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.

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.

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.

Background: Relapsed or refractory classical Hodgkin lymphoma (cHL) remains a difficult treatment challenge. Although checkpoint inhibitors (CPI) have provided clinical benefit for these patients, responses are generally not durable, and progression eventually occurs. Discovering combination therapies which maximize the immune response of CPI therapy may overcome this limitation. We hypothesized that adding ibrutinib to nivolumab will lead to deeper and more durable responses in cHL by promoting a more favorable immune microenvironment leading to enhanced T-cell-mediated anti-lymphoma responses. Methods: We conducted a single arm, phase II clinical trial testing the efficacy of nivolumab in combination with ibrutinib in patients ≥18 years of age with histologically confirmed cHL who had received at least one prior line of therapy. Prior treatment with CPIs was allowed. Ibrutinib was administered at 560 mg daily until progression in combination with nivolumab 3 mg/kg IV every 3 weeks for up to 16 cycles. The primary objective was complete response rate (CRR) assessed per Lugano criteria. Secondary objectives included overall response rate (ORR), safety, progression free survival (PFS), and duration of response (DoR). Results: A total of 17 patients from two academic centers were enrolled. The median age of all patients was 40 (range 20–84). The median number of prior lines of treatment was five (range 1–8), including 10 patients (58.8%) who had progressed on prior nivolumab therapy. Most treatment related events were mild (<Grade 3) and expected from the individual side effect profiles of ibrutinib and nivolumab. In the intent to treat population (n = 17), the ORR and CRR were 51.9% (9/17) and 29.4% (5/17), which did not meet the prespecified efficacy endpoint of a CRR of 50%. In patients who received prior nivolumab therapy (n = 10), the ORR and CRR were 50.0% (5/10) and 20.0% (2/10), respectively. At a median follow up of 8.9 months, the median PFS was 17.3 months, and the median DOR was 20.2 months. There was no statistically significant difference in median PFS between patients who received previous nivolumab therapy versus patients who were nivolumab naïve (13.2 months vs. 22.0 months, p = 0.164). Conclusions: Combined nivolumab and ibrutinib led to a CRR of 29.4% in R/R cHL. Although this study did not meet its primary efficacy endpoint of a CRR of 50%, likely due to enrollment of heavily pretreated patients including over half of who had progressed on prior nivolumab treatment, responses that were achieved with combination ibrutinib and nivolumab therapy tended to be durable even in the case of prior progression on nivolumab therapy. Larger studies investigating the efficacy of dual BTK inhibitor/immune checkpoint blockade, particularly in patients who had previously progressed on checkpoint blockade therapy, are warranted.

Background: Relapsed or refractory Hodgkin lymphoma (R/R HL) is a challenging disease with limited treatment options beyond brentuximab vedotin and checkpoint inhibitors. Herein we present the time‐trend analysis of R/R HL patients who received allogeneic hematopoietic cell transplantation (allo‐HCT) at our center from 2001–2017.Methods: The patients were divided into two distinct treatment cohorts: era1 (2001–2010), and era2 (2011–2017). The primary endpoint was overall survival (OS). Secondary endpoints included progression‐free survival (PFS), non‐relapse mortality (NRM), and cumulative incidence of acute and chronic graft versus host disease (GVHD).Results: Among the 51 patients included in the study, 29 were in era1, and 22 were in era2. There was decreased use of myeloablative conditioning in era2 (18% vs. 31%) compared to era1 and 95% of patients in era2 previously received brentuximab Vedotin (BV). Haploidentical donors were seen exclusively in era2 (0% vs. 14%) and more patients received alternative donor transplants (7% vs. 32%) in era2. The 4‐year OS (34% vs. 83%, p < 0.001) and 4‐year PFS (28% vs. 62%, p = 0.001) were significantly inferior in era1 compared to era2. The incidence of 1‐year NRM was lower in era2 compared to era1 (5% vs. 34%, p = 0.06). The cumulative incidence of acute GVHD at day 100 was similar in both eras (p = 0.50), but the incidence of chronic GVHD at 1 year was higher in era2 compared to era1 (55% vs. 21%, p = 0.03).Conclusions: Despite the advent of novel therapies, allo‐HCT remains an important therapeutic option for patients with R/R HL.