), and ACE inhibitor/ARB use for microalbuminuria (OR: 9.37; 95% CI: 3.11, 28.23). Among patients who saw the embedded PCP, patients had significantly more annual outpatient visits (post-PCP: 4.2 vs pre-PCP: 2.7, p < 0.0001) and, while insignificant, fewer annual inpatient admissions (post-PCP: 1.4 vs pre-PCP: 1.9, p = 0.4869). Embedding a PCP within the adult SCD care team was associated with improved guideline‑based preventive care and more annual outpatient visits, which was consistent with more coordinated, outpatient‑focused management.

PURPOSE: Azacitidine and venetoclax is a standard frontline treatment regimen for newly diagnosed older adults with AML; however, long-term outcomes remain poor. Revumenib is an oral menin inhibitor with clinical activity in AML patients with nucleophosmin-1 mutation ( NPM1m ) or lysine methyltransferase 2A rearrangements ( KMT2Ar ). METHODS: We conducted a phase I dose-escalation and expansion study of azacitidine, venetoclax, and revumenib at two dose levels (113 mg or 163 mg orally every 12 hours in combination with strong cytochrome P450 inhibitor azoles) in patients aged 60 years and older newly diagnosed with AML with NPM1m or KMT2Ar (ClinicalTrials.gov identifier: NCT03013998 ). RESULTS: Overall, 43 patients were enrolled and treated. There was no maximal tolerated dose identified. Differentiation syndrome was present in eight (19%) patients and QTc Fridericia prolongation was present in 19 (44%) patients, and neither required permanent discontinuation of revumenib. The overall response rate with an intention-to-treat population was 88.4% (95% CI, 74.9 to 96.1; NPM1m : 85.3%; KMT2Ar : 100%), the rate of composite complete remission (complete remission [CR] + CR with partial or incomplete hematologic recovery) was 81.4% (95% CI, 66.6 to 91.6; NPM1m: 79.4%; KMT2Ar: 88.9%), and the rate of CR was 67.4% (95% CI, 51.5 to 80.9; NPM1m : 65%; KMT2Ar : 78%). No patient had refractory disease after 1-2 cycles of treatment. The median time to first response was 28 days, and 84% of responders achieved remission within the first cycle. All 37 patients evaluated had no evidence of measurable residual disease by a centralized flow cytometry assay. CONCLUSION: In older adults newly diagnosed with NPM1m or KMT2Ar AML, the combination of azacitidine, venetoclax, and revumenib was able to be safely administered with high rates of CR and clinical activity.

Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly phase 3 trials, have unnecessarily restrictive eligibility criteria. This study aims to evaluate the most common eligibility criteria according to phase of trial and to determine whether criteria correspond with drug safety signals. We identified MDS clinical trials registered on ClinicalTrials.gov from 1 January 2000 to 1 September 2023 and analyzed the eligibility criteria of 191 therapeutic MDS trials. We found that categorical inclusion and exclusion criteria are remarkably similar in representation across trial phases. Additionally, only 13% of trials are concordant with drug safety signals, suggesting that the eligibility criteria are often arbitrary. On behalf of the icMDS (International Consortium for Myelodysplastic Syndromes), an association of international MDS experts, we provide a position statement on restrictive eligibility criteria for MDS clinical trials that should be avoided with the aim of removing barriers to clinical trial enrollment.

Although the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A “mutation score” was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: −1 to 0 points (“Beat-AML intermediate”) vs 1+ points (“Beat-AML adverse”). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined “Beat-AML favorable-risk” group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making.

Sickle cell disease (SCD) is a genetic disorder affecting 100 000 people with an estimated annual medical cost of $3 billion in the United States; however, the economic impact on patients is not well described. We aimed to examine the indirect economic burden and test the hypothesis that socioeconomic status and greater social vulnerability risks are associated with increased absenteeism and employment loss. We surveyed adults and caregivers of children with SCD at 5 US centers from 2014 to 2021. Logistic regression models were used to examine the associations of employment loss and missed days of work with demographics and social determinants. Indirect costs were estimated by multiplying the self-reported missed days of work and job loss by 2022 average wages by the state of the participating institution. Of the 244 participants, 10.3% reported employment loss in the last 5 years, and 17.5% reported missing 10 or more days of work. Adults had 3 times more employment loss compared with caregivers of children with SCD (OR, 3.18; 95% CI, 1.12-9.01) but fewer missed days of work (OR, 0.24; 95% CI, 0.11-0.0.51). Participants who did not live with a partner reported increased employment loss (OR, 4.70; 95% CI, 1.04-21.17) and more missed days of work (OR, 4.58; 95% CI, 1.04-20.15). The estimated annual indirect economic burden was $2 266 873 ($9290 per participant). Adults with SCD and caregivers of children with SCD commonly report employment loss and missed days of work as important risk factors. The high indirect economic burden suggests that future economic evaluations of SCD should include SCD-related indirect economic burden.