Outcomes of clinical trial screening in patients with Myelodysplastic Syndromes and chronic myelomonocytic leukemia

Abstract Background: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are hematologic malignancies characterized by bone marrow (BM) dysplasia and ineffective hematopoiesis. Therapies are limited and survival outcomes dismal, especially once all standard-of-care options are exhausted. Clinical trial enrollment is paramount, though many barriers have resulted in disparate participation. Here, we sought to evaluate the impact of clinical trial enrollment on survival outcomes and identify barriers to clinical trial participation. Methods We retrospectively evaluated all screening instances of patients with MDS or CMML at a tertiary cancer center from February 2023 through April 2024. Clinical patient characteristics and BM data were assessed at the time of screening. Overall survival (OS) was analyzed using Kaplan-Meier method and compared using log-rank test. Multivariable analysis (MVA) was performed using Cox proportional hazards model. Results A total of 593 patients were screened for clinical trial enrollment, with 233 (39%) treated on protocol and 360 (61%) screen failures. Patients enrolled on clinical trials were older (74 vs 72 years, p=0.031); resided in metropolitan areas (Rural-Urban Commuting Area codes 1 vs 1, p=0.038); and had higher BM blasts (8 vs 4%, p<0.001), less neutrophils (absolute neutrophil count [ANC] 1.26 vs 1.77 x109/L, p=0.019), higher-risk disease by both International Prognostic Scoring System (IPSS; p<0.001) and Revised IPSS (IPSS-R; p<0.001), and had more often failed hypomethylating agent (HMA) therapy (52 vs 32%, p<0.001). Median OS was 67.4 months (95% confidence interval [CI]: 56.6, 110.0) from diagnosis and 17.9 months (95% CI: 16.3, not estimable [NE]) from the time of screening. There were no differences in OS from the time of diagnosis or screening by clinical trial enrollment (p=0.821 and p=0.242, respectively). By MVA, increasing age (p=0.020), higher BM blasts (p=0.004), lower hemoglobin levels (p=0.002), thrombocytopenia (p=0.026), higher ANC (p=0.041), more adverse cytogenetics (p<0.001), and HMA failure (p<0.001) predicted for inferior OS. When including only untreated patients (n=351), OS was not reached (NR; 95% CI: 134, NE) from diagnosis and NR (95% CI: NE, NE) from screening. There were no differences in median OS by clinical trial enrollment (from diagnosis: p=0.108, from screening: p=0.181). However, when evaluating only patients with HMA failure (n=235), patients treated on a clinical trial had improved OS than those who were not (67.4 [95% CI: 44.4, 122.3] vs 38.1 months [95% CI: 33.1, 57.9], p=0.013). From the time of screening, median OS was 9.7 months (95% CI: 8.3, 14.2) for those treated on clinical trials and 7.7 months (95% CI: 4.9, 12.4) for those on standard therapies. By MVA, increasing age (p=0.009), higher BM blasts (0.026), thrombocytopenia (p=0.018), poorer risk cytogenetics (p<0.001), and treating off protocol (p=0.017) predicted for inferior survival. Reasons for screen failure included patient/physician decision in 224 (62%), comorbid conditions in 69 (19%), and trial logistics in 61 (17%). Six patients (2%) passed away prior to any treatment on or off a clinical trial and are subsequently excluded. Median OS from time of screening was NR, 14.2 (95% CI: 8.1, NE), and 17.2 months (95% CI: 12.4, NE) in the patient/physician decision, comorbidity, and logistics subgroups, respectively (p=0.009). In frontline screen failures, median OS was NR (95% CI: NE, NE) in both patient/physician decision and logistics subgroups and NR (95% CI: 11.2, NE) in the comorbidity subgroup (p=0.016). In those with HMA failure treated off protocol, median OS was also more inferior in those with comorbidities (patient/physician decision: 12.1 [95% CI: 6.8, NR], comorbidity: 4.9 [95% CI: 2.7, NR], logistics: 9.9 [95% CI: 1.5, NR]; p=0.070). Conclusions Clinical trial enrollment was more prevalent in older patients with MDS with higher-risk disease who resided in metropolitan areas and had already received HMA. Treating on investigative therapies resulted in better survival outcomes in patients with HMA failure MDS. Though comorbidities accounted for only 19% of screen fails, those patients had inferior survival than others who were not enrolled on clinical trials due to patient/physician decision or logistical issues. Therefore, less restrictive eligibility criteria in clinical trials are warranted for consideration in future investigative efforts.