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Abstract Background: The t(11;14) translocation occurs in 50-60% patients with systemic AL amyloidosis. Venetoclax, an oral BCL2 inhibitor, has shown promising efficacy across t(11;14)-positive plasma cell disorders. However, till date, there are no prospective data in patients with previously treated AL amyloidosis, including those with prior exposure to anti-CD38 monoclonal antibodies (mAbs). Methods: We conducted an investigator-initiated phase 1/2 multicenter open-label trial of venetoclax (± dexamethasone) in patients with relapsed/refractory AL amyloidosis. Key inclusion criteria were central-laboratory confirmed t(11;14) by FISH analysis in ≥5% of CD-138-selected cells on bone marrow aspirate, measurable hematologic disease (dFLC≥2 mg/dL and/or M-spike ≥0.5 g/dL), prior exposure to anti-CD38 mAb, and ≥1 prior line of therapy. Key exclusion criteria were NT-proBNP>8500 pg/mL, NYHA class IIIb/IV, and ECOG>2. Phase 1 dose escalation utilized Bayesian Optimal Interval Network (BOIN) design to determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) across four levels: DL1 (venetoclax 200mg), DL2 (400mg), DL3 (400mg + dexamethasone 10mg weekly), and DL4 (400mg + dexamethasone 20mg weekly). A maximum of 6 cycles of therapy on the protocol were planned, with dose limiting toxicities (DLTs) being evaluated in cycle 1. The design accommodated 12-15 patients with ~67% probability of selecting the dose closest to the 25% target toxicity rate. Here, we present the results of the Phase 1 portion of the study, which has completed enrollment. Accrual in Phase 2 portion is currently ongoing. Results: Of 16 patients screened, 12 were enrolled and evaluable for safety and efficacy. Screen failures were attributed to second malignancy (n=2), t(11;14) positivity in <5% CD-138-selected cells (n=1), and t(11;14) negativity (n=1). Enrolled patients had a median age of 64 years, with 25% female, and 17% Black representation. At screening, the median percentage of CD-138-selected cells with t(11;14)-positivity on FISH was 65%. All patients had prior anti-CD38 mAb-exposure by protocol design, with 11/12 patients also exposed to bortezomib. The median number of prior lines of therapy was 1 (range, 1-5). Disease markers at treatment initiation included median dFLC of 14.35 mg/dL (range, 2.13-186.28), median NT-proBNP of 712.5 pg/mL (range, 54-8831), and the median serum creatinine of 0.99 mg/dL (range, 0.69-3.01). Regarding safety, there were no DLTs encountered during the specified timeframe. One patient each received DLs 1, 2, and 3, with all remaining patients receiving DL 4 (400mg + dexamethasone 20mg weekly), which is the RP2D in this trial. There was only one patient that developed grade 3 infection (lung infection; COVID-19). No tumor-lysis syndrome, grade 3 or higher cytopenia, or treatment-emergent deaths occurred. Hematologic overall response (PR or better) was achieved in 11/12 patients (91.7%), with 9/12 (75%) attaining ≥VGPR [4/12 (33.3%) heme-CR, with the remaining being VGPR]. The median time from treatment initiation to best response was 29 days. Among 7 patients that were evaluable for cardiac response, one underwent heart transplant after 3 cycles of study treatment (while in heme-CR), hence was no longer evaluable for cardiac organ response. Of the remaining 6 patients, 2 have achieved cardiac response till date. Renal organ response was observed in 4/7 evaluable patients. At a median follow-up of 8.8 months, 4 out of 12 patients have completed 6 treatment cycles, with 2 receiving ongoing therapy. Six patients discontinued treatment early due to hematologic progression (n=1), suboptimal hematologic response (n=2), patient preference (n=2), and heart transplant (n=1). Patient-reported outcomes (assessed by PROMIS-29) showed no significant changes in Physical Functioning and Fatigue domains among 5 patients with paired baseline and end-of-treatment assessments. Updated follow-up data will be presented at the meeting. Conclusions: To our knowledge, this represents the first prospective evaluation of venetoclax-dexamethasone in relapsed/refractory t(11;14) AL amyloidosis. The combination demonstrated substantial hematologic efficacy (75% ≥VGPR rate) and a favorable safety profile without dose-limiting toxicities. Our results support investigation of venetoclax-based combinations in the frontline treatment of newly diagnosed t(11;14) AL amyloidosis.

Abstract BackgroundWarm autoimmune hemolytic anemia (wAIHA) is clinically characterized by autoantibody-mediated (typically IgG) erythrocyte destruction at body temperature. While oral corticosteroids remain first-line therapy, rituximab is frequently used as a second-line agent, mostly supported with concomitant background medications, yet real-world evidence is limited and utilization is driven by published retrospective data and expert opinion. Real-world evidence characterizing its utilization patterns and outcomes is needed to inform clinical practice. AimsThis study aimed to: 1) describe treatment patterns among patients with newly diagnosed wAIHA, 2) evaluate rescue therapy use and healthcare resource utilization (HCRU) with current standard of care (SOC), 3) characterize patterns of rituximab use during the first year. MethodsNewly diagnosed wAIHA patients were identified from multiple US databases (MarketScan® Databases, IQVIA PharMetrics, Optum Clinformatics®, and Optum PanTher EHR). Patients with ≥1 wAIHA diagnosis code in any position (ICD-10-CM D59.11) from October 2020 to December 2023 and 12-month post-index follow-up were pooled together. Secondary wAIHA was defined with evidence of hematologic malignancy, solid tumors, immunodeficiencies, or autoimmune diseases in the 6 months prior to diagnosis. Patients on treatment were defined by use of oral corticosteroids (OCS), immunosuppressants (IST) (including azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, or tacrolimus) or rituximab. Initial therapy was defined as the first treatment occurring ≥ 30 days prior to diagnosis. Therapies were identified as combination when initialized within 21 days of each other. The regimen is considered active until all therapies are discontinued or a new agent is initiated. Rituximab regimens were classified as standard (4 weekly doses), alternative (2 doses given 2 weeks apart), single infusion, or extended (>4 infusions). Results Among 2,028 wAIHA patients (median age 62.0 years, 59% female), 55% had secondary wAIHA. Among patients on treatment (n=1,439), 64% received OCS monotherapy; rituximab and IST, alone or in combination with OCS were received by an additional 28% and 5% of patients, respectively. Overall, 80% of treated patients received OCS in some combination during initial therapy. Within 12 months following diagnosis, 1 in 4 patients required ≥ 1 blood transfusion, 1 in 8 required either erythropoiesis-stimulating agents (ESA) or intravenous immunoglobulin (IVIG). Within 12 months of diagnosis, 35% of patients required ≥ 1 hospitalization, average length of stay 3.8 days; AIHA was the principal diagnosis for 65% cases. Greater than 1/3 of patients (38%) had ≥ 1 emergency department visit. Almost all wAIHA patients (98%) had an all-cause outpatient visit with a median of 31 visits per patient. Among patients receiving rituximab in any line (n=613), median time from diagnosis to first administration was 59.0 days (interquartile range: 42.0-171.0). For the first course of rituximab, 62.2% of patients received a complete course (standard, alternative, or extended courses). Among patients with a completed course, 39.8% had >4 infusions without a 90-day gap between administrations with a median of 8 administrations within 12 months. Of the nearly 38% of patients that did not receive a complete course of rituximab, 33% received a single infusion. The use of rescue medications in the period prior to rituximab treatment was compared to the period after treatment (defined as 60 days to 12-months post final rituximab infusion). Use of blood transfusions was observed to increase from 9.0% to 32.8%, while the use of ESA and IVIG were stable at approximately 2% and 4%, respectively.Conclusion With current wAIHA SOC, US HCRU remains high, posing a financial burden in terms of the rate of outpatient and emergency department visits, and inpatient stays. Rituximab is an early line therapy post-diagnosis, typically in combination with OCS. No changes in rescue treatments, and an increase in blood transfusions after rituximab infusion suggest treatment gaps remain. Analysis reveals heterogeneity in rituximab dosing patterns including high deviation from standard dosing practices; this variance from published expert opinion along with common use of rescue therapies suggests continued need for standardized guidelines and development of targeted therapies in wAIHA.

Abstract Background Multiple myeloma, the second most common hematologic malignancy, has witnessed incremental progress in its management over the past decade underscored by substantial improvement in patient outcomes, although it remains largely incurable. Due to its relapsing-remitting course with current therapies, patients experience considerable burden, particularly with the use of parenteral regimens that are administered on a continuous basis. As such, exploration of newer oral, finite-duration therapeutic options may be of benefit. Selinexor, an oral selective exportin (XPO)-1 inhibitor has an established synergistic activity with other antimyeloma therapies, including immunomodulatory drugs and proteasome inhibitors. In combination with dexamethasone, selinexor is currently approved at 80 mg twice a week dose, and in combination with bortezomib plus dexamethasone, it is approved at 100 mg once weekly dose for patients with relapsed and/or refractory multiple myeloma (RRMM). Herein, we present the results of Arm B of the 2-arm SCOPE trial that examined an all-oral regimen of selinexor, pomalidomide and low-dose dexamethasone (SPd) regimen for RRMM. Methods The SCOPE trial is an investigator-initiated, single arm, phase 2 study that assessed the efficacy and safety of selinexor (S), 60 mg orally (PO) weekly, pomalidomide (P), 4 mg PO, days 1-21 and dexamethasone (d), 40 mg PO, weekly in 28-day cycles given for a fixed duration (total 18 cycles ) in patients who were exposed to up to 2 prior lines of antimyeloma therapy, at least one of which included both a proteasome inhibitor and the immunomodulatory agent, lenalidomide. Olanzapine, along with a 5-HT3 antagonist comprised the mandatory anti-emetic prophylactic regimen. The trial's primary endpoint was overall response rate (ORR), based on confirmed response, and the key secondary endpoints were progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety of SPd. The International Myeloma Working Group (IMWG) 2016 criteria were used for response assessment in addition to reporting of the minor response. The distribution of PFS and OS was estimated using the Kaplan Meier method. Toxicity was graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5. Results At the data cutoff date (May 28, 2025), 28 of 29 enrolled patients with RRMM were evaluable. The median age at study entry was 67.5 years (range: 65-72 years). SPd was used as the first salvage regimen in 21% of patients, and the remaining 79% of patients had previously received 2 lines of therapy at study entry. All patients had previously been exposed to a proteasome inhibitor and an immunomodulatory agent, and 32% were dual refractory. Notably, 64% of patients had previously been exposed to the anti-CD38 monoclonal antibody, daratumumab, and 11% of patients were daratumumab-refractory. The median follow-up was 23.9 months (range: 2.9-38.8 months). The patients had received a median of 9 cycles of SPd (range:1-18 cycles), and at data cutoff, 36% of patients had completed all the planned 18 cycles of SPd. The ORR was 61% (95% CI:41-78) and the rate of measurable residual disease (MRD)-negative complete response (CR) was 21%, CR 11%, very good partial response (VGPR) 18%, partial response (PR) 11% as the best response achieved. Additionally, 7% and 25% of patients had attained a minor response (MR) and stable disease (SD), respectively. The median PFS was 24 months [95% CI: 7.1– not-estimable (NE)] months, and the median DOR was not reached (NR). 2-year OS rate was 93%. The toxicity associated discontinuation rate was 7%, and no grade (Gd) 5 events or unexpected toxicities were encountered during treatment. Gd 3 or higher hematologic toxicities occurred in 43% [Gd 3/4 anemia (11%/0%), thrombocytopenia (14%/0%), neutropenia (25%/7%), lymphopenia (4%/4%)]. Gd 3+ non-hematologic toxicities occurred in 46% [Gd 3 /4 (%) infections (21%/0%), fatigue (4%/0%), nausea (7%/0%) and anorexia (0%/7%). No patients experienced Gd 3 or 4 diarrhea, vomiting or weight loss. Additional data will be presented at the meeting. Conclusion Weekly selinexor in combination with pomalidomide and dexamethasone is an effective and safe, all-oral regimen for patients with RRMM who are previously exposed to a proteasome inhibitor and lenalidomide. SPd regimen is currently being examined in an ongoing phase 3 randomized controlled trial.

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: The recently published BLAST clinical risk model for chronic myelomonocytic leukemia (CMML) and its molecular version (BLAST-Mol) differentiate low, intermediate, and high risk groups (Blood 2025; blood.2024027170. doi: https://doi.org/10.1182/blood.2024027170). The objective of the current study was to examine the survival impact of allogeneic stem cell transplant (ASCT) in a consecutive series of Mayo Clinic patients with CMML, overall and adjusted for baseline BLAST/BLAST-Mol risk category. Methods: CMML diagnosis and sub-categorization were according to the International Consensus Classification, which included CMML1 (bone marrow/peripheral blood blasts &lt;10%/&lt;5%) vs CMML-2 (bone marrow/peripheral blood blasts ≥10%/≥5%) and CMML-MP (leukocytes ≥13 x 10⁹/L) vs. CMML-MDS (leukocytes &lt;13 x 10⁹/L) [Arber et al. Blood 2022;140:1200]. The BLAST score is based on clinical risk factors including circulating blasts ≥2%, leukocytes ≥13 x 10⁹/L, and severe or moderate anemia whereas BLAST-Mol also accounts for mutations and karyotype. Comparative parameters and overall survival (OS) were calculated from the time of initial CMML diagnosis for both the transplant and non-transplant groups. Statistical analyses were performed using JMP Pro 17.1.0, (SAS Institute, Cary, NC, USA). Results: A total of 775 consecutive Mayo Clinic patients with CMML (68% males, median age 71 years) were included in the current retrospective study (1994-2024). At a median follow-up of 77 months, 151 (20%) patients underwent ASCT. Compared to those in the non-ASCT cohort (N=624), patients who underwent ASCT were younger (median age 61 vs. 73 years; p=0.01) and were more likely to have CMML-2 (22% vs 12%; p&lt;0.01) or high-risk BLAST-Mol (34% vs 21%; p=0.03) categories. Otherwise, BLAST clinical risk distribution and specific mutational frequencies were similar between the ASCT and non-ASCT cohorts. Overall, OS was longer in the ASCT (median 77 months; HR 0.3, 95% CI 0.28-0.46; p&lt;0.01), compared to the non-ASCT (median 28 months), cohort. The significant difference in OS between the ASCT and non-ASCT cohorts was retained after adjusting for BLAST clinical risk groups: high-risk (median 50 vs. 14 months; HR 0.19, 95% CI 0.1-0.3; p&lt;0.01), intermediate-risk (81 vs. 28 months; HR 0.2, 95% CI 0.1-0.4; p&lt;0.01), and low-risk (111 vs. 65 months; HR 0.6, 95% CI 0.3-0.99; p=0.04), respectively. The same was mostly the case when OS comparison was adjusted for BLAST-Mol with respective p values of &lt;0.01, &lt;0.01, and 0.08. The survival benefit of ASCT was individually ascertained for most unfavorable (ASXL1 p&lt;0.01; SETBP1 p&lt;0.01; NRAS p=0.02; RUNX1 p=0.02; U2AF1 p=0.04; DNMT3A p=0.06) and favorable (TET2 p&lt;0.01; PHF6 p=0.07) mutations as well as unfavorable karyotype (p&lt;0.01). CMML patients who received transplant without history of blast transformation (BT) and with bone marrow blast percentage &lt;5% at the time of ASCT had the best survival outcome with median survival that was not reached and with 5/10-year survival rate of 66%/60%. By comparison, median survival was 44 months for patients with pre-transplant history of BT (HR 0.4, 95% CI 0.2-0.6) and 74 months for transplanted patients without history of BT but bone marrow blast percentage of 5% or more at the time of ASCT (HR 0.5, 95% CI 0.2-0.9). For reference, median survival was 31 months for non-transplanted patients without history of BT (HR 0.2, 95% CI 0.1-0.3), and 21 months for their counterparts with history of BT (HR 0.2, 95% CI 0.1-0.2). In multivariable analysis (MVA), predictors of superior OS in the ASCT cohort included bone marrow blasts less than 5% at the time of ASCT (HR 0.4, 95% CI 0.2-0.8; p=0.02), absence of BT prior to ASCT (HR 0.4, 95% CI 0.2-0.7; p&lt;0.01), normal karyotype at time of diagnosis (HR 0.5, 95% CI 0.3-0.9; p=0.02), and CMML-1 vs. CMML-2 (HR 0.5, 95% CI 0.3-0.9; p=0.03). A similar analysis of parameters at diagnosis in the non-ASCT cohort identified CMML-MP (p&lt;0.01), CMML-2 (p&lt;0.01), ASXLMUT (p&lt;0.01), DNMT3AMUT (p&lt;0.01), TET2WT (p&lt;0.01), male gender (p=0.03), and unfavorable karyotype (p=0.02) as independent risk factors for OS. Conclusions: The current study highlights the benefit of ASCT for all three BLAST and BLAST-Mol risk groups in CMML and its potential to overcome the adverse impact of high risk cytogenetic or molecular abnormalities. These observations support the early use of ASCT in CMML, ideally before BT and regardless of genetic characteristics.