Cuker, Adam

Background: Since publication of the American Society of Hematology 2019 Guidelines for Immune Thrombocytopenia (ITP), new clinical trials have been completed and new treatments have become available. Objective: These evidence-based guidelines from the American Society of Hematology (ASH) are a focused update of the 2019 ASH ITP guidelines, centering on treatment of adults with primary ITP. Methods: ASH formed a multidisciplinary guideline panel including two patient representatives that was balanced to minimize potential bias from conflicts of interest. The University of Oklahoma supported the guideline development process, including updating or performing systematic evidence reviews (up to July 19, 2025). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and identification of areas with new data or where application of new methods would be of benefit. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks and the GRADE framework for multiple comparisons, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on recommendations in adults with primary ITP regarding initial therapy and second-line treatment in patients who failed first-line corticosteroids. The panel also issued good practice statements on thrombopoietic agent switching and splenectomy. Conclusions: Novel recommendations of these guidelines include: (1) initial therapy with a combination of rituximab plus corticosteroids or a thrombopoietic agent plus corticosteroids rather than corticosteroids alone (conditional recommendation) and (2) a thrombopoietic agent (strong recommendation) or rituximab (conditional recommendation) for patients who failed first-line corticosteroids.

Abstract Maternal iron deficiency (ID) affects nearly 85% of all pregnancies worldwide by the third trimester and is strongly linked with maternal morbidity, poor birth outcomes, and cognitive and behavioral developmental deficits in children. Despite its burden on maternofetal health, no guidelines exist for routine screening of ID in pregnant individuals in the United States. The World Health Organization uses a diagnostic (ie, nonscreening) ferritin threshold of 15 μg/L for ID in the first trimester of pregnancy, with no guidance for the second and third trimesters. Routine screening for ID in pregnancy could identify a large proportion of mothers who remain undiagnosed and untreated under the current clinical status quo. Accordingly, we conducted, to our knowledge, the first cost-effectiveness analysis of ferritin-based ID screening in pregnant women in the United States, comparing thresholds of (1) 30 μg/L vs (2) 15 μg/L vs (3) no screening from a modified US societal perspective accounting for wages lost to infusion time, infusion administration costs, and the cost of annual hematology follow-up. We found that screening at 30 μg/L was the preferred strategy across extensive base-case, threshold, and sensitivity analyses and across all examined willingness-to-pay thresholds, with an incremental cost-effectiveness ratio of $34 000/quality-adjusted life year (QALY; 95% credible interval, $32 000-$36 200/QALY) compared with no screening. No parameter variation changed this outcome, and screening at 30 μg/L was favored in 100% of 10 000 Monte Carlo iterations. Population-level regular second- and third-trimester screening for ID using physiologically informed ferritin ranges should be considered for all pregnant women in the United States.

Abstract Iron-deficiency anemia (IDA) affects nearly one-third of women globally, with heavy menstrual bleeding (HMB) being a significant risk factor among those of reproductive age. Despite the substantial burden of HMB-related IDA, patients often face delays in receiving effective treatment. Oral iron is typically used as first-line therapy, despite frequent gastrointestinal side effects and challenges in treatment adherence. This study evaluated the reproductive life span cost-effectiveness of first-line intravenous (IV) vs oral iron therapy for women with HMB and IDA. We developed a Markov model simulating a cohort of women aged 18 to 51 years, comparing first-line treatment with IV iron dextran, IV ferumoxytol, IV iron sucrose, or oral ferrous sulfate. Costs and quality-adjusted life years (QALYs) were estimated from the societal perspective. IV iron dextran was the cost-effective treatment, yielding 19.26 QALYs at a cost of $157 500, compared with 19.10 QALYs at $152 900 for oral ferrous sulfate. The incremental cost-effectiveness ratio for IV iron dextran was $28 600 per QALY. Treatment with IV ferumoxytol and iron sucrose cost $158 300 and $163 500, respectively, and did not provide additional QALY benefit compared with IV iron dextran, which remained the cost-effective treatment across a range of scenarios and sensitivity analyses. Our findings indicate that first-line treatment with IV iron dextran is the cost-effective strategy for managing IDA in women with HMB at commonly accepted willingness-to-pay thresholds. These results support expanding access to IV iron as a first-line option, and highlight the need to reduce treatment delays and insurance-related barriers.

Abstract Systems-based hematology (SBH) is an emerging discipline focused on optimizing care delivery for patients with hematologic disorders within complex health care systems. Despite its growing importance, the field lacks a formal definition, standardized curriculum, and clear career pathway, hindering widespread adoption and training of future SBH experts. We sought to define core principles, competencies, challenges, and future directions of SBH to identify foundational components for a potential educational curriculum. Semistructured interviews were conducted with 8 SBH experts. Expert participants were identified through their committee involvement with the American Society of Hematology. Five overarching themes emerged: (1) The accidental expert: SBH careers have developed organically and reactively in response to pressing institutional needs, not through formal training; (2) Defining the unseen: experts define the field pragmatically by its function and roles; (3) The SBH toolkit: success requires a hybrid skillset combining clinical hematology expertise with health systems science (HSS) principles; (4) The architect's dilemma: the field's growth is hindered by interdependent challenges of building a curriculum, awareness, and securing resources; and (5) Charting the future: the discipline is poised for growth, driven by increasing health care complexity and specialization. SBH represents the nexus of HSS principles and hematology care. Formalizing SBH requires a multipronged approach, including developing a standardized curriculum that equips learners with a hybrid skillset, creating clear value for health systems and patients, and fostering a community of practice through professional societies. These findings provide a foundational framework for developing educational resources and institutional support necessary to continue advancing SBH.

Abstract Introduction: The Duffy null variant (genotype or phenotype) is associated with lower circulating absolute neutrophil counts (ANC) without increased risk for infection. It is found in ~66% of people identifying as Black or African American vs <1% of people of Asian or European ancestry. Many ANC reference intervals (RI) are not representative of the Duffy null population. There are no adult Duffy null WBC RI and no pediatric Duffy null ANC or WBC RI. Thus, we aimed to assess Duffy null ANC and WBC distributions as well as develop WBC and ANC RI for adults and pediatrics. Methods: Twenty-three sites across the United States collected samples with all sites excluding participants with conditions or medications that could impact ANC or WBC. Only Duffy null participants were included. Sex, race, ethnicity, age, sample collection type, practice setting, Duffy testing method, ANC, and WBC were recorded. The non-parametric method for determining lower limit of normal (LLN), upper limit of normal (ULN), and 90% confidence intervals (CI) around the limits was performed according to the Clinical and Laboratory Standards Institute guidelines. Specific ULN and LLN are not reported as these are preliminary data. The Mann-Whitney U test was used to compare sex and prior data; differences by age groups were assessed with Kruskal-Wallis test. Results: 316 participants 18+ years-old (y/o) were assessed of whom 62.3% (n=197) are female, 97.5% (n=308) identified as Black or African American, and 94.9% (n=300) identified as non-Hispanic. Median age was 47 y/o (IQR: 32-60.5). Median ANC was 2600/uL (IQR: 1860-3530; range: 400-7400); 28.6% (n=90) of participants had ANC <2000/uL, 13.6% (n=43) had ANC <1500/uL, and 2.5% (n=8) had <1000/uL. The 90% CI around the LLN was 810-1070/uL and 5570-7130/uL around the ULN. Consistent with prior data, there was a difference in median ANC by sex (male: 2400/uL; female: 2710/uL; p=0.02). There was no significant difference between this ANC data and previously published Duffy null ANC data (p=0.28). Median WBC was 5.4x109/L (IQR: 4.4-6.5; range: 2.10-11.64) with 4.1% (n=13) of participants with WBC <3.0x109/L. The 90% CI around the LLN is 3.68-4.30x109/L and 11.02-12.97x109/L around the ULN. 515 participants between 0-17 y/o were assessed with 51.8% (n=267) females, 94.8% (n=488) identified as Black or African American, and 94.0% (n=484) identified as non-Hispanic. Among pediatric participants, 56.8% (n=291) had ANC <2000/uL, 38.7% (n=198) had ANC <1500/uL, and 14.4% (n=74) had ANC <1000/uL. For those <1 y/o (n=29), median ANC was 950/uL (IQR: 840-1360; range: 111-3910). There are currently too few samples to predict ULN and LLN. Median WBC was 8.85x109/L (IQR: 7.03-10.16; range: 4.17-13.53). For those 1-5 y/o (n=143), median ANC was 1735/uL (IQR: 1100-2550; range: 207-5810) with a 90% CI around the LLN of 207-820/uL and 4020-5810/uL around the ULN. Median WBC was 6.72x109/L (IQR: 5.64-8.25; range: 3.68-12.97). For those 6-11 y/o (n=128), median ANC was 1590/uL (IQR: 1090-2470; range: 420-5490) with a 90% CI around the LLN of 420-910/uL and 4340-5490/uL around the ULN. Median WBC was 5.42x109/L (IQR: 4.45-6.70; range: 2.80-10.50). For those 12-17 y/o (n=215), median ANC was 2190/uL (IQR: 1460-2930; range: 204-5850) with a 90% CI around the LLN of 540-930/uL and 4350-5510/uL around the ULN. Median WBC was 5.06x109/L (IQR: 4.26-6.20; range of 2.04-9.91). There is a significant difference in ANC by age category (p<0.0001). Conclusion: This is the first report of healthy pediatric Duffy null ANC and WBC data and the first large-scale verification of adult Duffy null ANC and WBC data. Final RI are expected in September 2025. Among adults with the Duffy null phenotype, ANC LLN are likely between 810-1070/uL. Pediatric ANC LLN are likely as low as 207-820/uL (1-5 y/o), 420-910/uL (6-11 y/o), and 540-930/uL (12-17 y/o). These findings redefine “normal” as a significant proportion of healthy participants have ANC or WBC below current RI or below thresholds typically defined as disease. Limitations include heterogeneous sample populations and collection methods. Future analyses will assess differences between collection sites or methods. Ultimately, this work lays the foundation for a more scientifically sound and equitable approach to medical care by ensuring that RI accurately reflects health for the entire community. Healthcare systems are strongly encouraged to adopt Duffy null-specific ANC and WBC RI.

Abstract Introduction: Iron deficiency (ID) is among the five leading causes of years lived with disability in women of reproductive age worldwide and affects >50% of pregnancies. Both ID and its terminal sequela, iron deficiency anemia, are associated with adverse maternal-fetal outcomes including postpartum hemorrhage, impaired fetal neurocognitive development, preterm labor, and maternal mortality. At present, no United States (US) guidelines exist for the universal screening of ID in pregnancy. Moreover, diagnostic thresholds for ID established by the Centers for Disease Control and Prevention (CDC; <15µg/L ferritin in all trimesters) and the World Health Organization (WHO; <15µg/L ferritin in first trimester and no guidance in second or third) fall below more sensitive physiologically-based thresholds of no less than 20-25µg/L ferritin in pregnancy. As such, ID screening and treatment represents an enormous gap in the health of expectant mothers and in which intravenous iron supplementation has been established as an effective and safe treatment option. We sought to address this gap by conducting the first cost-effectiveness analysis of screening ferritin thresholds for ID diagnosis and treatment in pregnancy. Methods: We built a Markov simulation to examine the cost-effectiveness of screening all individuals for iron deficiency in the second and third trimesters of pregnancy with the following strategies: 1) ferritin threshold <30µg/L, 2) ferritin threshold <15µg/L, and 3) status quo (i.e., no screening). The analysis was conducted over a lifetime horizon, from the US health system perspective and across all accepted willingness-to-pay (WTP) thresholds measured in $ per quality-adjusted-life-year (QALY). Costs were assessed in 2025 USD, inclusive of age- and sex- specific annual healthcare costs informed by the US Medical Expenditures Panel Survey. Age-specific fertility rates were sourced from the US National Vital Statistics Reports and used for model internal validation. The trimester-specific prevalence of ID was informed by the largest published longitudinal prospective cohort study of iron status in pregnant women to date. The probability of iron-related adverse events including anaphylaxis was sourced from the World Health Organization Vigibase data. Aligning with prospective data of ID in pregnancy, women entered the model at age 15 and were screened (or not screened) for ID per treatment strategy during the second and third trimester of each pregnancy in their lifetime. If found to be iron deficient, patients were treated with a single dose of 1g intravenous iron dextran. A separate scenario analysis from a societal perspective also incorporated the cost of wages lost to infusion time. Effectiveness was measured in QALYs and parameterized multiplicatively using age-, sex-, pregnancy-, and ID-specific utility values, exclusively assessing maternal benefit in pregnancy without accounting for any fetal benefit. The primary outcome of interest was the incremental cost-effectiveness ratio (ICER). We conducted deterministic and probabilistic sensitivity analyses, capturing uncertainty across all parameters simultaneously over 10,000 Monte Carlo iterations. Results: Internal model validation demonstrated an average fertility rate of 1.62 [95% credible interval (CI) 1.59-1.65], in line with the US fertility rate of 1.62. Screening for ID with a ferritin threshold of 30µg/L versus 15µg/L versus no screening accrued $213,000, $212,800, and $212,400 and 25.12, 25.11, and 25.09 QALYs per individual, respectively. Screening at a ferritin threshold of 30µg/L was the cost-effective strategy in 100% of 10,000 Monte Carlo iterations, with an ICER of $23,000/QALY [95% CI $20,000-$27,000/QALY], below all accepted WTP thresholds. Screening at 30µg/L remained the cost-effective strategy from a societal perspective, at an ICER of $33,000/QALY [95% CI $29,000-$38,000/QALY]. Deterministic sensitivity analysis revealed that no parameter variations changed this conclusion.Conclusion: The identification and treatment of ID beginning in the second trimester at a ferritin threshold of <30µg/L is the cost-effective intervention, in comparison to a threshold of <15µg/L or no screening. These results fill a critical gap in maternofetal medicine and may help inform the forthcoming American Society of Hematology Clinical Practice Guidelines on the Diagnosis and Treatment of Iron Deficiency.

Abstract Intracranial hemorrhage (ICH) and resulting neurologic disability are severe complications for a subset of infants with severe hemophilia A (HA). Although prophylactic factor replacement reduces bleeding risk, it is typically delayed until after age 1 year due to risks associated with central venous access placement. Emicizumab, a subcutaneous activated factor VIII (FVIII) mimetic, has demonstrated safety and efficacy in preventing ICH in infants aged <12 months in the HAVEN 7 trial. Despite its high cost, the cost-effectiveness of emicizumab prophylaxis initiated during the first year of life for infants with severe HA is not known. We developed a Markov cohort model to compare emicizumab prophylaxis to standard care (no prophylaxis) in infants aged 0 to 1 year with severe HA without FVIII inhibitors. The analysis was conducted from a US societal perspective over a lifetime horizon across all accepted willingness-to-pay (WTP) thresholds. The primary outcome was the incremental cost-effectiveness ratio (ICER) in US dollar per quality-adjusted life-year (QALY). Emicizumab prophylaxis and standard care accrued 25.6 and 25.1 QALYs at costs of $13.12 million and $13.07 million, respectively, resulting in an ICER of $99 900 per QALY (95% credible interval [CI], 84 000-120 000). Scenario analysis examining prophylaxis with low-dose emicizumab resulted in an ICER of $19 600 per QALY (95% CI, 12 000-29 000). Probabilistic sensitivity analyses showed that standard-dose emicizumab is the cost-effective strategy in 100%, 66%, and 0% of 10 000 Monte Carlo iterations at WTP thresholds of $150 000, $104 000, and $50 000 per QALY, respectively, and in 100% across all WTP thresholds for low-dose emicizumab.

ABSTRACT Iron deficiency (ID) is a top five leading cause of disability‐adjusted life‐years in women of reproductive age around the world. Despite its enormous health burden, no screening guidelines exist for the detection and treatment of ID in women of reproductive age. We sought to determine the cost‐effectiveness of screening versus no screening for ID in women of reproductive age in the United States. A lifetime simulation of women of reproductive age was conducted using a Markov cohort model under three strategies: (1) no screening, (2) screening at a ferritin threshold of 15 μg/L, and (3) screening at a ferritin threshold of 25 μg/L, from the US health system perspective, and at a willingness‐to‐pay threshold of $100 000/quality‐adjusted life year (QALY). Epidemiologically informed ID prevalence estimates sourced from the National Health and Nutrition Examination Survey were employed for model parameterization. The primary outcome was the incremental cost‐effectiveness ratio (ICER, in $/QALY). Base‐case results for the three strategies accrued $209 700, $210 200, and $210 200 discounted lifetime costs and 23.6, 24.0, and 24.4 discounted lifetime QALYs, respectively. Screening at a ferritin threshold of 25 μg/L was the cost‐effective intervention with an ICER of $680/QALY (95% credible interval $350–$750/QALY). In dual base‐case analyses examining intravenous rather than oral iron repletion for treatment, screening at a ferritin threshold of 25 μg/L remained the cost‐effective intervention with an ICER of $2300/QALY (95% CI $1800–$3800/QALY). In probabilistic sensitivity analyses, screening at a ferritin threshold of 25 μg/L was the cost‐effective intervention in 100% of 10 000 second order Monte Carlo iterations.

Introduction: Systems-based hematology (SBH) is an emerging field focused on improving hematology care delivery through quality improvement (QI) and health systems science (HSS). However, a universal definition and standardized training curriculum are lacking. This study aimed to explore experts' perspectives on defining SBH, identify core knowledge and skills, and discuss challenges and opportunities in developing a curriculum. Methods: Semi-structured interviews were conducted with eight hematologists who have expertise in SBH through practical experience, scientific publications, and serve on related committees for the American Society of Hematology. These interviews were automatically transcribed through Microsoft Teams. Thematic analysis, using both inductive and deductive coding, was employed to identify themes and subthemes from the verbatim interview transcripts. This was accomplished with a large language model (LLM; Google Gemini Advanced, June 2024). Results: In combination, these semi-structured interviews lasted approximately 400 minutes and generated 231 pages of transcript text with 63117 words for analysis. Five main themes and associated subthemes were identified. (1) Defining SBH: experts highlighted the lack of a universal definition for SBH, emphasizing the reason it is often defined by its functions, such as improving healthcare delivery, ensuring appropriate use of resources, and addressing disparities in care. They often compared SBH to other fields like antimicrobial stewardship or implementation science to illustrate its expansive role and scope. (2) The Role and Scope of SBH: experts described SBH as encompassing a broad range of activities, including improving healthcare delivery, implementing QI initiatives, conducting pragmatic research, and advocating for policy changes at various levels. They emphasized the importance of data-driven approaches and collaboration with other healthcare professionals. (3) Training and Education in SBH: the lack of formal training programs and curricula for SBH was a recurring theme. Experts suggested that a comprehensive curriculum should include QI methodologies, implementation science, clinical informatics, health economics, leadership skills, and hematology-specific examples and case studies. They proposed various delivery methods, including asynchronous online modules, virtual workshops, and in-person sessions, targeting hematology fellows, junior faculty, and other healthcare professionals involved in hematology care. They unanimously agreed that a SBH curriculum could borrow heavily from an established HSS curriculum but should incorporate hematology-specific examples. (4) Challenges and Barriers to Implementing SBH: experts identified several challenges, including the lack of awareness and recognition of SBH among healthcare professionals and administrators, resource constraints, and the need for institutional buy-in. They also highlighted the technical difficulty of measuring and demonstrating the value of SBH interventions, particularly in terms of cost savings and improved patient outcomes. (5) The Future of SBH: despite the challenges, experts expressed optimism about the future of SBH, predicting its growing importance and expanding scope, including malignant hematology, community practice, and pediatrics. They envisioned SBH playing a crucial role in addressing rising healthcare costs, quality concerns, and disparities in care. They also anticipated the integration of new technologies like artificial intelligence, “virtual” care delivery, and molecular genetics into SBH practice. Conclusions: This study provides valuable insights into the current state of SBH and the need for a standardized curriculum. The findings can inform the development of educational resources and training programs to equip future practitioners with the necessary knowledge and skills to effectively practice SBH and improve hematology care delivery. This study also sheds light on the utility of qualitative research within SBH and the emerging analytical tools that will require further exploration and standardization (e.g., LLM prompt engineering).