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Abstract Introduction: Langerhans Cell Histiocytosis (LCH) is a rare histiocytic neoplasm, with approximately 90% of patients exhibiting alterations in the MAPK pathway. BRAF and MEK inhibitors have shown promising results in treating MAPK pathway-altered LCH. However, treatment interruptions due to adverse effects are common, and limited access to targeted therapies complicates care globally. While chemotherapy remains a common treatment for LCH, the outcomes for patients with MAPK pathway-altered LCH specifically receiving chemotherapy are still unclear. Methods: This multi-institutional international retrospective cohort study analyzed adult patients with BRAF or MAP2K (gain-of-function, GOF) altered LCH that were consecutively seen at Mayo Clinic, MN, AZ, and FL, University of Alabama at Birmingham, and Peking Union Medical College Hospital in China between 2007 and 2024. All patients who were included in this study were treated with chemotherapy, and those who have received targeted therapies or other modalities of frontline treatment were excluded. All time-to-event analyses were performed from the frontline therapy initiation, using the Kaplan-Meier method. Progression-free survival (PFS) included death and progression as events and was measured from the time of treatment initiation. The response assessment was based on radiographic evaluation in accordance with the most recent Histiocyte Society consensus guideline. Risk organ involvement was defined as disease involving the liver, spleen, bone marrow or central nervous system. Results: A total of 63 patients with LCH were included. The median age of the population was 34 years (range: 27-43), and males were 59%. Risk organ involvement was seen in 44 (70%) of patients and multisystemic LCH was observed in 48 (76%) patients. Among the 63 patients, BRAF gain-of-function alterations were observed in 79%, MAP2K mutations in 19%, and BRAF fusions in 2%. Of the BRAF gain-of-function alterations, BRAFV600E mutation was seen in 64% patients and [p.N486_P490del] deletion in 36%. There was no significant difference in organ involvement (single-system versus multisystem) or risk organ involvement between patients with BRAF and MAP2K alterations. All 63 patients received systemic therapy with chemotherapy and the regimens included Cytarabine (n=43), Cladribine (n=5), Etoposide (n=1), Methotrexate (n=1), and combined Methotrexate and Cytarabine (n=13). The median follow-up for the entire cohort was 3.8 years (range 3.2–5.0 years), with similar durations observed in patients with single-system vs. multisystem involvement and those with risk-organ involvement vs. no risk-organ involvement. The overall response rate among patients who received chemotherapy was 89%, with complete responses in 15 patients (26%) and partial responses in 40 patients (64.5%). The median progression-free survival (PFS) for the entire cohort was 2.61 years (95% CI: 2.06–NA). The 3-year PFS did not significantly differ based on risk organ involvement: 50.6% (95% CI: 36–71) for patients with risk organ involvement versus 47.4% (95% CI: 28–81) for those without, p=0.52. Patients with single-system disease experienced longer PFS compared to those with multisystem disease; the 3-year PFS was 80.2% (95% CI: 58.7–100) versus 42.2% (95% CI: 29–61.5), respectively, p=0.04. Conclusions: Our results indicate that LCH patients with a GOF alteration in the MAPK pathway derive significant clinical benefit from chemotherapy, achieving deep and durable responses. Therefore, patients should not be excluded from treatment due to the absence of targeted therapies, as they can still attain substantial responses and clinical improvement with chemotherapy, even in the context of MAPK pathway-driven disease.

Abstract Introduction: Castleman disease (CD) is a heterogeneous group of lymphoproliferative disorders classified anatomically as unicentric (UCD), oligocentric (OligoCD), or multicentric (MCD). Human herpesvirus 8 (HHV-8)-negative MCD is referred to as idiopathic MCD (iMCD), which includes clinical subtypes with distinct phenotypes and treatment responses: TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction and/or reticulin fibrosis, and organomegaly), idiopathic plasmacytic lymphadenopathy (IPL), and not otherwise specified (NOS). While UCD and iMCD, including TAFRO, have been more clearly defined, OligoCD and iMCD-IPL remain under-characterized, particularly in Western cohorts. This study aimed to validate the updated clinical classification of CD using a large institutional cohort by retrospectively reclassifying patients based on lymph node distribution and clinicopathologic criteria. We further examined whether OligoCD and IPL represent clinically and prognostically distinct entities compared to UCD or iMCD, and other iMCD subtypes. Methods: This study included 217 patients evaluated for CD at our institution between January 2004 and August 2024. All cases were reclassified based on the extent of lymph node involvement and iMCD subtype. UCD was defined as the involvement of a single lymph node region. OligoCD was defined as involvement of ≥2 contiguous lymph node stations without sufficient systemic symptoms to meet iMCD criteria. Patients with POEMS syndrome or HIV/HHV-8–associated CD, or lacking pathologic confirmation, were excluded. We evaluated clinical presentation, laboratory data, histopathology, treatment regimens, and outcomes. The primary endpoint was overall survival (OS), and the secondary endpoint was event-free survival (EFS), defined as time from first-line treatment to progression, change in therapy, or death. Survival outcomes were assessed using the log-rank test. Results: Among 217 CD patients, 123 (57%) had UCD, 43 (20%) had OligoCD, and 51 (23%) had iMCD. iMCD-defining symptoms were more common in iMCD compared to UCD and OligoCD. Among all, only fatigue and organomegaly were more common in OligoCD than in UCD. Laboratory values related to CD disease activities, including hemoglobin, serum creatinine, albumin, CRP, and plasma IL-6, showed significant differences in iMCD compared to UCD and OligoCD. No significant difference in the laboratory findings was observed between UCD and OligoCD, although patients with OligoCD had intermediate values between UCD and iMCD. With median follow-up of 4.0, 7.6, and 4.6 years for UCD, OligoCD, and iMCD, respectively, the 5-year OS was 99.0%, 97.7%, and 89.5% without differences among groups. Corresponding 2-year EFS rates were 95.2% for UCD, 68.0% for OligoCD, and 53.8% for iMCD. With OligoCD being the reference, UCD had a significantly lower hazard ratio (HR) of 0.20 (95% CI 0.10–0.41), and iMCD had a significantly higher HR of 2.0 (95% CI 1.1–3.6). Among OligoCD patients initially treated with surgery (40%), none required systemic therapy thereafter. Those treated with rituximab or glucocorticoid monotherapy required subsequent therapy in 50% and 43%, respectively. Within iMCD subtypes (TAFRO (n=16), IPL (n=9), and NOS (n=26)), the 5-year OS was 80.4%, 100%, and 91.0%, respectively, without significant differences among the subtypes. However, 1-year EFS rates were 40.2%, 100%, and 65.6%, respectively, with an HR of 4.3 (95% CI 1.2–15.2; p = 0.02) in TAFRO and 1.6 (95% CI 0.77–3.5) in NOS compared to IPL. Patients with IPL had a high rate of symptomatic improvement assessed by a physician of 89% with a longer time-to-next treatment. Conclusions: This extensive, retrospective cohort study supports the clinical relevance of updated CD subtype classification. As the present study spans two decades, it reflects evolving diagnostic criteria and therapeutic standards, including the 2014 FDA approval of siltuximab, the iMCD consensus criteria in 2017, with the addition of OligoCD and iIPL. The findings confirm the aggressive clinical nature of iMCD and suggest that OligoCD demonstrated intermediate features between UCD and iMCD, though closer to UCD in outcome. Also, the results reconfirmed that TAFRO is associated with severe symptomatic diseases, and validated that patients with IPL, even in the Western cohort, likely have favorable responses to treatment. Continued prospective efforts are warranted to confirm the clinical distinctions.

Abstract Introduction: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product. TRANSFORM (NCT03575351) is a global, randomized, open-label, phase 3 study of liso-cel versus SOC as second-line therapy in adults with R/R LBCL. In the TRANSFORM study, liso-cel showed superior, more durable efficacy versus SOC, with a potential long-term survival benefit and a favorable safety profile, highlighting the curative potential of liso-cel for second-line R/R LBCL. Upon completion of TRANSFORM, patients who received liso-cel could enroll into a separate, long-term follow-up (LTFU) study (NCT03435796). Here, we report results after approximately 4 years of follow-up in patients from TRANSFORM who consented to the LTFU study. Methods The TRANSFORM study compared liso-cel versus SOC (chemotherapy [R-DHAP, R-ICE, or R-GDP] followed by high-dose chemotherapy [HDCT] + ASCT) in adults aged ≤ 75 years with LBCL primary refractory to or relapsed within 12 months of first-line therapy and eligible for ASCT. Patients in the liso-cel arm underwent lymphodepletion followed by liso-cel (100 × 106 CAR+ T cells). Crossover to receive liso-cel was allowed for patients in the SOC arm. The LTFU study enrolled patients who received liso-cel and discontinued early or completed TRANSFORM; liso-cel was not administered during the LTFU study and subsequent therapies were administered at investigator discretion. Selected AEs considered related to liso-cel (malignancies, neurologic, hematologic, or rheumatologic/autoimmune disorders) and OS would be assessed at each visit (month 3 and then every 6 months from years 1 to 5, and then annually) for up to 15 years from liso-cel infusion until study withdrawal or death, whichever occurred first. OS for the combined study was defined as the time from randomization to death due to any cause. PFS for the combined TRANSFORM and LTFU studies incorporated data from TRANSFORM, assessed by an independent review committee, and from LTFU, assessed by investigators, and was defined as the time from randomization to disease progression or death from any cause. For LTFU only, OS and PFS were measured from LTFU consent to event or censoring. In cases where the patient was censored at last assessment date (without receiving new therapy) in TRANSFORM and enrolled in LTFU, LTFU data were used. For patients from the liso-cel arm of TRANSFORM who did not enroll in the LTFU study, the data from TRANSFORM were considered (ie, either an event or censored) at their last adequate assessment date or before starting new therapy. Results are reported descriptively. Results In total, 184 patients were randomized in TRANSFORM (92 per arm); key demographics and baseline characteristics were previously reported (Abramson, et al. Blood 2023). The LTFU study enrolled 67 patients who received liso-cel (liso-cel arm, n = 43; crossover from SOC arm, n = 24). The median follow-up (range) for the liso-cel arm was 16.9 months (1.3–29.7) in the LTFU study and 40.1 months (2.2–61.9) combining the TRANSFORM and LTFU studies. The median follow-ups for OS and PFS for the liso-cel arm in the LTFU study were 17.1 (16.1–21.9) and 16.9 months (16.0–21.8), respectively. In patients from the LTFU study in the liso-cel arm (n = 43), median PFS and OS were both not reached (NR) with 95% CIs of NR–NR. The 24-month rates (95% CI) of PFS and OS were 94.7% (87.4–100.0) and 95.1% (88.4–100.0), respectively. In the 92 patients randomized to the liso-cel arm, using combined data from the TRANSFORM and LTFU studies, median (95% CI) PFS was NR (12.6–NR); 48-month PFS rate was 52.2% (41.5–62.8). Median (95% CI) OS was NR (NR–NR); 48-month OS rate was 61.5% (51.2–71.7). Safety results from the LTFU study in the liso-cel arm showed no new signals compared with previous reports from TRANSFORM. AEs of any grade occurred in 2 patients (hypogammaglobulinemia and dyspnea; n = 1 each), with no second primary malignancies or serious infections. AEs of grade 3 or 4 occurred in 1 patient (dyspnea). No AEs led to death.Conclusions: After a median follow-up of approximately 4 years combining data from the TRANSFORM and LTFU studies, liso-cel continued to demonstrate long-term clinical benefit with high PFS and OS rates in patients with second-line R/R LBCL. The safety profile of liso-cel continued to be manageable with no new safety signals observed during LTFU. These results further support liso-cel as an effective second-line treatment with curative potential for R/R LBCL.

Abstract Preiser's disease (PD), or idiopathic avascular necrosis of the scaphoid, is a debilitating condition leading to wrist pain, dysfunction, and pan-carpal arthritis. While impaired scaphoid vascularity is central to its pathogenesis, identifying individuals at risk is challenging due to the morphological distortion of the scaphoid as the disease progresses. This study aims to investigate the association between a novel capitate morphology classification, scaphoid morphology, and their impact on PD prevalence and characteristics. We also re-evaluate negative ulnar variance (NUV) as a potential risk factor for PD. This retrospective case–control study included 34 PD patients and 340 age-matched controls. Capitate morphology was classified into Type I/II on anteroposterior (AP) radiographs based on capitotrapezoid–scaphocapitate (CT–SC) joint line angle and ratio. Scaphoid morphology was assessed via the waist index on contralateral healthy wrists. Radiographic measurements of ulnar variance and PD staging were also performed. Statistical analyses compared morphological prevalence and risk factors between groups. Type II capitate was significantly more prevalent in the PD group (35.3%) than in controls (17.1%, p = 0.018). Similarly, NUV was significantly higher in PD patients (29%) compared with controls (6.8%, p < 0.001). We found a strong correlation between Type II capitate and slender (Type II) scaphoid morphology in healthy wrists. No significant differences in age, gender, or affected side were observed. Interobserver and intraobserver agreements for capitate classification were substantial (kappa ≥0.882). Our study introduces a reliable radiographic method for classifying capitate morphology, which strongly correlates with intrinsic scaphoid shape and potential vascular vulnerability. Both Type II capitate morphology and NUV are significant predisposing factors for PD. These findings offer valuable insights for identifying at-risk individuals and improving understanding of PD's multifactorial etiology. Diagnostic Level III.

Abstract Allogeneic hematopoietic cell transplantation (HCT) using an HLA mismatched unrelated donor (MMUD) with calcineurin inhibitor-based graft versus host disease (GVHD) prophylaxis results in increased incidence of non-relapse mortality (NRM) and lower survival compared to matched donor HCT. The NMDP sponsored 15-MMUD study demonstrated that post-transplant cyclophosphamide (PTCy)-based prophylaxis following bone marrow derived MMUD HCT resulted in reduced incidence of GVHD and favorable survival. Because marrow grafts can be difficult to procure and vary in quality, we conducted a phase II, prospective, multicenter study to evaluate PTCy-based GVHD prophylaxis in adult recipients of MMUD using peripheral blood stem cell (PBSC) allografts. The primary study aim was to estimate the probability of one-year overall survival (OS) post HCT. Secondary aims were to assess other key clinical endpoints and determine the rate of severe infections. Initial results of the first 70 recipients who received reduced intensity conditioning (RIC) were previously reported by Al Malki et al (JCO 2025) demonstrating a 1-year OS of 78.6% (95% CI, 67% to 86.5%). Here, we report results from a planned expansion of the study that included 123 additional RIC recipients, with updated results from the initial cohort of 70 patients (total N = 193 subjects) treated at 33 centers. Study participants received cyclophosphamide 50 mg/kg (ideal body weight) administered on days 3 and 4 post HCT with tacrolimus and mycophenolate mofetil as previously described (Al Malki, JCO, 2025). The median study participant age was 65.0 (range: 22.9-78.9); 92 (47.7%) of participants were male, and 84 (43.5%) identified as having other than non-Hispanic white ancestry. The HCT comorbidity index was high-risk (&gt;3) in 65 (33.7%). Underlying histologic diagnosis was AML in 96 (49.7%) participants, MDS in 43 (22.3%), ALL in 20 (10.4%), lymphoma or CLL in 24 (12.4%), and CML/other leukemias in 10 (5.2%). Conditioning regimens used were fludarabine and melphalan (100 or 140 mg/m2) (N=120; 62.2%), 2-day busulfan and fludarabine (N=38; 19.7%), and fludarabine, cyclophosphamide and total body irradiation (200 cGy) (N=32; 16.6%). Donor HLA matching (considering HLA-A, -B, -C, and -DRB1) was 7/8 in 131 (67.9%) of participants, 6/8-matched in 51 (26.4%), and 4-5/8-matched in 11 (5.7%) participants. Median donor age was 25.5 years (range: 18.7-35.7). The one-year overall OS estimate was 79.6% (95% confidence interval [CI]: 73.2-84.7). Survival was similar among HLA 7/8-matched donor recipients (77.8%, 69.7-84%) and &lt;7/8 matched donor recipients (83.7%, 71.8-90.9%). The one-year GVHD-free, relapse-free survival (GRFS) was 49.9% (42.6-56.9%) and the one-year progression-free survival was 70.2% (63.2-76.2%). The one-year cumulative incidence (CI) rates of NRM and relapse were 12.5% (8.3-17.6%) and 17.3%(12.3-23%), respectively. The 6-month CI of grade II-IV and grade III-IV acute GVHD were 40.0% (33.0-46.8%) and 7.8% (4.6-12.1%), respectively. The one-year incidence of all chronic GVHD and severe chronic GVHD were 15.6% (10.7-21.2%) and 3.7% (1.6-7%), respectively, by NIH consensus criteria. The CI of grade 1-4 cytokine release syndrome (CRS) by day 7 post HCT was 28.0% (21.8-34.9%), and grade 3-4 CRS was 0.5% (0-2.9%). Primary engraftment failure occurred in 9 (4.7%) participants. Among 145 evaluated participants, 85.5% were &gt;95% donor in blood chimerism at day 100 post HCT. Within the first 100 days after HCT, CTCAE grade 2-5 infections occurred in 113 (58.5%) of participants and grade 3-5 infections occurred in 59 (30.6%) of participants. The most common etiologies of grade 2-5 infections were bacterial (N=78), followed by viral (N=48). The most common grade 3-5 non-infectious toxicities were cardiac disorders, which occurred in 4 (2.1%) of participants. In conclusion, the results including this expansion cohort demonstrate encouraging 1-year OS, NRM and relapse rates in RIC recipients of PTCy-based GVHD prophylaxis and PBSC allografts from MMUDs. This larger cohort of 193 recipients re-affirm the results from the initial cohort with greater robustness.Measures to mitigate infection risk are likely to further improve outcomes. Reducing the dose of PTCy is a candidate approach currently being tested in the ongoing OPTIMIZE trial (NCT 06001385).These results support the extension of PBSC MMUD using PTCy to individuals who lack an HLA-matched donor and require RIC HCT.

Abstract Background Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare blood disease characterized by uncontrolled complement activation with potentially life-threatening complications. Therapeutic options comprise both terminal complement inhibition, targeting C5 to prevent intravascular hemolysis (IVH), and proximal complement inhibition, intervening upstream within the complement cascade to address IVH and extravascular hemolysis (EVH). Pegcetacoplan, the first C3 and C3b inhibitor, demonstrated efficacy and safety in complement inhibitor (CI)–experienced (CIexp) and –naïve (CInaive) patients in two phase 3 studies with a three year follow up (PEGASUS [NCT03500549] and PRINCE [NCT04085601]). The aim of this study was to describe real world clinical and treatment outcomes in CIexp and CInaive PNH patients prescribed pegcetacoplan. Methods Data were drawn from the Adelphi PNH II Disease Specific Programme™, a real-world cross-sectional survey of hematologists and their consulting PNH patients. Data were collected from November 2023–January 2025 in Canada, France, Germany, Italy, Spain, the UK, and the US. Patients prescribed pegcetacoplan for ≥3 months were included and described as CIexp if they had previously been treated with CI, or CInaive if patients had never been prescribed CI therapy. Physicians reported patient demographics, clinical characteristics, and treatment outcomes. Patients provided data on patient-reported outcomes, including the EQ-5D-5L and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Response to pegcetacoplan was categorized as no, minor, partial, good, major or complete response per SAAWP-response criteria (Risitano et al, 2019). Analyses were descriptive. Results Overall, 54 physicians provided data for 77 patients prescribed pegcetacoplan (54 CIexp patients and 23 CInaive patients). Median (interquartile range [IQR]) age was 45.0 (33.5–55.0) years (CIexp, 47.0 [37.0–60.8]; CInaive, 39.0 [30.0–45.0]), 63.6% (Cexp, 64.8%; Cnaive, 60.9%) were male, 57.9% (CIexp, 50.9%; CInaive, 73.9%) were in employment. Median (IQR) time since diagnosis was 2.4 (1.3–4.9) years (Cexp, 3.1 [2.0–5.5]; Cnaive, 1.3 [0.8–2.3]) with median (IQR) time since start of pegcetacoplan initiation being 0.6 (0.4–1.0) year (CIexp, 0.6 [0.4–0.9]; CInaive, 0.6 [0.5–1.2]). Clinical outcomes were measured at treatment initiation and the time of survey, and reported as median (IQR). Hemoglobin levels increased from 9.0 (8.0–9.2) to 11.0 (10.3–12.1) g/dL, and 9.0 (7.0–10.5) to 11.5 (10.6–12.0) g/dL, for Cexp (n=52) and Cnaive (n=21), respectively. Lactate dehydrogenase levels decreased from 490 (295–594) to 260 (189–377) U/L for Cexp (n=53), and 275 (214–775) to 220 (187–278) U/L for Cnaive (n=18). Absolute reticulocyte counts decreased from 200 (135–275) to 113 (105–217) x109/L for Cexp (n=19) and 160 (113–250) to 110 (100–134) x109/L for CInaive (n=7). Positive movement by at least one response category since pegcetacoplan initiation were observed in 85.2% CIexp (n=27) and 61.5% CInaive (n=13); with patients classified as having a ‘good’, ‘major’ or ‘complete’ response increasing from 3.7% to 74.1% for CIexp and 23.1% to 69.2% for CInaive. Perceived severity of PNH improved after pegcetacoplan initiation, with ‘mild’ severity increasing from 13.0% to 68.5% and 34.8% to 87.0%; patients experiencing no fatigue increased from 5.6% to 57.4% and 8.7% to 65.2%, for CIexp and CInaive, respectively. For both CIexp and CInaive, complete treatment adherence was reported for 87.0% of patients. Since pegcetacoplan initiation, proportion of ‘well’ or ‘very well’ controlled PNH patients increased from 14.8% to 96.3% for CIexp and 52.2% to 100.0% for CInaive. Overall, 25 patients self-reported data (n=14 CIexp; n=11 CInaive). Patients reported a mean (Standard Deviation [SD]): EQ-5D VAS score of 66.8 (16.0) and 76.7 (18.7); EQ-5D utility score of 0.86 (0.16) and 0.91 (0.13); FACIT-Fatigue 41.1 (9.5; n=13)and 37.1 (12.2; n=11) for CIexp and CInaive, respectively. Conclusion Improvements in clinical values, perceived PNH severity, control of PNH, and both physician and patient-reported fatigue were observed in CIexp and CInaive patients. These data suggest that pegcetacoplan has positive outcomes regardless of prior CI exposure. These findings indicate that the efficacy of pegcetacoplan in a real-world clinical practice is consistent with results from clinical trials and other real-world evidence for both CIexp and CInaive patients.

Abstract Background Accurate diagnosis and risk stratification in myeloproliferative neoplasms (MPNs) rely on expert interpretation of complex clinical records. Outside major academic centers, specialist expertise is scarce, and time-consuming chart reviews extend clinic visits and delay treatment decisions, underscoring the need for automated, point-of-care phenotyping for MPN patients. Methods Patients with the ICD codes of PV, ET and MF were identified from the electronic health record. Cases were defined as patients meeting the 2017 WHO diagnostic criteria for PV, ET or MF or those with a definitive MPN diagnosis determined by a hematologist. Controls were the patients who met neither the diagnostic criteria nor had a hematologist-assigned diagnosis. Two clinicians extracted demographic, clinical (symptoms, thrombotic history), laboratory (complete blood count, serum chemistry), genetic (mutations, karyotype), bone marrow morphology, diagnostic mentions and prognostic score information from unstructured clinical notes and pathology reports. Prognostic scores included the conventional risk model for PV, the International Prognostic Score of Thrombosis (IPSET) for ET and the Dynamic International Prognostic Scoring System (DIPSS), DIPSS-plus or Mutation-enhanced International Prognostic Scoring System (MIPSS-70) for MF. Discrepancies in data extraction were resolved by a consensus. A random sample of 510 patients (PV: 85, ET: 85, MF: 85, controls: 255) was split into prompt development (n=60) and test (n=450) sets for iterative workflow engineering and evaluation. The workflow included: (i) a rule-based algorithm for automated retrieval of demographic details, the first bone marrow biopsy report, the first clinical note after biopsy and the latest laboratory results within 90 days preceding biopsy (ii) a HIPAA-compliant LLM (GPT-4 turbo) for data extraction from the clinical notes and pathology reports (iii) a regular expressions-based algorithm for post-processing extracted data into structured tables, (iv) a clinician-informed source prioritization algorithm to select data from preferred sources, (v) a modified WHO-informed diagnostic characterization tool incorporating hematologist-assigned diagnoses to distinguish cases from controls and; (vi) an NCCN guidelines-based algorithm for prognostic tool selection and risk-stratification based on available data. Structured prompts were used to extract demographic, clinical, laboratory, genetic and pathological data in a zero-shot deterministic setting. The performance of automated data extraction, diagnostic characterization and prognostication was compared against the manually curated data. Accuracy and F1 scores were computed for data extraction and prognostication tasks while sensitivity and specificity were calculated to assess diagnostic performance. Results A total of 450 (PV: 150, ET: 150, MF: 150) pathology reports and 50 (PV: 52, ET: 55; MF: 65) clinical notes were identified for 450 test set patients. The test set data extraction accuracy was 95% (reports: 97%, notes: 92%) for PV, 93% (reports: 92%, notes: 94%) for ET and 98% (reports: 99%, notes 97%) for MF. The test set F1 score was 0.95 (reports: 0.96, notes: 0.93) for PV, 0.95 (reports: 0.95, notes: 0.96) for ET and 0.98 (reports: 0.99, notes: 0.97) for MF. PV patients were diagnosed with 100% sensitivity and 98% specificity whereas ET and MF patients were diagnosed with 100% sensitivity and specificity. The accuracy of risk stratification was 100% for PV and ET and 94% for MF. The F1 score for risk stratification was 1.00 for PV and ET and 0.94 for MF. Conclusions The first-in-class automated framework successfully identified pertinent clinical information, performed accurate data extraction from unstructured records and enabled clinician-guided source prioritization for accurate diagnosis and risk stratification of MPN patients. Prospective validation of the framework is required for widespread clinical implementation.

Abstract Background: As mounting numbers of patients receive allogeneic hematopoetic stem cell transplantation (allo-SCT) for hematologic malignancies, focus on survivorship and post-transplant complications is increasing. 30-60% of patients develop pulmonary complications, making the lungs the most affected organ post-transplant. While obstructive lung disease post-allo-SCT has been studied as a manifestation of graft-versus-host-disease (GVHD) in the form of bronchiolitis obliterans syndrome, many patients' post-transplant pulmonary function tests (PFTs) reveal restrictive patterns of disease which have been understudied. The pathophysiology, risk factors, and clinical course of restrictive lung disease (RLD) post-allo-SCT have not been fully elucidated. This retrospective study sought to characterize baseline characteristics, imaging findings, and possible risk factors of patients with RLD post-allo-SCT. Methods: The study included all patients receiving allo-SCT at our institution between 2005 and 2021 with at least one screening PFT with a restrictive pattern. Restriction is defined as normal forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio and total lung capacity (TLC) less than the lower limit of normal. Data collected via chart review included demographic information; indication for and type of transplant; myeloablative or nonmyeloablative conditioning; pre-existing lung disease; history of lung or chest-wall irradiation; acute post-transplant complications; documented acute or chronic graft-versus-host-disease (GVHD) of the lungs, skin, or other organs; and chest imaging findings on x-ray or computed tomography. For patients with at least two PFTs (n=168), average rate of change of TLC since transplant was calculated. Average monthly change in TLC post-transplant was compared between multiple groups detailed under Results. Analysis of variance or unpaired t-test and linear regression were used for comparison of categorical and continuous variables, respectively. Statistical analyses were completed using BlueSky Statistics 10.3.4, R version 4.1.3. Results: 234 patients were included. Median age at transplant was 51 years (range 18-74), and 163 (70%) were male. Average BMI at transplant was 29.6 (17.9–51.4). 107 (46.3%) underwent myeloablative conditioning, and 124 (53.2%) underwent reduced intensity or nonmyeloablative regimens. The most common indications for transplant were AML (n=87), MDS (n=41), and ALL (n=40). Most had no pre-existing lung disease (n=131, 56.2%), and 61 (26.1%) had evidence of restriction on pre-transplant PFTs. About half (n=119, 51.1%) had a history of lung or chest-wall irradiation. Within 30-days post-transplant, 55 (23.5%) had pulmonary complications (pneumonia or other hypoxic respiratory failure). 151 (64.8%) had either acute or chronic skin GVHD; 91 (39.1%) carried diagnoses of pulmonary GVHD. Most common associated imaging findings were infiltrates (n=120), scarring/atelectasis (n=73), pleural effusion (n=62), and air-trapping (n=50). Mean rate of change in TLC following transplant among all subjects was -0.0473 L/month. Comparative analysis revealed no statistically significant differences in mean values of average change in TLC between those with myeloablative and nonmyeloablative regimens (-0.0733 vs -0.0227 L/month, p = 0.176); pulmonary GVHD or not (-0.0752 vs -0.0203 L/month, p=0.141); GVHD or not (-0.0514 vs -0.0373 L/month, p=0.731); or with or without prior chest irradiation (-0.0234 vs -0.0687 L/month, p=0.226). Women had, on average, positive change in TLC compared to men (+0.00963 vs -0.0709 L/month, p=0.049). Decline in TLC was faster in overweight or obese patients (p=0.006). Conclusion: Our study establishes and describes a cohort of patients with restrictive lung disease post-allo-SCT, a poorly understood and incompletely characterized, yet highly morbid, set of diverse entities into which our findings provide insight. Based on the descriptive analysis we completed, patients experience decline in TLC due to a variety of processes – infiltrative pathology, pleural effusions, and chest wall weakness/restriction. Rate of decline increases with BMI and male gender. Diagnosis of pulmonary GVHD does not seem related to progression of restriction. As more long-term data is obtained from screening PFTs, examining larger datasets may allow for more granular analysis of the numerous possible etiologies.

Abstract Introduction: Telomere biology disorders (TBDs) are caused by germline pathogenic or likely pathogenic variants in telomere maintenance genes and result in multisystem manifestations, including impaired bone health. Patients with TBDs experience reduced bone mineral density (BMD), avascular necrosis, and increased rates of fragility fractures. However, the underlying mechanisms of these bone complications remain poorly understood, and no TBD-specific treatments for bone health currently exist. Our objective was to characterize the clinical features, management, and outcomes of TBD-related bone health issues, including fractures and reduced BMD. Methods: We conducted a retrospective, multicenter, international cohort study using data from 232 patients with TBDs enrolled across 12 centers participating in the Clinical Care Consortium of Telomere-Associated Ailments. Medical records were reviewed for fracture history and BMD assessments by dual-energy X-ray absorptiometry (DXA). The primary endpoint was fracture incidence; secondary endpoints included BMD assessment and fracture management. Data were stratified by pediatric (≤18 years) and adult (&gt;18 years) age groups. Analyses were based on data availability; specific denominators are provided where applicable. Result: Data were available for 53 (23%) pediatric and 179 (77%) adult patients. TERT mutations were the most frequently identified variants in both groups (28% pediatric, 23% adult). Fractures occurred in 25% (13/53) of pediatric patients and 35% (62/178) of adults. In contrast, fractures are estimated to occur in 10-15% of the general pediatric population. The median age at first fracture was 8.2 years (range 2.5–17) in children and 29.2 years (range 18.3–66.9) in adults. Among those with fracture data (n=20 pediatric, n=22 adult), fragility fractures were more common in adults (57%) versus predominantly traumatic fractures in children (61%). Multiple fractures occurred in 65% of affected pediatric patients and 45% of affected adults. Fracture management also differed: non-surgical treatments were used in 60% of pediatric fractures (n=12/20) versus 36% (n=8/22) of adult fractures; surgical interventions were more common in adults (36%). The inheritance pattern (autosomal dominant versus recessive or X-linked) was not associated with fracture risk but the subset of patients with CTC1 mutations were associated with increased fracture risk (n=5 of 124 patients with fracture history, 4% vs n=2 of 247 patients with no fracture history, 0.8%; p=0.04). We also assessed whether vascular manifestations were associated with fracture risk comparing patients with and without fractures. Pulmonary arteriovenous malformations (AVMs) were significantly more common in patients with fractures (17%, 7/42) versus those without (5.4%, 6/112; p=0.04). No significant differences were found in rates of retinal vasculopathy or hemorrhage (13% vs 7.2%, p=0.23) or gastrointestinal bleeding (22% vs 16%, p=0.35). DXA data were available for 171 patients (22 pediatric, 149 adult). The median age at first DXA was 11.4 years (range 4–17.7) for children and 58.2 years (range 20.8–79.4) for adults. Among pediatric patients, the median lumbar spine Z-score was –1.2 (IQR –3.0 to –0.2, n=18), with 39% (7/18) showing a Z-score &lt; –2. Among adults, the median femoral neck T-score was –1.1 (IQR –1.7 to –0.5, n=118), with 21% (29/138) demonstrating T-scores &lt; –2, indicating low BMD. Conclusions: Fractures and reduced BMD are common in both pediatric and adult patients with TBDs, with a substantial burden of early-onset and recurrent fractures. Our findings underscore the importance of early bone health screening and surveillance in TBDs and suggest a possible link between vascular abnormalities and skeletal fragility in this population that requires further study.

Abstract Introduction: Inherited & acquired bone marrow failure syndromes (BMFS) have “stress erythropoiesis” with macrocytic anemia, elevated fetal hemoglobin (HbF) & erythropoietin (EPO) levels. The degree of HbF elevation & its capacity to discriminate between patients with inherited & acquired BMFS needs to be systemically studied. Genetic testing is often delayed & it is important to establish an early clinical diagnosis to make clinical decisions such as initiation of immunosuppressive therapy. Methods: After institutional review board approval, we compiled a clinically & genetically well-annotated cohort of patients with BMFS evaluated at Mayo Clinic. All patients were required to have at least cytopenia(s) & evidence of low or variable bone marrow cellularity upon a bone marrow evaluation. Patients with pre-clonal or malignant disorders were excluded. Clinical diagnoses were independently verified for accuracy. Detailed clinical & laboratory features were recorded. Germline genetic testing was performed as clinically appropriate on peripheral blood or bone marrow samples through targeted panels. Distribution of continuous variables was statistically compared using nonparametric (Mann-Whitney or Kruskal-Wallis) tests, while nominal variables were compared using the Chi-Square test. Kaplan-Meier estimate of overall survival (OS) was computed from the date of diagnosis to date of death or last follow-up (also censored at the time of allogeneic hematopoietic stem cell transplant). Results: Between years 1998 - 2023, 129 patients met criteria for inclusion in the study. Among these, clinical diagnoses included immune-mediated aplastic anemia (AA, n=56, 43%, 21% severe or very severe as per the Camitta criteria), telomere biology disorders (TBD, n=37, 29%), Fanconi anemia (n=10, 8%), GATA2 haploinsufficiency (n=8, 6%), Diamond-Blackfan anemia (DBA, n=2, 2%), deficiency of adenosine deaminase-2 (DADA2, n=2, 2%), congenital dyserythropoietic anemia (CDA, n=1, 1%), congential amegakaryocytic thrombocytopenia (CAMT, n=1, 1%), Schwachman-Diamond syndrome (n=1, 1%) & undefined (n=11, 9%). Among the inherited group, 63% had an identifiable germline pathogenic variant (most commonly, TERT/TERC 30%, FANC group 25% & GATA2 15%) with the rest diagnosed on a clinical basis. Elevated HbF &gt;1% was noted in 79% of all BMFS patients; 83% AA, 70% TBD, 50% in DADA2 & 67% in undefined patients (no data was available for other inherited subtypes). In patients with an elevated HbF, absolute monocyte count (p=0.04) was significantly higher; however, there were no other significant associations with variables at diagnosis such as hemoglobin (p=0.5), white blood cell count (WBC, p=0.14), absolute neutrophil count (p=0.5), platelet count (p=0.7), mean corpuscular volume (MCV, p=0.2), absolute lymphocyte count (p=0.1), absolute reticulocyte count (p=0.4), EPO level (p=0.3), presence of a PNH clone (p=0.2), or presence of a germline variant (p=0.3). When diseases were grouped into inherited & acquired (AA) subgroups, median HbF was not significantly different (median%, 4.5 versus 2.3, p=0.4), with elevated HbF (&gt;1%) in 75% versus 83% (p=0.6) patients respectively. On the other hand, minor PNH clone (&gt;0.1% in at least two cell types) was detectable in the acquired group only (0 versus 55%, p&lt;0.0001). Similarly, acquired group had a shorter (&lt;3 months) onset of cytopenias preceding diagnosis (P&lt;0.0001), with no significant differences in MCV (p=0.2), marrow dysplasia (p=0.09) or atypia (p=0.6), & splenomegaly (p=0.9). At median follow-up of 7 years, Kaplan-Meier estimate of transplant-censored median OS was lower in inherited versus acquired group (16 years versus median not reached, p=0.02). Elevated HbF did not significantly predict adverse OS in either group. Conclusions: Fetal hemoglobin is elevated in both patients with inherited & acquired (aplastic anemia) BMFS. When compared to established variables, elevated HbF has neither diagnostic utility nor prognostic relevance in predicting adverse outcomes. On the other hand, onset of cytopenias and presence of a minor PNH clone are both useful clinical variables in differentiating patients with inherited from acquired BMFS. Our data offers practical clinical utility in making early treatment decisions for patients with BMFS.