Muñoz, Javier

7062 Background: MCL is a rare and aggressive subtype of B-cell non-Hodgkin lymphoma that remains incurable. Bruton tyrosine kinase (BTK) inhibitors are an established standard of care for R/R MCL. However, comparative effectiveness data for different BTK inhibitors for R/R MCL are limited. This study evaluated the real-world effectiveness of zanu and acala in US patients with R/R MCL based on overall survival (OS) and time to next treatment (TTNT). Methods: A retrospective cohort study was conducted using Komodo health administrative claims data. Eligible patients were adults (aged ≥18 years) with ≥2 MCL diagnoses and continuous enrollment or activities within 1 year prior to and 3 months following the index date. Patients were required to initiate monotherapy with zanu (index period: November 2019 to August 2025) or acala (index period: October 2017 to August 2025) as a second-line or later (2L+) treatment, with index date defined as the first observed claim for zanu or acala. Patients with evidence of clinical trial participation, end stage renal disease or prior stem cell transplant were excluded. Outcomes included OS (time from index date to all-cause mortality) and TTNT (time from index date to subsequent therapy with an allowable gap of 120 days). If an outcome was not observed, patients were censored at the date of last activity or enrollment end date. Survival analyses were conducted using Kaplan-Meier estimates and Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was adjusted for age, sex, US region, treatment initiation year and Charlson Comorbidity Index (CCI). Results: In total, 2219 patients (zanu, n=931; acala, n=1288) were eligible and included in the study. The mean age was higher in the zanu (72.3 years; SD, 9.4) vs acala cohort (71.4 years; SD, 9.7). Most patients were male (zanu, 71%; acala, 75%), non-Hispanic white (zanu, 73%; acala, 74%), and the mean CCI was 3.5 (SD, 3.2) and 3.6 (SD, 3.1) in the zanu and acala cohorts, respectively. Median follow-up was 14.8 and 18.2 months in zanu and acala cohorts, respectively. Median TTNT was 26.7 months for zanu and 20.8 months for acala. Median OS was not reached for zanu and was 60.6 months for acala. In the unadjusted model, zanu had a longer TTNT (HR, 0.86; 95% CI, 0.76-0.97; P =.012) and OS (HR, 0.74; 95% CI, 0.62-0.88; P <.001). After IPTW adjustment, TTNT and OS favored zanu treatment (TTNT: IPTW-adjusted HR, 0.86; 95% CI, 0.76-0.98; P =.025; OS: IPTW-adjusted HR, 0.81; 95% CI, 0.68-0.98; P =.03). Conclusions: In this real-world analysis of US health claims data, zanu monotherapy demonstrated significantly longer TTNT and improved OS compared with acala in patients receiving 2L+ therapy for MCL. These findings support zanu as an effective BTK inhibitor for R/R MCL.

CD19-directed chimeric antigen receptor (CAR) T-cell therapies have been instrumental in improving outcomes of refractory or relapsed B-cell malignancies. However, there have been safety concerns due to recent reports of second primary malignancies (SPMs) related to CAR T-cell therapies. We reviewed articles from Embase, PubMed, and Cochrane Library records and included SPM case reports as well as cohort studies. Across published cohorts, secondary cutaneous or peripheral T-cell lymphoma (PTCL) after diffuse large B-cell lymphomas (DLBCLs) have been reported at low incidence (generally in the low single-digit percentage range). While CAR T-cell therapy is associated with these rare secondary malignancies and lineage-switch events primarily described in acute leukemia, they are clinically significant and have resulted in increased surveillance. The currently available evidence suggests that most secondary malignancies after CAR T-cell therapy are due to background risk and prior treatment exposures rather than direct CAR T-cell therapy induced oncogenesis. However, rare CAR T-cell therapy-associated second primary T-cell malignancies have been reported. To properly define incidence, mechanisms, and risk factors for CAR T-cell therapy-associated malignancies, continued prospective registry follow-up and additional research will be needed.

Abstract Introduction: Epcoritamab (epcor) was the first CD3xCD20 bispecific antibody approved for treatment of R/R DLBCL in May 2023 based on its efficacy and safety in EPCORE NHL-1. Patients (pts) enrolled in clinical trials are highly selected, and those with high-risk features, such as primary refractory disease, early post-CAR T relapse, poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), and CD20+ status are often underrepresented or excluded. As epcor use expands in more heterogeneous, real-world populations, there is increasing interest in understanding pt characteristics and response outcomes associated with its use outside of clinical trials. In particular, pts with DLBCL that is resistant to, or relapse soon after, CAR T are left with limited treatment options and often present with rapidly progressive, resistant disease, making them especially challenging to manage. Generating real-world evidence is critical for informing optimal use of epcor in routine practice. Methods: Real-EPCOR is a multicenter US retrospective chart review study at &gt;8 academic and community oncology centers designed to evaluate the real-world use of epcor. Eligible pts are adults (≥18 years) with R/R DLBCL and ≥2 prior lines of therapy (LOT) who initiated epcor outside of a clinical trial after 5/19/23. Pt demographic, clinical, and treatment data were collected, including ECOG PS, refractory status, prior CAR T, and CD20+ status. Overall response rate (ORR) was evaluated during epcor treatment and defined as the proportion of pts achieving complete response (CR) or partial response among pts with ≥1 evaluable response assessment or who died due to disease progression before response assessment. ORR and CR rate were calculated for the entire cohort, for pts receiving ≥2 cycles of epcor (full cycle is 28 days), and for pts who received prior CAR T. Results: This interim analysis included 34 pts from 2 centers. Data collection and analysis is ongoing and updated results with additional pts and longer follow-up may be included at time of presentation. Median age was 67 years; 68% pts were male and 85% were White. Median time from DLBCL diagnosis to initiation of epcor was 15.5 months. The most common comorbidities were cardiovascular disease (59%) and diabetes mellitus (29%). ECOG PS was ≥2 in 29% of pts, and 85% of pts had Ann Arbor stage 3-4 disease. Nearly all (97%) had CD20+ DLBCL. High-risk features were common at time of epcor initiation, including 53% with International Prognostic Index (IPI) ≥3, 26% with double-hit, and 24% with non-GCB subtype. Among pts who received ≥2 cycles of epcor (n=15), 20% had ECOG PS ≥2 and 33% had IPI ≥3; in post-CAR T pts, 22% had ECOG PS ≥2 and 57% had IPI ≥3. Median number of prior LOT was 3 (range: 2–9); 44% of pts initiated epcor as 3L therapy. Prior to epcor, 41% had primary refractory disease. Following their most recent therapy, 72% had refractory disease, and 43% had DLBCL that was refractory to all prior LOT in those with known refractory status. Most pts (68%) received prior CAR T, with a median interval of 4.6 months from infusion to epcor initiation, and 23% initiated epcor ≤2 months from CAR T. 15 pts (44%) received CAR T in the LOT immediately prior to epcor, 9 (60%) of whom were refractory to CAR T. The ORR was 50% and CR rate was 29% in the overall evaluable population (n=24). 10 pts were not evaluable, as they did not undergo a response assessment either because they remained alive without assessment or experienced a non-progression-related event. Among pts who received ≥2 cycles of epcor, ORR was 85% and CR rate was 54% in the evaluable population (n=13). Among 23 post-CAR T pts, ORR was 53% and CR rate was 33% in the evaluable population (n=15). Conclusion: In this real-world interim analysis, pts with R/R DLBCL treated with epcor had a high proportion of CD20+ disease, higher-risk clinical features, greater comorbidity burden, and more complex treatment histories, including a substantial proportion with prior CAR T, compared to pts in EPCORE NHL-1. Therefore, the ORR remains highly meaningful in the overall cohort despite being lower than the trial. Encouraging ORRs among those who received ≥2 cycles of epcor or had prior CAR T suggest that epcor monotherapy may provide clinical benefit even in difficult-to-treat pts in the real-world setting. Ongoing real-world survival analyses will inform the optimal use of epcor within the evolving treatment landscape of R/R DLBCL.

Abstract Background and Significance Diffuse large B-cell lymphoma (DLBCL) and other LBCLs account for 35–40% of non-Hodgkin lymphoma cases in North America, Europe, and East Asia. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard first-line treatment for DLBCL, achieving cure rates in approximately 60–70% of patients. However, 30–40% of patients will relapse or become refractory (R/R) to treatment, facing poor prognosis. Patients with high International Prognostic Index (IPI) scores (3–5) and those with IPI 1–2 who have bulky disease and/or very high lactate dehydrogenase (LDH) are recognized as high-risk (HR) subsets with suboptimal outcomes (Maurer et al, ASH 2023, #4512). Novel combination strategies are an area of focus for improving efficacy in this population. GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin [COO]) and immunomodulatory activity. In the Phase 1b study CC-220-DLBCL-001, GOLCA in combination with R-CHOP demonstrated a predictable and manageable safety profile with high rates of durable responses, irrespective of COO, in previously untreated aggressive B-cell lymphomas (BCL), including promising activity in HR patients (Amzallag et al, ASH 2024, #579). The median relative dose intensity for GOLCA and CHO components was high (97–99%), indicating uncompromised delivery of curative standard-of-care treatment and combinability. GOLCA ± rituximab has also shown encouraging efficacy and safety in patients with R/R DLBCL (Bachy et al, ICML, #148). These findings support the further study of GOLCA + R-CHOP combination in the Phase 3 setting. Study Design and Methods GOLSEEK-1 (NCT06356129) is a randomized, double-blind, placebo-controlled, Phase 3 study evaluating GOLCA + R-CHOP versus placebo + R-CHOP in patients with previously untreated HR LBCL. Approximately 850 patients with previously untreated LBCL will be randomized 1:1 to either GOLCA + R-CHOP or placebo + R-CHOP. Eligible patients include those with histologically confirmed LBCL per WHO 2022 criteria—including DLBCL (not otherwise specified [NOS], ABC/GCB), high-grade BCL with MYC and BCL2 rearrangements or NOS, T-cell/histiocyte–rich LBCL, or Epstein Barr Virus-positive DLBCL. HR status is defined by IPI ≥3, or IPI 1–2 with HR features: LDH &gt;1.3× upper limit of normal and/or bulky disease (≥7 cm lesion). All patients must have measurable disease as defined by Lugano criteria. Key exclusion criteria are other lymphoma subtypes such as primary mediastinal LBCL; primary cutaneous DLBCL-leg type, grade 3b follicular lymphoma (FL); transformed indolent lymphoma; anaplastic lymphoma kinase (ALK) positive LBCL; primary effusion lymphoma; and Burkitt lymphoma and known or suspected central nervous system involvement. Randomization will be stratified by IPI score (HR 1–2 and 3 vs 4–5) and bulky disease status (≥7 cm vs &lt;7 cm). After a screening period of ≤4 weeks, patients will receive either GOLCA (0.4 mg) or placebo orally once daily for 7 consecutive days in each of 6 cycles, combined with R-CHOP every 21 days. The primary endpoint is progression-free survival (PFS) by investigator assessment per Lugano Response Criteria. Key secondary endpoints include PFS in non–high-grade BCL, event-free survival, independently assessed complete metabolic response, undetectable minimal residual disease by PhasED-Seq (defined as undetectable circulating tumor DNA levels at end of treatment), and overall survival. Patients will be followed up for up to approximately 67 months after beginning treatment. This study is currently recruiting at 309 sites in 36 countries , across the United States, Europe, Latin America, and East Asia. Acknowledgement BMS Artificial Intelligence was used to revise existing text with human author oversight.

Abstract Background: The coexistence of systemic mastocytosis (SM) and lymphoid neoplasms is rare and remains poorly defined. These cases are classified under SM with associated hematologic neoplasm (SM-AHN) in the WHO framework, though the ICC distinguishes SM with associated myeloid neoplasm (SM-AMN) as a separate entity. Emerging evidence points to SM with associated lymphoid neoplasms (SM-ALN) as a biologically distinct and clinically indolent subgroup (Aperna F et al, 2025). We performed a multisite retrospective study to characterize the clinico-molecular features and outcomes of SM-ALN. Methods: We conducted a retrospective analysis across Mayo Clinic sites, reviewing records from January 1980 to December 2024 to identify patients with SM-ALN. IRB approval was obtained. Of 22 cases identified, 4 were excluded due to co-occurring myeloid neoplasms. The final cohort included 18 patients. Variables analysed included age, sex, SM subtype, KIT mutation, symptoms, treatment, and survival outcomes. Results: Eighteen patients were included (median age: 61.5 years; range: 38–80; 11 female). Most had indolent SM (ISM, n=16); two had aggressive SM (ASM). SM preceded the lymphoid neoplasm in 4 cases (22%), followed it in 6 (33%), and was concurrent in 8 (44%). Low-grade lymphomas (n=12, 67%) included follicular lymphoma (n=2), CLL (, n=2), marginal zone (n=1), lymphoplasmacytic (n=1), and mantle cell (n=1). High-grade lymphomas (n=6, 33%) included diffuse large B-cell lymphoma (DLBCL, n=3), Hodgkin lymphoma (n=2), and T-cell acute lymphoblastic leukemia (n=1). SM-related symptoms were present in 16 of 18 patients (89%). The most common manifestations included dermatologic symptoms (rash/pruritus, 56%), systemic complaints (fatigue/weight loss, 39%), GI symptoms (17%), and anaphylaxis (6%). KIT D816V testing mutation was positive in 10 of 16 patients tested (63%). Tryptase was elevated (&gt;20 ng/mL) in 15 of 18 (83%). NGS data was available for 9 patients: among the two ASM cases, both harbored SRSF2 mutation; one also had JAK2, DNMT3A, RUNX1, TET2, and TP53, while the other carried DNMT3A and IDH1. Mutations observed in ISM cases included CCND3, CXCR4, NOTCH2, SF3B1, MYD88 L265P, ASXL1, and TET2. SM management was divided into two categories: (1) Conservative approach, including observation alone in 4 patients (22%) and symptomatic therapies such as antihistamines or leukotriene inhibitors in 7 (39%); and (2) Cytoreductive treatments, comprising avapritinib in 5 patients (28%), cladribine in 1 (6%), and imatinib in 1 (6%). Management of lymphoid neoplasms included intensive regimens such as R-CHOP and hyper-CVAD for high-grade subtypes (e.g., DLBCL and T-ALL), while indolent forms (e.g., CLL and follicular lymphoma) were treated with bendamustine-rituximab or observation depending on disease burden. Overall, 13 patients (72%) received systemic therapy. At a median follow-up of 81 months (6.7 years), 17 of 18 patients (94%) were alive and progression-free. Median OS and PFS were not reached. The sole death occurred in a patient with ASM, while all ISM cases remained alive. ASM was associated with a higher (though nonsignificant) risk of death (OR 33.0; 95% CI, 0.89–1220.9; p = 0.111). Among patients with high-grade lymphomas (n=5), 80% were alive at follow-up, compared to 100% with indolent lymphomas (n=13). Discussion: Our findings support SM-ALN as a clinically indolent and biologically distinct subset within SM-AHN. Most patients had ISM and low-grade lymphoid neoplasms, with favorable outcomes regardless of lymphoma subtype or diagnostic sequence. High-risk mutations were confined to ASM cases, reinforcing underlying biologic differences. These findings align with prior Mayo Clinic data showing longer survival in SM-ALN compared to SM-AMN (median OS 8.1 vs 2.0 years; p&lt;0.01). Treatment was primarily directed by the lymphoid malignancy, with limited need for cytoreduction in ISM. Larger, prospective studies are needed to confirm these observations and optimize management strategies. Limitations include the study's retrospective, single-center design and limited racial diversity. Multi-institutional studies are warranted to validate these findings and guide optimal management. Conclusion: SM-ALN is a rare but distinct SM subtype characterized by indolent behavior, favorable treatment responses, and prolonged survival. Recognition of this subset is critical to avoid over-treatment and to guide risk-adapted management strategies.

Abstract Introduction: CD20xCD3 bispecific antibodies (BsAb) have been approved for use in relapsed/refractory (RR) large B-Cell lymphomas (LBCLs) with manageable toxicities. The main adverse events of clinical interest are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The risk factors for CRS and ICANS are not well understood. Knowledge of variables that contribute to increased risk may help clinicians identify and tailor management for high-risk patients (pts) and increase the comfort level for providers using these therapies in community practices. Methods: We performed a multicenter retrospective study at 21 US centers evaluating pts with RR LBCLs receiving commercially available epcoritamab (epco) or glofitamab (glofit) between 2023 and 2025. We obtained baseline characteristics, safety and efficacy outcomes. Univariate analysis was performed to identify associations between CRS, ICANS, and clinical variables of interest. Results: As of May 31, 2025, a total of 312 pts with RR LBCLs were treated with BsAb, Epco n=193 (62%), Glofit n= 119 (38%); median age 68; 63% male; 70% ECOG PS 0-1. Most common histologic type was diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) (n=239, 84%) followed by high-grade B-cell lymphoma (HGBL) (n=46, 16%). 179 pts (57%) were previously treated with chimeric antigen receptor T-cell (CAR-T) therapy, with 47% receiving CAR-T &lt;6 months (mo) prior to BsAb. Among pts with prior CAR-T, CRS with CAR-T therapy of any grade occurred in 63%, with 26% ≥ grade 2. ICANS of any grade (G) occurred in 25% of pts (9.4% ≥ G3). Overall and complete response (ORR and CR) rates to BsAb were 51% and 29%, respectively. With a median follow up of 5 mo, median progression-free and overall survival (PFS and OS) were 2.3 and 7.3 mo, respectively. With BsAb treatment, CRS of any grade occurred in 117 (39%) patients: 24% G1, 8.7% G2, 4% G3, 1% G4 and 1% G5. The max grade CRS occurred most frequently after the third dose of epco (35%) and the first dose of glofit (23%). CRS was managed with additional steroids in 24% of pts and tocilizumab in 22%. 13% of pts experienced ICANS: 5.8% G1, 3.4% G2, 2% G3, 1% G4 and 0.3% G5. Factors that increased the risk for any grade CRS included: bulky disease ≥ 7.5 cm at time of BsAb treatment (OR 2.04, 95% CI 1.17 – 3.55, p = 0.012), elevated LDH (OR 2.56, 95% CI 1.45– 4.76, p = 0.002) and treatment with epco compared to glofit (OR 1.69, 95% CI 1.04- 2.77, p = 0.036). As G ≥2 CRS generally requires inpatient monitoring and management, we next compared the risk factors between pts with no CRS or G1 CRS and G ≥2 CRS. Factors associated with increased risk for high grade CRS included: bone marrow involvement by lymphoma (OR 3.47, 95% CI 0.97 – 11.3, p = 0.043), platelet count ≤ 75 (OR 2.46, 95% CI 1.21 – 4.87, p = 0.011), ≥ 2 extra nodal sites (OR 2.04, 95% CI 1.07 – 3.97, p = 0.032) and ≥G2 CRS with prior CAR-T (OR 3.35, 95% CI 1.13 – 9.97, p = 0.027). Factors that increased the risk for ICANS included: bulky disease (OR 2.67, 95% CI 1.28 – 5.49, p = 0.008), elevated Cr ≥ 1.5x ULN (OR 3.79, 95% CI 1.25 – 10.4, p = 0.012), elevated AST/ALT ≥ 3x ULN (OR 4.65, 95% CI 0.92 – 19.9, p = 0.042), low albumin (OR 2.85, 95% CI 1.49 - 5.5, p = 0.002), and co-occurrence of CRS with BsAb (OR 9.1, 95% CI 3.85- 25, p &lt; 0.001). No other clinical variables including older age, histologic subtype, ECOG PS, B symptoms, IPI score, cell of origin or histologic subtype, baseline labs such as ALC, CRP, fibrinogen or D-dimer were significantly associated with CRS or ICANS risk. There was no difference in ORR or CR rates in patients who experienced CRS or ICANS. Conclusions: Our analysis of pts treated with commercial BsAb for LBCL shows an increased risk for CRS and ICANs based on clinical variables that are routinely obtained at baseline including tumor bulk, sites of disease, laboratory parameters, and history of prior CRS with CAR-T therapy. Differences in baseline populations receiving epco and glofit treatments in this real-world analysis have been previously reported (Brooks et al, Blood 2025) and the comparative risk for CRS between these treatments remains unclear. Future plans including multivariable analysis may allow for development of a predictive model to identify pts at high risk of CRS and ICANS with BsAb treatment, potentially leading to prospective clinical trials evaluating prophylactic interventions for high-risk pts.

207 Background: CAR-T & bispecific antibodies (BsAb) for large B-cell lymphoma offer deep responses, but have unique toxicities requiring close monitoring. Different practice settings have varied strategies for managing these toxicities, leading to increased costs, healthcare resource use, & reduced quality of life. With no direct comparison, rationale for therapy selection may vary. This study explores provider choices, sequencing strategies & access barriers. Methods: A survey of US-based Hematologists was conducted on practice demographics, therapy availability, preferences, & barriers in LBCL. Responses were analyzed across clinical scenarios. Results: Responses were received from 45 physicians. Availability of CAR-T & BsAb varied with 75% prescribing both, & only BsAb being available at 9% of providers’ centers. There was a strong preference for CAR-T over BsAb—higher among academic vs. nonacademic providers (96% vs. 78%; p = 0.03) & at CAR-T vs. non-CAR-T centers (100% vs. 72%; p = 0.001). Even at BsAb-only centers, preference leaned toward CAR-T, though notably lower compared to CAR-T centers. Among centers without either, 86% preferred CAR-T. Practice volume had no impact. Reasons for favoring CAR-T included perceived better outcomes (55%), shorter treatment (26%), center choice (19%), more experience (48%), & curative potential (21%). BsAb selection was driven by CAR-T unavailability & logistical barriers (distance to specialized center, insurance delays, referral complexity, manufacturing time, & hospitalization needs). Axi-cel was preferred by 69% ( p = 0.0001) vs. other CAR-T for third-line or later due to experience with use, response rates, center choice, & logistical ease. Liso-cel (26%) & Tisa-cel (2%) were chosen for perceived favorable toxicity over Axi-cel. Axi-cel was also preferred second-line vs. Liso-cel (73% vs. 24%; p < 0.0001) for similar reasons. Among BsAb, Epcoritamab was favored by 56% for administration ease (subcutaneous), experience, & center preference; Glofitamab by 42% for shorter duration, experience, & center preference. There was no difference by academic vs nonacademic practice & volume for both CAR-T & BsAb. In patients with prior non-CAR-T anti-CD19 therapy, providers chose CD19 CAR-T over CD20 BsAb (80% vs. 18%; p < 0.0001). For relapse after second-line CAR-T, 78% providers preferred BsAb as the next line over other options ( p < 0.0001) due to more favorable response rates, toxicity profile, & experience with use. Providers prioritized response rates, survival, & toxicity profile in their treatment decisions. Logistics, duration, frequency, & cost were less important. There were no differences based on practice setting & CAR-T experience. Conclusions: Despite higher preference for CAR-T due to perceived superior outcomes, access barriers exist. Efforts to streamline referral pathways, logistics, & expand availability are crucial to improve outcomes.

Autologous Chimeric antigen receptor (CAR) T-cell therapies have demonstrated substantial efficacy in patients with relapsed or refractory hematologic malignancies; however, their implementation has been constrained by regulatory barriers. Risk Evaluation and Mitigation Strategies (REMS), mandated by the U.S. Food and Drug Administration (FDA), were initially implemented to mitigate risks associated with cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and other treatment-related toxicities. On 27 June 2025, the FDA removed REMS requirements for all approved B-cell maturation antigen (BCMA) and CD19-directed autologous CAR T-cell therapies, citing that current product labeling sufficiently communicates safety information. Key regulatory changes include the elimination of site certification and tocilizumab stocking requirements, a reduction in the recommended post-infusion proximity period from four weeks to two weeks, increased flexibility regarding monitoring locations, and a shortened driving restriction from eight weeks to two weeks. This review examines the rationale for the REMS requirements for CAR T-cell therapies, synthesizes contemporary safety data from clinical trials and real-world practice, and explores the implications of this regulatory shift for access to care, particularly in rural and underserved populations. The removal of REMS requirements may facilitate broader implementation of CAR T-cell therapies and alleviate logistical and institutional barriers, offering the potential to expand access while preserving patient safety.

ABSTRACT Anaplastic lymphoma kinase‐positive large B‐cell lymphoma (ALK+ LBCL) is a rare, aggressive subtype of diffuse large B‐cell lymphoma with poor outcomes using standard chemotherapy. In this multi‐institutional retrospective study, we analyzed 39 cases of ALK+ LBCL identified at six US academic centers from 2002 to 2024, with treatment including conventional cytotoxic regimens in frontline and biologically informed and nonchemotherapy‐based strategies in the relapsed setting. Ninety‐two percent of patients received frontline anthracycline‐based chemotherapy; 43% received intensified regimens, and 15% underwent upfront autologous stem cell transplantation (ASCT). Despite these approaches, outcomes remained poor. At a median follow‐up of 5.4 years, median event‐free survival (EFS) was 0.6 years (95% CI, 0.4–0.9), and median overall survival (OS) was 1.5 years (95% CI, 1.3–NR). One‐ and five‐year EFS rates were 28% and 17%, while corresponding OS rates were 72% and 42%, respectively. Advanced stage and high IPI scores were associated with inferior outcomes. Twelve patients received ALK inhibitors, with alectinib showing more durable responses than crizotinib. Lenalidomide and immune checkpoint inhibitors also demonstrated activity, including durable complete responses. Five patients underwent allogeneic stem cell transplantation, with three achieving sustained remission. In conclusion, our findings highlight the limited benefit of chemotherapy, even when intensified or followed by ASCT, and support the integration of biologically targeted therapies, which may have contributed to improved OS in our cohort compared to historical outcomes. Prospective, collaborative studies are needed to better understand disease biology and define optimal use of modern therapies in this rare lymphoma.