Go, Ronald S.

Abstract Background: In 2022, Medicare alone spent $42.1 billion on prescription drugs, with antineoplastic and classical hematology drugs accounting for 44% and 8% of the total, respectively (2024 MedPAC Data Book). While antineoplastic drugs have been extensively studied, classical hematology drugs have received comparatively little attention. We analyzed US Food and Drug Administration (FDA) approvals of classical hematology drugs over the past 30 years and examined their per-patient costs and annual total US sales. Methods: We identified all classical hematology drugs (those prescribed by hematologist/oncologists for non-malignant indications) approved by the FDA from January 1, 1995 to December 31, 2024, including novel pharmaceuticals (synthesized from chemical compounds), biologics (derived from living organisms), and biosimilars (highly similar, but not identical, to biologics previously approved). Cost estimates for 2024 were based on wholesale acquisition costs (WAC), using annual WAC for continuous-duration treatments and typical course WAC for fixed-duration treatments. WAC and US gross sales data for 2024 were obtained from IPD Analytics (Aventura, FL). Results: A total of 98 classical hematology drugs were approved over the past 30 years—11% in 1995–2004, 26% in 2005–2014, and 63% in 2015–2024. These included pharmaceuticals (36%), biologics (54%), and biosimilars (10%). Six gene therapies received approval: 3 for hemophilia and 1 each for sickle disease, beta thalassemia, and sickle cell disease/beta thalassemia (dual indication). Common categories of indications included bleeding (31%), anemia (30%), neutropenia (9%), and thrombocytopenia (9%). Leading diagnoses were hemophilia (25%), chemotherapy-induced neutropenia (9%), thromboembolism (8%), paroxysmal nocturnal hemoglobinuria (PNH; 7%), anemia of chronic kidney disease (6%), iron deficiency anemia (6%), and immune thrombocytopenia (5%). The median cost for gene therapies was $2.9 million per treatment (range: $2.2 million–$3.5 million). Among non-gene therapies, median costs were $3,000 per course for fixed-duration treatments (range: $64–$378,000) and $467,000 annually for continuous-duration treatments (range: $2,400–$1.8 million). The most expensive fixed-duration treatments targeted hemophagocytic lymphohistiocytosis ($378,000/8-week course), while the most expensive continuous-duration treatments were for hemophilia (median: $630,000/year; range: $270,000–$853,000). Estimated 2024 US gross sales across all drugs exceeded $70 billion. Top-selling indications included thromboembolism ($43.5 billion), hemophilia ($6.9 billion), immune thrombocytopenia ($4.9 billion), PNH ($4.7 billion), chemotherapy-induced neutropenia ($2.8 billion), anemia of chronic kidney disease ($2.0 billion), and iron deficiency anemia ($1.8 billion). Total sales for all gene therapies combined were $143 million. Six drugs have been discontinued (year approved/year discontinued/reason): betrixaban (2017/2020/business), daprodustat (2023/2024/business), fidanacogene elaparvovec (2024/2025/business), oprelvekin (1997/2011/business), peginesatide (2012/2013/safety), and voxelotor (2019/2024/safety). There are limitations to our study. Some drugs have non-classical hematology indications (anticoagulants in atrial fibrillation; luspatercept in myelodysplastic neoplasm) and/or may also be prescribed by non-classical hematologists (erythropoiesis stimulating agents by nephrologists and medical oncologists). We were unable to disaggregate the sales data in these situations. Therefore, the annual sales for certain indications may be overestimated. Conclusions: Classical hematology drugs contribute substantially to US prescription drug spending, with over $70 billion in annual sales and medications for thromboembolism accounting for over half of the costs. Approvals have accelerated over the past three decades, doubling each decade. Biologics and biosimilars now represent two-thirds of approvals. Continuous-duration treatments, particularly for rare hereditary diseases like hemophilia, carry significant financial burden, with annual costs per patient often exceeding $0.5 million. In these conditions, if gene therapies demonstrate durable efficacy, they may prove to be cost-effective alternatives. As more gene therapies are developed, evaluating their long-term value relative to chronic high-cost treatments will be essential for shaping future reimbursement and access strategies.

Abstract Background: The landscape of healthcare delivery in hematology has undergone significant transformations with the increasing adoption of telehealth services for appointments and communications in conjunction with the 2016 21st Century Cures Act providing patients complete access to their health information. Digital healthcare services in hematology offer benefits, including convenience and equitable access to those limited by travel or financial burdens. However, they also have inherent risks, including loss of in-person communication, disparities in access to technology, differences in digital literacy, and increased provider workload and burnout. Thus, we analyzed contemporary utilization patterns of hematology healthcare and provider preferences to optimize implementation of evolving hybrid care models. Methods: We analyzed data from the Mayo Clinic (Rochester, MN) Hematology Appointments Office and the Hematology Call Center as well as digital messaging practices using Epic's SlicerDicer tool. Data was collected between January 2023 and January 2025, during which patients had access to the electronic health record (EHR) and direct messaging capabilities. An optional survey was distributed to Hematology providers including physician consultants, fellows, and advanced practice providers (APP) to assess practice preferences. Results: During the analyzed period, a total of 85,899 hematology appointments were completed and captured all adult ages, including 18-34 (4.6%), 35-49 (9.2%), 50-64 (25.3%), 65-79 (48.3%), and 80+ (12.6%). Although in-person, video, and telephone visit options were available, in-person visits predominated across all age groups, with 80.6% of all completed appointments occurring in-person, 12.9% via video, and 6.5% via telephone. Notably, patients aged 80+ had the second highest combined use of video and telephone visits, with over 20% of their appointments conducted virtually. There was a total of 6,893 no-show and cancelled appointments, with 79.9% of these scheduled in-person, 14.8% via video, and 5.3% via telephone. There were over 4,000,000 portal messages in the hematology division with over 1,000,000 sent directly to hematology providers. Patients sent 105,284 new messages, of which 47.2% were new patient advice requests to providers which cascaded to 343,103 additional messages. Patients made 155,036 telephone calls, which cascaded to 407,578 messages over the portal, 78.5% of which were sent directly to providers. Notably, utilization of both portal messaging and telephone calls was similar across all age cohorts, including those 80+ years. Providers only initiated 14,159 new messages to patients yet sent a total of 354,172 messages. The hematology provider survey had a response rate of 42% (53 of 129). Respondents included 45.3% consultants, 45.3% fellows, and 9.4% APPs. 92.5% and 90.6% of providers preferred in-person appointments for new visits and established visits on therapy, respectively. In contrast, 52.8% preferred virtual appointments for established patients not currently receiving therapy. 73.6% and 52.8% of survey respondents either strongly agreed or agreed that virtual appointments are advantageous for patients and providers, respectively. Additionally, only 49.1% felt portal messages were necessary to provide high quality care and 64.2% preferred appointments over communicating through messages. 86.8% of providers reported spending more than 30 minutes daily responding to in-basket messages, however, 94.3% reported not routinely billing for their time. Conclusions: In the digital era, hematology healthcare delivery is multifaceted and increasingly demanding with high rates of patient engagement in their care via various mediums. To our knowledge, this is the largest analysis combining EHR utilization and appointment data with provider preferences to better understand digital hematology care. Digital appointments and communications were common amongst all age groups, including older patients, and had relatively low cancellations rates. Promotion of virtual visits to facilitate patient-provider conversations in addition to standardization of digital communication workflows are low-risk, high-yield interventions to mitigate the cascading of EHR-based communications, especially for those not actively receiving therapy. Together, these could decrease provider burnout while increasing healthcare system operational capacities to provide optimal patient care and satisfaction.

Abstract Background Measurable residual disease (MRD) negativity post- autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM) is associated with favorable outcomes and may overcome the adverse impact of high-risk cytogenetic abnormalities (HRCAs). However, as the definition of high risk evolves and MRD emerges as a key endpoint, understanding its prognostic value within individual HRCAs is critical for treatment guidance. Methods We retrospectively included patients with NDMM that underwent an ASCT between September 19, 2016, and October 19, 2023, and achieved MRD negativity on Day 100 post ASCT. The MRD testing was conducted using multiparameter flow cytometry with a sensitivity of 2x10. HRCAs were defined as del(17p), 1q21+ gain or amplification (1q21+), t(4;14), t(14;16), t(14;20) and del(1p) and rest were considered standard risk (SRCA). Patients were grouped by the number of HRCAs (0, 1, ≥2). An adaptation of the recently proposed International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) classification for high-risk disease (TP53 mutation unavailable) was also used. Progression-free survival (PFS), measured from stem-cell infusion to progression or death, was estimated using Kaplan–Meier methodology and compared using log-rank test. Results We identified 386 patients with MRD negativity post ASCT, of which 381 had cytogenetic data available for analysis. The median follow-up for the study cohort was 47.3 months (95% CI: 43.2-50). The median age at the time of ASCT was 65.7 (25.4-79.2) years and 58.3% patients were males. A total of 49% (n=189) patients had standard-risk cytogenetics, 31.4 % (n=121) harbored 1 HRCA, 15.3% (n=59) patients had two HRCAs and 3.1% (n=12) had 3 HRCAs. The individual HRCA by their prevalence were: 1q21+ in 35.5%(n=137), del(17p) in 14.3% (n=55), t(4;14) in 10.9% (n=42), t(14;16) in 5.4% (n=21), del(1p) in 4.2% (n=16), and t(14;20) in 1.04% (n=4) of patients. The most common double-hit lesions were1q21+ gain and/or amplification co-occurring with t(4;14) (33.9%, n=20) and del(17p) with 1q21+ (18.6%, n=11). Despite universal MRD negativity at Day 100, several HRCAs remained prognostically significant for PFS. Patients with del(17p) had worse 3-year PFS (71%) than those without (81%) [hazard ratio (HR)=1.85, 95% CI 1.11–3.07, p = 0.0172], though 3-year OS did not significantly differ at data cutoff (80% vs. 92%, p=0.1176). Presence of 1q21+ was associated with an inferior 3-year PFS (73%) compared to those without [84%, HR: 1.96 (95% CI: 1.25–3.06), p=0.0026], while 3-year OS was similar (88% vs. 91%, HR:1.33 p=0.36). Isolated 1q21+ had inferior PFS with comparable OS when compared to SRCA [3-year PFS of 82% vs. 88% respectively (HR:1.97, p=0.0177)]; 3-year OS was 91% vs. 94% (HR:1.38, p=0.44)]. Among 1q21+ patients, those with co-occurring HRCAs had a 3-year PFS of 66% vs. 81% for isolated 1q21+ (HR: 1.47, p=0.21). Patients with t(4;14) had worse 3-year PFS (64%) vs. 82% in non t(4;14) [HR 2.11(95% CI: 1.21-3.67) p=0.0064], and 3-year OS of 82% compared to 91% [HR 2.14 (95% CI: 1.02–4.49), p=0.038]. Isolated t(4;14) showed a 3-year PFS of 59% vs. 87% in standard-risk (p=0.06), and 3-year OS of 90% vs. 93% [HR 3.29, 95% CI 0.95–11.33, p = 0.06]. The presence of t(14;16), t(14;20), and del(1p) did not significantly affect 3-year PFS (all p>0.1), likely due to small subsets. When patients were grouped by the number of HRCAs, PFS declined with increasing cytogenetic complexity. Compared to standard risk, the 3-year PFS was 77% for 1 HRCA vs [HR = 2.11 (95% CI: 1.29–3.46), p = 0.0027], 67% for ≥2 HRCA [HR = 2.64 (95% CI: 1.53–4.57), p = 0.0005]. Maintenance therapy was used in 98% of patients. Patients with HRCAs received a doublet maintenance compared to SRCA (p<0.0001), even in MRD negative disease post ASCT. Conclusion In patients with certain HRCA, achievement of MRD negativity post-ASCT does not overcome the adverse impact of HRCA on PFS. In our cohort, patients with del(17p), t(4;14), or 1q21+ continued to exhibit significantly shorter PFS despite achieving MRD-negative status. These findings underscore the need for ongoing risk-adapted strategies even in patients with MM who attain MRD-negative state. The OS estimates are immature at this time.

Abstract Background Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM), characterized by the presence of more than 5% circulating plasma cells on a peripheral blood smear. Despite advancements in therapy, including novel agents and autologous stem cell transplantation (ASCT), pPCL remains associated with markedly poorer survival outcomes compared to newly diagnosed MM. Although disease progression is common in pPCL, individual courses vary widely upon relapse and thereafter. We aim to describe the natural history of pPCL, focusing on clinical features and survival outcomes at the time of relapse or disease progression. Methods Patients with pPCL who were followed at our institution's cancer center between 2006-2024 were included for retrospective analysis. The electronic health record was reviewed to provide detailed information on patient demographics, disease characteristics, treatment regimens, and clinical outcomes. Time to next treatment (TTNT) and overall survival (OS) analysis were performed using the Kaplan-Meier method. Statistical analyses were performed using the SAS biostatistical software JMP 17.0.1 (SAS Institute Inc). Results We analyzed a cohort of 106 patients with relapsed pPCL after first-line therapy, all of whom received induction with novel agents. To date, 64 patients (60%) have died. Across the entire cohort, median OS is 39 months (mos) (95% CI: 25-68). 59 patients (56%) were diagnosed after 2015. Baseline FISH cytogenetics were available for 100 patients; 57 (57%) had one or more high-risk cytogenetic abnormality. Nearly all patients (96%) had ≥50% clonal plasma cells on initial bone marrow biopsy. While most patients (n = 61; 58%) were planned to undergo upfront ASCT, 20 (33%) experienced disease progression during induction therapy and required a more intensive salvage regimen (often infusional chemotherapy) prior to ASCT. The median TTNT after first-line therapy (TTNT#1) for the entire cohort was 10.4 mos (95% CI: 8–14). The median TTNT after second-line therapy (TTNT#2) for the entire cohort was 5.7 mos (95% CI: 4.3–7.1). Clinical details at first relapse, prompting initiation of second-line therapy, were available for 91 patients. Of these, 26 patients (29%) had symptomatic relapses—due to CRAB features or extramedullary disease—while 65 patients (71%) experienced asymptomatic biochemical progression. Symptomatic relapses were followed by significantly shorter TTNT#2 (3.9 vs. 7.0 mos; p = 0.039) and inferior OS from the start of second-line therapy (7.5 vs. 31.2 mos; p <0.0001) compared to asymptomatic relapses. The median TTNT#2 for patients who relapsed during induction and received salvage ASCT was 6.9 mos (n=20). In contrast, those treated after relapse with non-ASCT regimens (n = 86) fared worse; those receiving novel agent-based combinations, including doublets, triplets, or quadruplets (n=64) had respective median TTNT#2 of 3.3, 6.0, and 3.3 mos. Patients treated with infusional chemotherapy (n = 9) had the poorest outcomes, with a median TTNT#2 of just 1.4 mos. The median TTNT diminished with each subsequent line of therapy: TTNT#3 (n = 73) was 5.8 mos, TTNT#4 (n = 53) was 4.0 mos, and TTNT#5 (n = 35) was 2.6 mos. Patients with pPCL harboring the t(11;14) cytogenetic abnormality who were treated with venetoclax-based regimens (n = 8) during any line of therapy had a longer corresponding median TTNT of 15.0 mos. Additionally, 23 patients received anti-BCMA CAR-T cell therapy as a post-relapse line of therapy. At last follow-up, 15 of these patients (65%) had not relapsed, and after a median 20.7 mos of follow-up, the median TTNT following CAR-T cell therapy had not yet been reached. Patients who received CAR-T after 1-3 prior lines (n=15) had a median TTNT that was not reached; those who had received 4 or more prior lines (n=8) had a median TTNT of 20 mos. ConclusionsDespite the use of novel agent-based combination regimens and ASCT as first-line therapy, most patients with pPCL eventually experience disease progression. Consistent with MM, symptomatic relapse in pPCL is associated with poorer outcomes compared to asymptomatic biochemical progression. Additionally, the duration of response shortens with each successive line of therapy. Notable exceptions include venetoclax-based regimens in patients with t(11;14), and anti-BCMA CAR-T cell therapies: each appear to confer more durable responses than historical treatments in patients with relapsed pPCL.

Abstract Introduction: Aplastic anemia (AA) affects approximately 1 in a million people per year in the United States and can present as a new diagnosis, progression, or relapse during pregnancy. Due to the rarity of the disease, there are limited data on its clinical presentation, hematologic parameters, treatment strategies, and maternal-fetal outcomes to guide diagnosis and management. Methods: We conducted a comprehensive literature review using PubMed, Google Scholar, and ScienceDirect to identify peer-reviewed studies published between 2001 and 2024. Articles were selected based on relevance and availability of clinical outcome data. We included cases of AA that were active during pregnancy—newly diagnosed, relapsed, or persistent. Data collected included patient demographics (age, sex), AA status (blood counts, disease severity, timing of presentation, management, and complications), fetal outcomes (gestational age and mode of delivery), and birth complications. Results: A total of 53 cases of AA during pregnancy were identified. Of these, 12 were diagnosed during pregnancy and 11 prior to pregnancy. For the 12 cases that developed during pregnancy, diagnoses were made across all trimesters: first (n=6), second (n=4), and third (n=2). Notably, in one patient, AA was active during the third and fourth pregnancies but not during the first or second, suggesting that AA can present intermittently across pregnancies in the same individual. The timing of diagnosis was unspecified in the remaining 30 cases. The median maternal age at AA diagnosis was 26.5 years (range: 19–38), and the median gestational age at birth was 37 weeks (range: 31–40). Among cases where timing was reported, 21% were diagnosed before pregnancy and 23% during pregnancy. Severity was reported in all 53 cases: 72% were classified as non-severe, 26% as severe, and 2% as very severe. Cesarean section was the primary delivery method in 66% of cases. At the time AA was diagnosed or active during pregnancy, median laboratory values were: hemoglobin 7.3 g/dL (range: 3.0–11.8), platelet count 26 × 10⁹/L (range: 8.0–103), and absolute neutrophil count 1.0 × 10⁹/L (range: 0.4–4.0). Maternal and fetal outcomes were reported in 60% and 59% of cases, respectively. Maternal complications included gestational hypertension (6%), gestational diabetes mellitus (6%), infections (23%), and bleeding (26%). Fetal outcomes were generally favorable, with approximately 57% of infants reported as healthy at birth. However, adverse outcomes such as preterm delivery (19%), intrauterine growth restriction (6%), low birth weight (6%), and neonatal intensive care unit admission (9%) were also observed. Maternal and fetal mortality occurred in 4% and 2% of cases, respectively. Treatments administered during pregnancy included red blood cell transfusions (17%), platelet transfusions (17%), and cyclosporine (15%). In the postpartum period, some patients required additional therapies: antithymocyte globulin (4%), eltrombopag (6%), and hematopoietic stem cell transplantation (8%). Conclusion: Aplastic anemia during pregnancy remains rare and clinically complex, with variable timing, severity, and outcomes. Our review underscores the need for early recognition and multidisciplinary management to reduce risks to both mother and fetus. The observation that AA may occur in some pregnancies but not others within the same individual raises important questions about underlying disease mechanisms. Broader, systematic studies are needed to clarify these patterns and to inform safer, more effective treatment strategies during pregnancy.

Abstract BACKGROUND Tovorafenib is a type II rapidly accelerated fibrosarcoma (RAF) kinase inhibitor approved by the FDA in 2024 for relapsing or chemotherapy-refractory pediatric low-grade gliomas with mutations or alterations in the gene BRAF. There is potential for the use of this drug outside the pediatric population. We present a single institution case series of adults with CNS tumors with mutations or alterations in BRAF treated (off-label) with tovorafenib. METHODS Chart review. RESULTS 8 adult (age >18) patients were treated with tovorafenib at our institution between March 2024 and June 2025. Age range was 21-66 years old (median age 42). The population included 5 males and 3 females. Indications for treatment were pilocytic astrocytoma (n = 2), high grade astrocytoma with piloid features (HGAP) (n = 2), Erdheim-Chester disease (n = 2), pleomorphic xanthoastrocytoma (n = 1), and otherwise unclassified low-grade glioma (n = 1). All patients had mutations or alterations in BRAF including KIAA1549 fusion (n = 4), V600E mutation (n = 3), or GAB2 fusion (n = 1). Radiographic response to therapy was seen in 5/8 patients with 3 cases of radiographic stability (though one patient later progressed) and 2 cases of decrease in tumor size (in a pilocytic astrocytoma and in an HGAP). Both cases of decreased tumor size after treatment were in tumors with KIAA1549 fusions. Adverse effects of tovorafenib included fatigue (n=2), headache, myalgias, diplopia, cytopenias, and transaminitis (n=1). 3/8 patients had to pause or stop treatment due to adverse effects (intolerable headache, cytopenias, and transaminitis respectively). CONCLUSION Tovorafenib is a promising new treatment for CNS tumors with BRAF mutations or alterations. Our single institution case series suggests the efficacy of this drug for multiple tumor types in adults. Certain tumor subtypes such as KIAA1549 fusions may be more likely to benefit from this treatment.

Abstract BACKGROUND Mixed histiocytic neoplasms with overlapping features of Erdheim-Chester Disease (ECD) and Rosai-Dorfman Disease (RDD) are extremely rare and diagnosis may be delayed due to lack of awareness and complex histology features. METHODS We report a case of mixed ECD/RDD misdiagnosed as IgG4-related disease and review the literature. RESULTS A 50-year-old man presented for evaluation of spastic paraparesis in the context of a thoracic dural lesion. Two years prior he developed an inflammatory monoarthritis concerning for rheumatoid arthritis unresponsive to methotrexate. Six months prior he developed leg spasms, gait spasticity, and urinary incontinence. MRI demonstrated a T2 hypointense enhancing epidural mass with spinal cord compression. Epidural biopsy showed fibrosis and non-specific inflammation. Given elevated serum IgG4 (170 mg/dL) and clinical findings, he was diagnosed with IgG4-related disease. He received high dose prednisone and etanercept without radiographic or clinical improvement. He then presented to our institution. Given high concern for RDD, he underwent FDG-PET CT which demonstrated an infiltrative process and FDG avid regions in the upper thoracic spinal cord, paranasal sinus, renal hilum, perivascular abdominal vessels, testicle, and multiple joint effusions. Biopsy of left testicle demonstrated CD163-positive histiocytes which coexpressed S100, cyclin D1, and OCT2, consistent with RDD. Biopsy of the left shoulder synovium demonstrated an atypical CD163-positive histiocytic infiltrate expressing Factor XIIIa, cyclin D1 and S100 (partial), and appeared negative for OCT2, consistent with ECD. The atypical histiocytes in both biopsies were negative for CD1a and BRAF V600E by immunohistochemistry. Genomic sequencing of the testicular tissue demonstrated a MAP2K1 (Q56P) alteration. He was treated with radiation therapy targeting the dural lesion with temporarily worsening symptoms improved with steroids and started on cobimetinib. DISCUSSION This case expands on the phenotypic description of mixed ECD/RDD. Histiocytic neoplasms should be considered in the differential diagnosis of dural based lesions.

469 Background: Febrile neutropenia (FN) is a potentially life-threatening complication of myelosuppressive chemotherapy. Multiple professional organizations, including the American Society of Clinical Oncology (ASCO), Infectious Diseases Society of America (IDSA), National Institute for Health and Care Excellence (NICE), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN), have developed clinical guidelines addressing FN management. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework offers a structured method for assessing the evidence underlying these recommendations. Methods: A comparative analysis was conducted across guidelines. Key domains, including definitions, risk stratification, empiric antimicrobial therapy, duration of antimicrobial therapy, use of granulocyte colony-stimulating factor (G-CSF), and antimicrobial prophylaxis were assessed. Recommendations were analyzed for concordance and the certainty of supporting evidence was appraised using the GRADE framework. The certainty of the evidence was graded as high, moderate, low, or very low. Results: All five guidelines uniformly defined FN as fever ≥38.3°C or sustained ≥38.0°C accompanied by neutropenia (absolute neutrophil count <500 cells/µL), despite very low-certainty evidence supporting these specific thresholds. Risk stratification using validated tools, such as the Multinational Association for Supportive Care in Cancer (MASCC) score and the Clinical Index of Stable Febrile Neutropenia (CISNE), is recommended based on moderate-certainty evidence. Empiric monotherapy with anti-pseudomonal beta-lactam agents is recommended across guidelines and supported by high-certainty evidence. Antifungal therapy is recommended for persistent fever beyond 4–7 days in high-risk patients based on low-certainty data. Variability was noted in the suggested duration of antibacterial therapy and the role of therapeutic G-CSF based on low-certainty evidence. Recommendations for antimicrobial prophylaxis are consistent across high-risk populations. Conclusions: Despite broad agreement in foundational management principles for febrile neutropenia, differences exist in the application of therapeutic G-CSF and the duration of empiric antibiotics. These findings underscore the need for high-quality clinical trials to inform harmonized, evidence-based recommendations. This synthesis identifies priority areas for stewardship initiatives and quality-of-care improvement.

606 Background: NCCN guidelines are among the most comprehensive and widely adopted clinical practice standards in oncology, frequently used by both clinicians and payors across the United States. Theys encompass three main categories: treatment, detection/prevention/risk reduction, and supportive care. While the evidence base for treatment recommendations has been examined in prior studies—and early detection guidelines largely align with those from other major medical societies—the strength of evidence supporting recommendations in supportive care guidelines remains poorly characterized. Methods: We conducted a systematic analysis of the categories of evidence and consensus (EC) supporting recommendations in 5 widely utilized NCCN supportive care guidelines (versions 2025): antiemesis, cancer-related fatigue, distress management, hematopoietic growth factors, and smoking cessation. Recommendations were classified into the following EC levels: category 1 (high-level evidence with uniform consensus [>85%]), category 2A (lower-level evidence with uniform consensus), category 2B (lower-level evidence with moderate consensus [50–84%]), and category 3 (any level of evidence with major disagreement). Results: Of the 120 recommendations found in the 5 guidelines of supportive care, the proportions of category I, IIA, IIB, and III EC were 18%, 82%, and 0%, and 0%, respectively. Recommendations with category I EC were found in antiemesis supportive care (30%), cancer-related fatigue (21%), distress management (12%), hematopoietic growth factors (20%), and smoking cessation (13%) guidelines. Conclusions: A substantial proportion of recommendations in the NCCN supportive care guidelines are derived from lower levels of evidence. While these guidelines are invaluable in standardizing care and guiding clinical decision-making, their reliance on expert opinion underscores a critical gap in the oncology evidence base. This situation presents both a challenge and a compelling opportunity to design and conduct rigorous clinical research that can validate current practices, inform future recommendations, and further improve patient outcomes. Level of recommendation by guideline. Guideline Recommendations I IIA IIB III Antiemesis 23 30% 70% 0% 0% Cancer-related fatigue 19 21% 79% 0% 0% Distress management 43 12% 88% 0% 0% Growth factors 19 20% 80% 0% 0% Smoking cessation 16 13% 87% 0% 0%