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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: 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 Background: Integrin αE (CD103) has been thought to mediate gut-homing Treg retention during GVHD by facilitating E-cadherin interaction on intestinal epithelial cells. However, only a small percentage of natural Tregs express CD103 in peripheral blood (PB). To leverage this mechanism and potentially enhance Treg therapeutic efficacy, we hypothesized that Tregs overexpressing CD103 (CD103high) would show improved gut-homing and GVHD mitigation. Methods: Murine CD4 Tregs were isolated from C57BL/6 (B6) mice via flow sorting and were retrovirally transduced with murine CD103 or truncated epidermal growth factor receptor as a control. Transduced Tregs were then tested in a murine acute GVHD model (B6 → BALB/c). Mouse organs, including small intestine (SI), colon, spleen, PB, axillary (aLN) and mesentric lymph nodes (mLN) were harvested on day 10 post-transplant and analyzed by flow cytometry, multiplex cytokine assay, histopathology, and single-cell RNA sequencing (scRNA-seq). Ex vivo expanded Tregs were subjected to 13C-glucose tracing assay to evaluate glycolytic flux, TCA cycle, and lipid biosynthesis. Results: Despite comparable FoxP3 expression at the end of ex vivo expansion, CD103high Tregs had significantly higher in vitro suppression compared to control Tregs (54% vs. 33% at Treg:Tcon ratio of 1:8, p=0.004). Upon re-stimulation, CD103high Tregs demonstrated increased proliferation compared to control Tregs (3.8 vs 2.8 fold expansion, p <0.0001). Bulk RNA seq on ex vivo expanded CD103high showed upregulation of immuneregulatory and metabolic programs including GTPase signaling and oxidative stress control. These transcriptomic changes suggest that CD103 intrinsically promotes a regulatory phenotype, stress tolerance and metabolic fitness. In vivo, CD103highTregs significantly decreased the severity and mortality of GVHD, compared to control Tregs, as measured by clinical scores, weight loss, and survival (50% vs 0% on day +60, p<0.0001 for three independent experiments combined; n = 24/group). Day 20 histopathology revealed significantly improved colitis scores in mice treated with CD103high Tregs vs controls (9.5 vs. 14.6, p=0.02). While these findings could be partially attributed to CD103 gut-homing function, we observed that CD103high Treg absolute number and frequency were higher not only in the the GI organs and mLN, but also in the spleen, PB, and aLN with similar distribution ratios across different organs (~5-fold higher). In vivo CFSE suppression assay, where CFSE labeled donor T cells were cotransferred with Tregs into B6 Rag1ko mice, demonstrated enhanced suppressive function of CD103high Tregs in the spleen (p=0.02), an effect that could not be accounted for by the conventional gut-homing mechanism attributed to CD103. Plasma cytokine analysis showed significantly elevated IL-10 levels in mice treated with CD103high Tregs (p<0.0001), consistent with increased Treg number and frequency. 13C-glucose tracing assay showed lower palmitate levels in CD103high Tregs, indicating lower de novo lipid synthesis, while glycolysis and TCA cycle tracing were similar. Day 10 scRNA-seq on colon samples revealed seven distinct immune clusters. The neutrophil cluster was absent in CD103high Treg group, suggesting reduced inflammation. Donor-derived dendritic cells (DCs) upregulated genes such as Cstb, and Slamf7, while pro-inflammatory genes including Cd52 and Cd74 were downregulated. STAT5 signaling was upregulated, indicating reprograming of myeloid cells toward an immunoregulatory state. Colon epithelial cells from CD103high Treg-treated mice displayed enhanced stress tolerance, with increased oxidative phosphorylation, fatty acid metabolism, and epithelial repair pathways. CellChat analysis revealed that CD103high Tregs reshaped the intestinal communication landscape, with DCs acting as key signaling hubs through interactions such as Ccl6–Ccr2 and Lgals3–Cd44. Enhanced DC-to-DC and DC-to-T cell communication suggest that CD103high Tregs promote a tolerogenic DC network that modulates downstream immune responses and supports epithelial recovery. Conclusion: Tregs overexpressing CD103 via retroviral transduction significantly improve overall survival and GVHD clinical scores in a murine transplant model. CD103High Tregs orchestrate broad remodeling of cell-cell communication across immune and stromal compartments, promoting an immunoregulatory microenvironment that underlies their protective effects in GVHD.

Abstract Introduction Odronextamab, a CD20×CD3 bispecific antibody, demonstrated compelling efficacy with a generally manageable safety profile in heavily pretreated patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) in the Phase 2 ELM-2 study (NCT03888105; Kim TM, et al. Ann Oncol 2024). Pts in ELM-2 received odronextamab monotherapy until disease progression or unacceptable toxicity, with dosing frequency reduced to every 4 weeks (Q4W) in those with sustained complete response (CR) for at least 9 months. Here, we report longer term outcomes in the global FL population of ELM-2, including efficacy and safety in pts who switched to Q4W dosing. Methods Details of the ELM-2 study for the R/R FL cohort have been reported previously. Odronextamab monotherapy was administered intravenously, with step-up dosing in Cycle (C) 1 to help mitigate the risk of cytokine release syndrome (CRS), followed by 80 mg in C2–4, then 160 mg every 2 weeks (Q2W) maintenance. Pts with a CR for ≥9 months switched from 160 mg Q2W to Q4W. Pts with the opportunity for response assessment at 12 weeks were included in this analysis. Primary endpoint was objective response rate (ORR) per Lugano criteria by independent central review (ICR). Key secondary endpoints included CR rate, duration of response (DOR), and progression-free survival (PFS) by ICR, overall survival (OS), and safety. Results As of May 5, 2025 data cutoff, 128 pts with R/R FL Grade (Gr) 1–3a were evaluable for efficacy and safety analysis (overall global population). Median duration of odronextamab exposure was 42.9 weeks (range 0.4–264.0) and median follow-up was 34.1 months (95% CI 33.8–37.9). Eligible pts (n=48) switched to Q4W dosing, with median duration of follow-up from time of switching to Q4W dosing of 19.7 months (95% CI 16.2–31.9). Baseline characteristics were generally similar between the overall population and the subgroup of pts who switched to Q4W dosing. The ORR by ICR in the overall population was 80.5% and CR rate was 74.2%, with a median DOR of 26.0 months and median duration of CR of 32.2 months. In pts with sustained CR for ≥9 months who transitioned to Q4W maintenance, the median DOR from time of switching was 31.5 months. In the overall population, the median PFS was 24.1 months and median OS was not reached (estimated 24- and 36-month OS rates: 70.1% and 64.3%, respectively). In pts with CR, median PFS was 38.0 months and median OS was not reached (24- and 36-month OS rates: 80.1% and 75.2%). All 128 pts had treatment-emergent adverse events (TEAEs), with Gr ≥3 TEAEs reported in 112 pts (87.5%). Discontinuation due to TEAEs occurred in 29 pts (22.7%), and 5 pts died due to treatment-related TEAEs. With the 0.7/4/20 mg step-up regimen, CRS was reported in 55.0% (33/60; Gr 3 in 1 pt) of pts, with no new CRS events observed after switching to Q4W. Infections occurred in 81.3% (Gr ≥3, 46.1%) of pts, with COVID-19 (any Gr, 39.8%) the most frequent. After switching to Q4W dosing, the rate of any grade infection was 81.3% (Gr ≥3, 39.6%). Opportunistic infections (narrow SMQ defined) were reported in 18% (Gr ≥3, 8.6%) of pts in the overall population, with 22.9% (Gr ≥3, 8.3%) of pts having an opportunistic infection after switching to Q4W. Conclusions In the ELM-2 study with ~3-year follow-up in heavily pretreated pts with R/R FL, odronextamab continued to demonstrate deep and durable responses, as well as encouraging PFS and OS, particularly in the majority of pts who achieved CR. Responses remain durable in those who switched to Q4W dosing, lasting for a median additional 31.5 months from the time of switching, demonstrating the long-term, continued therapeutic benefit of odronextamab in pts with R/R FL. The safety profile remained generally manageable, with no new safety signals observed, and no evidence of increased infection risk in pts who switched to Q4W maintenance. Updated data will be presented.

Abstract Introduction: Indolent systemic mastocytosis (ISM) is a clonal mast cell disease driven by the KIT D816V mutation in ~95% of cases and is associated with symptoms of mast cell activation and tissue infiltration. It can cause chronic, debilitating symptoms − including life-threatening anaphylaxis and impaired bone health. While historically most patients have relied on symptom-directed best supportive care (BSC) therapies, avapritinib is used as a new standard of care targeting KIT D816V, the primary driver for SM. Avapritinib is an oral, potent, selective KIT D816V inhibitor, and the first and only approved targeted therapy for adult patients with ISM in the USA and the EU. Approval was based on results from the phase 2 PIONEER trial. Here, we present the findings from ~3.5-year long-term follow-up. Methods: Adults with centrally confirmed ISM and uncontrolled moderate-to-severe symptoms who completed the randomized dose-finding (Part 1), or randomized, double-blind, placebo-controlled (Part 2) portions of PIONEER (NCT03731260) rolled over to the open-label, long-term extension (Part 3). This cumulative analysis includes patients who initiated avapritinib at the recommended dose of 25 mg once daily (QD) in either Parts 1, 2, or 3. All patients received BSC. Per investigator discretion and based on disease burden, dose titration up to 50 mg QD of avapritinib was permitted in Part 3. Long-term efficacy was assessed by measuring changes in symptoms and QoL, using the ISM-Symptom Assessment Form (ISM-SAF; ©2018 Blueprint Medicines, a Sanofi Company) and the Mastocytosis Quality-of-Life Questionnaire (MC-QoL). Safety was also assessed. Results: Overall, 226 patients initiated avapritinib 25mg QD across Parts 1, 2, and 3. This longer-term analysis is inclusive of 65 patients who dose titrated from 25 mg to 50 mg QD in Part 3. Median (range) treatment duration was 40.0 months (0.7‒67.2) as of February 21, 2025. Longer-term efficacy data with ~3.5 years of follow-up demonstrated sustained disease-related symptom improvements. The mean change (standard deviation [SD]) in total symptom score (TSS, per ISM-SAF), was −19.80 (19.81) at Week 144 (Month 33) and −20.43 (20.57) at Week 168 (Month 39) from a baseline of 48.08 (19.47). Additionally, avapritinib-treated patients demonstrated durable improvement in their most severe symptoms (mean change [SD] from baseline of −3.35 [3.02] at Month 33 and −3.47 [3.19] at Month 39) per ISM-SAF. Sustained responses were observed across all individual symptom domains (0–30) with mean changes (SD) at Month 33 and Month 39 of −3.77 (5.52) and −3.84 (6.05) for the gastrointestinal domain, −8.21 (7.70) and −8.20 (7.85) for the skin domain, and −4.66 (6.24) and −4.87 (6.51) for the neurocognitive domain. The mean percent change (SD) in MC-QoL was −34.67 (40.16) at Month 33 and −40.72 (33.24) at Month 39 from a baseline of 54.24 (18.32). Treatment with avapritinib was well tolerated, and its safety profile was similar to the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were Grades 1–2, and 7% of patients experienced Grade ≥3 TRAEs of which diarrhea, neutrophil count decrease, and weight increase occurred in >1 patient. No Grade ≥3 TRAEs of increase in transaminases were observed. Edema (peripheral and periorbital), the most frequently reported TRAE, was mostly Grade 1 and occurred most frequently during the first 3–4 months of treatment. Three patients (1%) experienced serious adverse events assessed as treatment related. However, none led to treatment discontinuation and no trends were observed. After approximately 3.5 years of follow-up, low rates of treatment discontinuations (n=7, 3%) due to TRAEs were observed. Conclusion: Longer follow-up of patients with ISM treated on the PIONEER trial, including some on avapritinib for up to 5 years, demonstrates that prolonged avapritinib therapy continues to be effective and well tolerated. Additional prospective analyses will be needed to determine effects of selective KIT D816V-inhibition on anaphylaxis. These data support a favorable benefit-risk profile of avapritinib as a chronic treatment for adult patients with ISM.

Abstract B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (CART) cell therapies have emerged as a potentially curative treatment for multiple myeloma (MM). However, 50-70% of patients relapse within 3 years. The MM tumor microenvironment (TME) is highly immunosuppressive with an abundance of bone marrow (BM) cancer-associated fibroblasts (CAFs), which contribute to BCMA-CART cell failure. Therapeutic targeting of BM-CAFs has been beset by 1) an incomplete understanding of CAF interactions with CART cells and other BM cells and 2) toxicity risks due to prolonged depletion of healthy fibroblasts and inefficient drug delivery to the BM. To elucidate how BM-CAFs drive BCMA-CART resistance, we performed single cell RNA sequencing (scRNAseq) of baseline BM aspirates from responders (R, n = 6) and non-responders (NR, n = 6) to BCMA-CART cell therapy. NR BMs were enriched for inhibitory CAFs (iCAFs) that highly express fibroblast activation protein (FAP). Spatial analyses of BM cells revealed greater iCAF-iCAF and iCAF-inhibitory macrophage interactions in NR. These findings suggest that FAP+ iCAFs in NR are abundant in the BM and exhibit significant interactions with immunosuppressive macrophages. Next, we sought to validate our scRNAseq data in preclinical models. Xenograft mice were intravenously (IV) engrafted with luciferase+ (luc+) BCMA+ OPM2 cells and/or patient-derived (pd) BM-CAFs (1x106 each). Following engraftment, mice received 1x106 BCMA-CART cells (IV). BCMA-CART cells eradicated tumors in mice engrafted with OPM2 cells, but not in mice engrafted with pdBM-CAFs and OPM2 cells (p<0.01). In NSG and humanized mice (NSG mice engrafted with human CD34+ cells in the first 48 hours of life), tumor growth was significantly accelerated in the presence of pdBM-CAFs (NSG: p<0.01; humanized: p<0.001). BCMA-CART, OPM2, and pdBM-CAF co-cultures also showed significant increases in immunosuppressive cytokines including IL-1Rα, IL-4 and IL-10 and inhibited CART cell proliferation compared to co-cultures without pdBM-CAFs (IL-1Rα, IL-10: p<0.01; IL-4: p<0.001; proliferation: p<0.05). To overcome CAF-mediated CART dysfunction, we engineered BCMA-CART cells to secrete molecules to target BM FAP+ iCAFs and remodel the MM-TME (STriKEs). We designed two BCMA-CART-STriKE strategies: 1) a tri-specific composed of IL-15, anti-FAP, and anti-CD16 molecules to activate innate immune cells to kill CAFs and 2) bi-specific anti-FAP, anti-SIRPα molecules linked to an antibody Fc region (Fc fusion) targeting the CD47/SIRPα axis to induce phagocytosis of FAP+ iCAFs. We hypothesized that BCMA-CART-STriKEs would surmount CAF-mediated immunosuppression without toxicity. We generated BCMA-CART-STriKEs from healthy human donor T cells. CAR expression, STriKE secretion, and binding were confirmed via flow cytometry. Co-cultures of BCMA-CART-STriKEs, donor-matched macrophages, OPM2 cells or BCMA+ MM1S cells, and pdBM-CAFs showed significantly higher OPM2 or MM1S killing (p<0.001), immune cell activation (p<0.01), and phagocytosis (p<0.05), compared to control BCMA-CART cells secreting IL-15 or Fc fusions targeting only FAP or only SIRPα. Next, we assessed BCMA-CART-STriKE efficacy in vivo. NOD-SCID-γ-/- (NSG) mice received 1x106 pdBM-CAFs and 1x106 luc+ OPM2 or luc+ MM1S cells via IV or subcutaneous (SQ) injection. Mice were randomized after confirming tumor engraftment (via bioluminescence imaging for IV or tumor caliper for SQ) and received IV treatment with 1x106 BCMA-CART-STriKEs (or controls) and 5x105 donor-matched macrophages or CD16+ immune cells. BCMA-CART-STriKE-treated mice achieved total tumor clearance. Treatment with BCMA-CART cells secreting IL-15 led to lethal weight loss despite tumor clearance while BCMA-CART cells secreting Fc fusions targeting only FAP or SIRPα failed to eradicate tumors. Lastly, we assessed the potential toxicities of BCMA-CART-STriKEs in humanized mice engrafted with OPM2 cells and pdBM-CAFs (1x106 each). CART cells expressing BCMA and FAP CARs (BCMA-FAP CART) served as a control. BCMA-FAP CART treatment resulted in significant toxicity and weight loss while BCMA-CART-STriKE treatment did not (p<0.01). In summary, we have identified iCAF interactions with immunosuppressive immune cells as key contributors to BCMA-CART cell failure and designed novel BCMA-CART-STriKEs that overcome this failure in MM preclinical models. These findings support the translation of BCMA-CART-STriKEs to a phase I clinical trial.

Abstract Introduction: The CARTITUDE-4 study (NCT04181827), which enrolled patients with lenalidomide-refractory multiple myeloma (MM) after 1–3 prior lines of therapy (pLOT), demonstrated a significant benefit of ciltacabtagene autoleucel (cilta-cel) over established triplet regimens. However, the benefit of cilta-cel for patients with standard-risk cytogenetics remains less defined. Here, we report outcomes in patients with standard-risk cytogenetics from the intent-to-treat and as-treated populations in CARTITUDE-4. Methods: InCARTITUDE-4, patients randomized to the cilta-cel arm underwent apheresis and bridging treatment with either pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd), followed by lymphodepletion therapy with cyclophosphamide and fludarabine, and then a single cilta-cel infusion. Progression-free survival (PFS) was assessed using a validated computerized algorithm. The intent-to-treat population included 208 patients; 32 patients progressed or died on bridging therapy, resulting in an as-treated population of 176 patients. Patients with high-risk cytogenetics, defined as del(17p), t(14;16), t(4;14), gain/amp(1q) (n=105), or with unknown cytogenetics (n=12), were excluded from the as-treated analysis. The 12-month minimal residual disease (MRD)-negative complete response (CR) was defined per the International Myeloma Working Group criteria as the proportion of participants with CR or better prior to and at 12 months (±3 months), achieving MRD-negative status at 12 months (+3 months) after cilta-cel infusion, as determined by next-generation sequencing (10-5), prior to progressive disease or subsequent anti-myeloma therapy. For the as-treated population, PFS rates were measured from the time of cilta-cel infusion. Results: In CARTITUDE-4, in the intent-to-treat population, at a median follow-up of 33.6 months, patients with standard-risk cytogenetics had a 30-month PFS rate (95% CI) of 71.0% (58.8–80.2) in the cilta-cel arm (N=69) vs 43.2% (31.3–54.5) in the standard-of-care (SOC) arm (N=70). Patients with standard-risk cytogenetics in the as-treated population (n=59) had a 30-month PFS rate of 80.5% (95% CI, 67.2–88.8). In CARTITUDE-1 (NCT03548207), which evaluated cilta-cel in patients with heavily pretreated relapsed/refractory MM (RRMM; ≥3 pLOT), the 30-month PFS rate among patients with standard-risk cytogenetics (negative for del(17p), t(14;16), or t(4;14); n=68) was 59.9% (95% CI, 47.2–70.5). In the CARTITUDE-4 as-treated population with standard-risk cytogenetics, 8 PFS events occurred within 1 year and 4 PFS events beyond 1 year of cilta-cel infusion. Twenty-six patients achieved MRD-negative CR at 12 months after cilta-cel; 100.0% of these patients were progression free at 30 months. Fourteen patients were not evaluable for MRD due to: calibration failure (n=12), no sample availability for testing (n=1), or indeterminate results post baseline (n=1). Conclusions: The PFS rate at 2.5 years for patients with standard-risk RRMM was higher in CARTITUDE-4 compared with CARTITUDE-1, supporting the use of cilta-cel as early as second line in the treatment course. In CARTITUDE-4 (as-treated population), 80.0% of patients with standard-risk cytogenetics were progression free and off treatment at 2.5 years. In patients with standard-risk disease who achieved MRD-negative CR at 1 year, this rate increased to 100.0%. The low rate of progression events in cilta-cel-treated patients with standard-risk cytogenetics shows the profound benefit of a single cilta-cel infusion in this population.

Abstract Background Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPN) characterized by myeloproliferation and an increased risk of thrombohemorrhagic complications, progression to myelofibrosis (MF), and reduced overall survival. Risk-adapted management of PV/ET favors treatment with cytoreductive therapy in high-risk patients. Hydroxyurea (HU) is the most frequently utilized first-line cytoreductive agent, however pegylated interferon alpha-2a (PEG) and the more recently approved, ropeginterferon alfa-2b (ropeg-IFN), have demonstrated a potential to induce molecular responses and improve event free survival (EFS) (Gisslinger Leukemia 2023). The Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 investigator-initiated clinical trials established the efficacy and safety of PEG in both treatment naïve (n=82) and HU intolerant/resistant (n=115) patients. MPN-RC 111/112 reported results up to 36 months with a median duration of treatment of about 24 months (Yacoub Blood 2019, Mascarenhas Blood 2022). This study aims to characterize the longer-term follow-up and outcomes of 111/112 trial patients treated at our center after the study terminated. Methods This is a single center retrospective review of 34 patients with high-risk ET or PV who were treated on the 111/112 trials with PEG and continued to be followed at Mount Sinai. IRB approval was obtained prior to data capture. Therapies initiated after PEG were examined, including duration of treatment, therapy-free intervals, and response to subsequent therapies. Clinical outcomes (during/after trial enrollment) included thrombotic/hemorrhagic events, progression to MF, leukemic transformation, hematopoietic stem cell transplantation (HSCT), and death. PEG related toxicity data included development of hypothyroidism, autoimmune disease, depression/mood disorder, liver dysfunction, and ocular toxicity. Results 34 patients were included in the analysis (16 ET and 18 PV) with median age of 73.5 years. 26 (14 PV and 12 ET) were enrolled on 111 from 2012 to 2015 and 8 (4 PV and 4 ET) were enrolled on 112 from 2011 to 2016. 26 (81.3%) patients had mutations in JAK2, 3 (9.4%) in CALR, 1 (3.1%) in MPL, and 2 (6.3%) were triple-negative. At 12 months on trial, 12 (35.3%) patients achieved a complete response, 12 (35.3%) had a partial response, and 10 (29.4%) had no response to PEG. The median duration of follow up was 104.8 months after trial termination. 8 patients received no further therapy after the end of study, 12 received one subsequent therapy, and 14 received two or more subsequent therapies. 13 patients continued receiving commercial PEG or received it at some interval after study end and 2 patients were treated with ropeg-IFN. The median duration of PEG was 25.3 months on trial and 30.9 months when including those who continued on commercial PEG after trial termination. Median EFS was 140.4 months (95% CI 121.1 - Not estimated) including 5 (15%) patients with a thrombotic event, 1 (3%) with a hemorrhagic event, 8 (24%) progression to MF, 1 (3%) HSCT, 1 (3%) leukemic transformation, and 5 (15%) who died (2 second primary malignancies, 1 sepsis, 1 hemorrhage, 1 unknown). 25 of 34 patients developed toxicities potentially related to PEG therapy, including hypothyroidism (n=3), autoimmune disease (n=4), depression/mood disorder (n=10), liver dysfunction (n=13) and ocular toxicity (n=2). DiscussionPEG therapy is an effective therapy for ET and PV with the potential for durable responses. With a median follow up of more than 8 years, this single center retrospective analysis demonstrated a long EFS of greater than 11 years, accompanied by low rates of leukemic transformation and MPN-related death. There was no statistical difference in EFS based on response to PEG at 12 months on the initial 111/112 trials. The relatively short duration of PEG therapy may explain the rates of MPN-related events, including thrombosis and progression to MF. Future analyses should identify additional predictors of EFS, including duration of PEG treatment, best response to PEG at certain landmark intervals, and depth and/or duration of molecular response. This analysis also demonstrated high rates of PEG-related toxicities, although definitive causality was often difficult to determine. Additional clinical and molecular data will be available at the time of the meeting.

ABSTRACT Pharmacists play a critical role in optimizing medication use, especially in vulnerable populations such as those with chronic kidney disease (CKD). Despite strong evidence and recent guideline endorsements, many pharmacists continue to rely on the Cockcroft–Gault (C‐G) equation for medication dosing. This opinion paper issues a call to action for the widespread adoption of a race‐free, body surface area–adjusted estimated glomerular filtration rate (eGFR BSAadj ) for medication‐related decision‐making, as endorsed by the 2024 Kidney Disease: Improving Global Outcomes CKD guidelines and the National Kidney Foundation and the American Society of Nephrology Taskforce. Persistent variability in pharmacy practice, institutional protocols, and pharmacy education underscores the need for coordinated change. We urge health systems to integrate eGFR BSAadj into electronic health records and clinical decision support to enhance medication decision‐making; institutions to align protocols with contemporary eGFR‐based prescribing standards; pharmacy educators to contemporize and standardize education on kidney function assessment and medication dosing; and regulatory bodies to update licensure and board examinations. The pharmacy profession must act decisively in order to align with evidence‐based, equitable kidney‐related dosing practices and ensure optimal medication management for all patients.