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Abstract Background: Until 2022, the United Arab Emirates (UAE) lacked in-country allogenic hematopoietic stem cell transplant (allo-HSCT) services, forcing patients abroad for curative treatment while local hematologists managed pre- and post-transplant care. This fragmented model created unique challenges in graft-versus-host disease (GVHD) monitoring and survival tracking. We present the first analysis of outcomes in this underserved population. Aims: To evaluate overall survival (OS) and GVHD rates in adults receiving allo-HSCT abroad with UAE-based follow-up, establishing benchmarks for emerging local transplant programs. Methods: Retrospective multicenter study of adults undergoing allo-HSCT outside the UAE (2009–2023) with follow-up at three tertiary centers (SSMC, SKMC, Tawam). Of 454 screened patients, we excluded pediatric cases (n=245), autologous HSCT (n=76; excluded due to distinct indications/outcomes), and rare allo-HSCT indications (n=33), focusing on the most common diagnoses: acute myeloid leukemia (AML, n=54), B/T-acute lymphoblastic leukemia (B/T-ALL, n=38), and sickle cell disease (SCD, n=8). Kaplan-Meier (KM) analysis estimated 1/3/5-year OS. Observed median survival was calculated for deceased patients. GVHD grading followed NIH consensus criteria. Log-rank tests compared subgroups (donor type). Results: Survival: AML 1/3/5-year OS: 96%/79.3%/55.5% (95% CI 48–63). KM-estimated median not reached; observed median in deceased patients: 20 months. Matched unrelated donor (MUD) recipients had inferior survival vs. matched related donor (MRD)/mismatched related donor (MMRD) (p=0.03). B-ALL: 1/3/5-year OS: 92%/76.4%/69.2% (95% CI 61–77). T-ALL (n=7): 1/3-year OS: 80%/50% (limited by small sample) SCD (n=8): 100% survival at all timepoints; no GVHD observed. GVHD: Any-grade GVHD: 68.5% (AML), 73.3% (B-ALL), 71.4% (T-ALL)—exceeding CIBMTR benchmarks (50–60%). Acute GVHD 35.2% (AML), 43.3% (B-ALL), 28.6% (T-ALL). Chronic GVHD 46.3% (AML), 40% (B-ALL), 57.1% (T-ALL). Conclusion: Despite high GVHD rates, survival outcomes support selective overseas referral for AML/B-ALL patients, particularly younger recipients. SCD results highlight the safety of HSCT in non-malignant disease. These findings underscore the need for local HSCT capacity to mitigate care fragmentation and establish a critical benchmark for UAE programs. Prospective studies should evaluate socioeconomic drivers of referral patterns and GVHD disparities.

Abstract INTRODUCTION Immune checkpoint inhibitors (ICIs) have emerged as a cornerstone of cancer therapy. However, despite their efficacy, ICIs can cause a unique spectrum of autoimmune toxicities known as immune-related adverse events (irAEs). In contrast to irAEs involving other organ systems, hematologic irAEs such as ICI-associated immune thrombocytopenia (ICI-ITP) are less common. As a result, existing data on ICI-ITP are largely confined to isolated case reports, single-center case series, and pharmacovigilance databases lacking granular clinical data. To address this key knowledge gap, we sought to comprehensively characterize the incidence, risk factors, clinical features, treatments, and outcomes associated with ICI-ITP. METHODS We performed a multicenter cohort study of adult patients who initiated ICI therapy at 29 hospitals across 7 major cancer centers in 11 geographically diverse states in the US between 2016-2023. ICI-ITP was defined as a decline in platelet count to <100 x109/L in the absence of an alternative more plausible etiology of thrombocytopenia. Patients with hematologic malignancies were excluded, as were those who received cytotoxic chemotherapy within 30 days prior to thrombocytopenia onset. For each patient identified as having ICI-ITP, we collected data on demographics, comorbidities, medications, laboratory values, treatments, and outcomes. All data were extracted by manual chart review. To identify risk factors for ICI-ITP and to examine its association with death, for each case of ICI-ITP we also collected data on two control patients who initiated ICI therapy at the same site and in the same year but without development of ICI-ITP. We used multivariable logistic regression to identify independent risk factors for ICI-ITP and its recovery (the latter defined according to criteria established by the ITP International Working Group). We used a multivariable Cox model to examine the association between ICI-ITP and its severity with all-cause mortality. RESULTS We identified a total of 214 patients who developed ICI-ITP among 86,648 examined (0.25%). The incidence was highly consistent across sites (range, 0.15–0.30%). Risk factors for ICI-ITP included simultaneous receipt of two different classes of ICIs, additional irAEs, and a lower baseline platelet count. ICI-ITP developed at a median of 8 weeks (IQR, 4–18) following ICI initiation. The median nadir platelet count was 41 x109/L (IQR, 17–64). Six out of 214 patients (2.8%) developed a major bleed, and 16 patients (7.5%) developed a clinically relevant non-major bleed. Cell-bound anti-platelet antibody testing was positive in 6 of 8 patients (75.0%) for whom it was assessed, and median circulating thrombopoietin levels (201 pg/mL [IQR, 178–295]) were similar to those seen in primary ITP. Treatments used included glucocorticoids (49.5%), immune globulin (18.2%), and thrombopoietin receptor agonists (13.6%). Overall, 161 patients (75.2%) recovered from ICI-ITP at a median of 2 weeks (IQR, 1–5) following ICI-ITP onset. Predictors of recovery included additional irAEs and a higher nadir platelet count. Treatment response was observed in 57.0%, 56.4%, and 58.3% of patients within 60 days following initiation of glucocorticoids, immune globulin, and thrombopoietin receptor agonists, respectively. Of 76 patients rechallenged with an ICI, 23 (30.3%) developed recurrent ICI-ITP at a median of 9 weeks (IQR, 2–15); 17 of these 23 patients (73.9%) recovered. Finally, ICI-ITP and its severity were monotonically associated with a higher risk of death (adjusted hazard ratio 2.96 [95% CI, 2.14–4.08] for those with severe ICI-ITP compared to those without ICI-ITP). CONCLUSION In this multicenter study involving patients treated with ICIs at 29 hospitals across the US, we identified 214 patients with ICI-ITP. For the first time, we characterize in detail the incidence, risk factors, clinical features, treatments, and outcomes of ICI-ITP, a relatively novel disease entity. We found that more than half of patients responded to conventional ITP-directed therapies, and that most patients rechallenged did not develop recurrent ICI-ITP. We also found that ICI-ITP was independently associated with an increased risk of death, including a nearly 3-fold increased risk in those with severe ICI-ITP. These findings highlight ICI-ITP as a rare but clinically significant complication of ICI therapy that hematologists must be equipped to recognize and manage.

Abstract Introduction The 2022 WHO/ICC classifications of myeloid neoplasms (MNs) incorporated genomics into the existing clinicopathologic framework, defining new (mono)genetic entities. However, this iterative approach resulted in a mix of pathologically and genomically-defined entities, reliant on arbitrary thresholds and historically-derived boundaries between entities. We hypothesised that integrating genomics with other features, de novo from first principles, might better incorporate modern molecular knowledge to define the biological continuum, evolutionary links and overlapping features across MN. Methods The discovery cohort comprised 6484 thoroughly annotated pts. Contemporary diagnoses included 1817 AML, 1695 MDS, 737 MPN, and 1101 MDS/MPN. Non-malignant pts (AA/CHIP/CCUS/ICUS) were included to explore beyond current neoplastic boundaries. 1407 pts had ≥1 follow-up sample/s. Validation was performed in an independent international cohort (n=2012). An unsupervised random forest algorithm was used to integrate status (and VAF) for 28 mutations, karyotypes, CBC features, sex and age (total parameters 144). Features were selected for potential to be independent of BM sampling. Proximity-based multidimensional scaling/PCA were used to visualize latent structure and identify variance-driving features. Results The model projected pts onto a continuous 3-dimensional space. We first applied clustering seeking 1st-order structure, revealing 4 major clusters (C1–C4). These were further subdivided into 58 distinct subclusters (SCs) by an unsupervised iterative clustering approach. All SCs were enriched for distinctive features, with diverse associations linking genomics to clinicopathological/outcome features. Notably, contemporary diagnoses were distributed widely throughout this landscape, with 9/58 SCs containing cases spanning multiple WHO/ICC MN categories. C1 displayed the most internal heterogeneity, with admixed AML, MDS and MDS/MPN pts. It naturally subdivided down to 4th-order subclustering. Ten SCs were dominated by splicing factor mutations. For example, SF3B1MT segregated into 3 SCs, alone or with high-VAF TET2/ASXL1 or DNMT3A mutations. A separate TET2/SRSF2 SC associated with elevated monocyte%, reflecting a discrete CMML-phenotype genomic entity. NPM1MT formed a distinct SC with FLT3-ITD, distinguished further by VAFs of FLT3, TET2, and NRAS. Current genomically-defined AML subtypes separated in the 4th subclustering. C2 encompassed classical MPN driver mutations across 6 SCs, including a distinct CALRMT group and others defined by variable JAK2 VAFs, co-mutation patterns and other CBC features: eg high-VAF SF3B1MT correlated with PB blast%, and concurrent TET2MT with higher Hb/monocyte counts. C3 was characterized by TP53 alterations, with 5 SCs differing by TP53MT burden, 17p lesions, karyotypic complexity and age. Two SCs, one marked by high TP53 VAF+complex karyotype, the other by ch17 lesions, were associated with the worst OS in the whole cohort. C4 contained most known non-malignant pts, dividing into 4 SCs: 2 largely comprising CCUS and AA, while 2 reflect overlaps/convergence between AA and MDS and MPN, respectively. Repurposing single-cell pseudotime analysis suggested multiple disease origins, with various progression trajectories converging on C3. Projecting them onto the model longitudinal samples moved along these derived paths, consistent with their known progression/remission changes, validating the model's biological relevance and predictive utility. Remarkably, the 58 SCs displayed distinct risks of clonal progression and survival. To maximize potential clinical utility we created a pan-MN prognostic score integrating these features. It performed robustly (c-index 0.84), matching/exceeding existing prognostic tools and validated in an independent dataset. Conclusion Integrating clinicopathologic and genomic data we developed ab initio a continuum model of MNs that transcends historical diagnostic boundaries, captures disease evolution and stratifies clinical outcomes. It may better reflect the core biology and natural histories of specific cases, placing more rational boundaries between discrete entities. Potential advantages extend to treatment selection/trial design (in the era of molecularly-targeted therapies) and personalised prognostication throughout each disease course. Expanded validation is needed to resolve complexity in some areas (notably in C2/C4) and validate/refine this prototype framework.

Abstract Introduction: Among Non-Hodgkin lymphomas (NHL), DLBCL is the most prevalent subtype (~30% of diagnoses). First-line (1L) chemoimmunotherapy cures many patients (pts), but 30-40% will relapse. Prognostic and predictive biomarkers are needed to identify pts refractory to 1L therapy or at high risk of relapse, enabling timely intervention and improved outcomes. This study evaluated tumor-informed WGS-based longitudinal ctDNA monitoring in a real-world DLBCL cohort. Methods: We retrospectively analyzed ctDNA data from 49 pts with DLBCL. Plasma samples were collected before, during, and at the end of 1L therapy (EOT, defined as ± 21 days from the last infusion (preferred when available) or ± 14 days from post-treatment PET imaging) and during surveillance/subsequent treatments. A WGS-based tumor-informed assay (Signatera™ Genome, Natera, Inc.) was used for ctDNA detection and quantification. The association of ctDNA dynamics with event-free survival (EFS) was evaluated using Cox regression analysis, restricted to pts completing at least 5 cycles of 1L therapy. Results: The median age of the cohort was 62 years (range: 56-74), and median follow-up was 22 months (range: 14-30). Pre-treatment ctDNA-positivity rate was 100% (31/31). A total of 19 pts achieved ctDNA clearance during 1L therapy (early clearance within 3 cycles, n=5; late clearance between cycle 4 and EOT, n=14). Pts with no clearance or ctDNA-positivity at EOT (n=7) had significantly inferior EFS compared to those achieving ctDNA clearance (HR 8.04, 95%CI: 1.87-34.62, p=0051). On further stratifying the clearance group and comparing with no clearances, pts with early clearance had superior outcomes (HR 13.22, 95%CI: 1.48-1741.94, p=0.0166), relative to late clearances (HR 5.65, 95%CI 1.46–25.16, p=0.0129). Notably, all 5 pts with early ctDNA clearance remained serially negative and relapse-free. Of the 49 pts, 9 proceeded to chimeric antigen receptor T-cell therapy (CAR-T). Among 6 of these pts with available ctDNA results pre and post therapy, all 3 who stayed ctDNA-positive after CAR-T relapsed (1.3, 2, and 4.5 months post-infusion); 1 pt with pre- and post-CAR-T ctDNA-negativity and 2 pts with ctDNA clearance post-CAR-T remained relapse-free for 9.6, 15.9, and 22.4 months, respectively. Taken together, the PPV and NPV for a single ctDNA time point post CAR-T infusion were 100% for predicting long-term clinical outcomes. Conclusions: Our data support longitudinal ctDNA monitoring as a valuable prognostic and predictive biomarker in DLBCL. ctDNA clearance, particularly early clearance within the first 3 cycles of 1L therapy, is associated with improved pt outcomes. Longitudinal ctDNA monitoring and dynamics can enable identification of high-risk pts who do not clear ctDNA and may benefit from earlier referral for CAR-T. Furthermore, ctDNA monitoring pre- and post-CAR-T infusion is predictive of treatment response and can identify pts at high risk of relapse.

Abstract Myeloid neoplasia encompasses a heterogeneous and complex molecular landscape whereby the distinct combinatorial patterns associated with clinical phenotypes are difficult to delineate. Given that genetic heterogeneity can be a consequence of the topology of the fitness landscape (peaked/non-peaked=high vs low fitness), we investigated co-mutational patterns in TP53 context as an example of hallmark genomic heterogeneity. Indeed, TP53 gene is characterized by hypomorphic/loss-of-function lesions, truncating mutations (frameshifts, stop codons), missense mutations often having a dominant-negative effect and loss of heterozygosity by chromosome 17p deletion driving clonal expansion. Clinical phenotypes of TP53 mutants are also heterogeneous. Here, we stratify TP53 mutations based on our previous published data1 whereby patients with single-hit TP53 and variant allelic frequency (VAF) >50% were classified as obligatory biallelic, patients with VAF between 23-50% as probable biallelic and <23% as probable monoallelic. A threshold of VAF 23% was optimal to separate monoallelic vs biallelic and was based on all-cause mortality. A tree-based model (RandomForestSRC) was used to build a survival model with VAF as a single covariate and minimum node size set to 15 to optimize the cut-off. Using this cut-off, we delineate the epistatic landscape and potential interactions among different TP53 mutational spectra and its fitness. We curated a cohort of 800 patients with TP53 mutations from our institution. In total 36% of the cases carried single hits while 64% had double hits genomic configuration. About 70% of the mutations were missense and were detected at canonical sites (R175H, Y220C, M237I, R273H, R282W, R248Q). We took into consideration 35 features and clustered our cohort of TP53 mutants using factor analysis. When we stratified the cohort based on our predetermined VAF threshold, we found that majority of the variants with high VAF, to be deemed as obligatory biallelic, co-occurred with complex karyotype. These cases were very homogeneous hence had on average a low number of additional variants, likely due to TP53 clones having reduced fitness in the presence of additional mutations. Conversely, patients without complex karyotype were mostly assigned to the monoallelic group due to low to median VAFs. Consequently, these samples had on average a higher number of additional hits, hence a heterogeneous molecular landscape. To substantiate this finding, we noticed that among monoallelic patients two characteristic pairs were observed (TP53-TET2 and TP53-SF3B1) and showed different patterns according to karyotypic associations. Indeed, both pairs in normal karyotype (TP53-TET2, 65%; TP53-SF3B1, 23%) had the highest number of additional mutations on average compared to other monoallelic hits in complex karyotype suggesting that clones resulting by these pairs were advantageous and produced higher fitness driving heterogeneity when together with other mutations. As a preliminary analysis to characterize the fitness landscape of canonical missense TP53 mutations, we investigated whether distinct TP53 mutations conferred differential clonal fitness by implementing a previously published model of stochastic hematopoietic stem cell growth based on the distribution of allelic frequencies across different age groups. Given a fixed stem cell population pool and a constant mutation rate, the distribution of allelic frequencies in the population of corresponding mutations across age can inform the fitness/selection coefficient. The model predicts that high fit mutations will expand more in the population (high VAF) depending on the time the mutation is allowed to expand (age). Based on the literature, we set the stem cell pool to 100,000 and the mutation rate to 1.4E-8.2We limited our analysis to mutations found in at least 10 individual in our cohort and to single hits due to potential epistatic interactions across multiple mutations in the same gene. Given this criterion two mutations R273H and R248Q were analyzed. Interestingly, we observed a 15% increase in fitness gain for R273H compared to R248Q. In summary, mutational heterogeneity and clonal fitness might provide clues to the diversity of TP53 mutational configurations. Our model will be further optimized for the upcoming ASH meeting by incorporating temporal sampling and increasing sample size to define differences in fitness according to mutation site.

Abstract Background The advent of T-cell redirecting bispecific antibodies (BsAb) therapies has led to deeper and durable responses in patients with RRMM. We sought to identify adverse prognostic factors for patients treated with BsAbs. We also explored whether the extent of the non-involved free light chain (niFLC) suppression could serve as a potential marker of T-cell engager activity, given the binding of BsAbs to both clonal and non-clonal plasma cells and the short half-life of serum FLCs. Methods We conducted a retrospective analysis of RRMM patients treated with BsAbs between 2022 and 2025 at Mayo Clinic. Baseline lymphocyte counts and ferritin levels were collected and analyzed both as continuous and dichotomized variables. niFLC was considered undetectable if it was below the quantification limit, while the magnitude of niFLC suppression was defined as the absolute difference between niFLC levels and the lower normal range threshold at the time of best response. In addition to standard statistical methods, interaction models were used to explore the potential effect modification of niFLC dynamics. Results A total of 158 patients were included (teclistamab, 73%; talquetamab, 15%; elranatamab, 12%). The median follow-up is 12 months (range 0 to 28 months). Median age is 71(range 65 to 77); 52% (n=85) were triple-class refractory (refractory to an IMiD, a PI, and CD38-antibody) and 37% (n=60) were penta-refractory. CAR-T therapy was previously administered in 28% (n = 46) patients, and 70% had undergone an autologous stem cell transplant. One or more high risk cytogenetic features including del(17p), gain(1q), amp(1q), del(1p), t(4;14), and t(14;16) were present in 57% (n = 90) of patients. Extramedullary disease was noted at the time of BsAb therapy in 44% of patients. Utilizing IMWG response criteria, 68% (n=107) achieved ≥partial response, and 64% (n=101) had ≥ very good partial response (VGPR) as best response following BsAb treatment. The median time to best response was 1.6 months (range 0.7 to 4.4). On multivariable analyses, baseline immunoparesis (HR 1.96; 95% CI, 1.08–3.58; p = 0.0274) and elevated ferritin levels (≥ 337 ng/mL) (HR 1.96; 95% CI, 1.24–3.09; p = 0.0041) were independent predictors of inferior progression-free survival (PFS). Lower baseline absolute lymphocyte count, analyzed as a continuous variable, was significantly associated with shorter PFS in the univariable analysis (HR 0.66; 95% CI, 0.44–0.98; p = 0.04), but not in the multivariable model (HR 0.75; 95% CI, 0.5–1.13; p = 0.166). Detectable niFLC at the time of best response was also significantly associated with inferior PFS (HR 1.80; 95% CI, 1.14–2.84; p = 0.0114). However, the magnitude of niFLC suppression did not show a statistically significant impact on PFS. The median PFS was 5 months in patients with high ferritin levels (≥ 337 ng/mL) and 21 months in those with lower ferritin (p = < 0.005). Similarly, PFS was 8 months in those with immunoparesis and not reached in those without baseline immunoparesis (p = 0.008). At the time of best response, detectable niFLC was associated with a trend toward shorter PFS (5 vs. 13 months), although the difference was not significant (p = 0.06). Logistic regression analysis supported these findings, with higher ferritin levels (OR 2.28; 95% CI: 1.09–4.96; p = 0.032) and the presence of baseline immunoparesis (OR 2.60; 95% CI: 1.18–6; p = 0.02) being significantly associated with higher likelihood of progression or death. Patients with deep reduction in niFLC achieved a VGPR or better. In contrast, those with detectable or higher-than-normal niFLC levels did worse in terms of response. Notably, niFLC became undetectable in 72% of patients with ≥VGPR (73/101), compared to 52% of those who did not achieve this level of response (30/57). Conclusion Among RRMM patients treated with BsAbs, baseline immunoparesis and elevated ferritin levels emerged as independent predictors of worse PFS. While failure to induce a deep reduction in niFLC at the time of best response suggests a tumor extrinsic mechanism of resistance, and it is also linked to inferior outcomes.

Abstract Background: Real-world data suggest that safety and efficacy of ide-cel and cilta-cel mirror data from pivotal trials, yet older adults remain underrepresented. We report outcomes of the largest cohort of RRMM patients aged ≥75 years receiving CAR-T and compare them with propensity-matched younger patients. Methods: We retrospectively analyzed RRMM patients receiving standard-of-care BCMA CAR-T at 15 centers from the US Myeloma Immunotherapy Consortium between May 2021 and December 2024. Patients ≥ 75 years were 2:1 propensity-matched to patients < 75 based on CAR-T product, sex, performance status, extramedullary disease, baseline ferritin, penta-refractory status, bridging therapy, prior autologous SCT and lines of therapy. Continuous outcomes were analyzed with multivariable linear regression, binary outcomes with logistic regression, and time-to-event endpoints with Cox proportional-hazards models. We estimated average treatment effects via G-computation, using cluster-robust standard errors to account for the matched sets. Results: After 2:1 propensity matching, the cohort included 194 patients ≥ 75 years (cilta-cel: 64 and ide-cel: 130) and 388 patients < 75 years (cilta-cel: 128, ide-cel: 260). Median ages were 78 (range: 75-90) for the older cohort vs 65 (range: 35-74) for the younger cohort. The older cohort had a higher frequency of t(14;16) (9% vs. 3%, p = 0.005), lower baseline ferritin (151 vs. 196 ng/mL, P = 0.046), and lower likelihood of prior ASCT (57% vs. 71%, P = 0.001). Median prior lines of therapy were 5. Median follow-up time for ≥ 75 and < 75 groups for cilta-cel was 11.5 and 11 months and for ide-cel was 16 and 24.3 months, respectively. ORR did not differ amongst the older vs younger patients: cilta-cel (97% vs. 97%) and ide-cel (90% vs. 88%).For patients ≥ 75 years, median PFS with cilta-cel was 28.7 months (95% CI: 13.3–NR) and with ide-cel was 16.4 months (95% CI: 12.1–22.4). In patients < 75 years, median PFS was not reached for cilta-cel but was 11.5 months (95% CI: 9.6–12.7) for ide-cel, reflecting inferior PFS with ide-cel in the younger group (HR 0.4, 95% CI 0.3–0.6). On sensitivity analysis by Cox proportional hazards model, we did not observe any statistically significant differences in PFS in older vs younger patients receiving cilta-cel, although older patients paradoxically had better PFS with ide-cel compared to their matched younger cohort. In the cilta-cel cohort, HR for PFS for older vs younger patients was 1.48 (95% CI:0.77-2.84; p=0.2) and in the ide-cel cohort it was 0.7 (95% CI: 0.5, 0.98; p=0.04). Median OS was reached only in the < 75-year ide-cel cohort at 40 months (95% CI: 32.5–43.5). Rates of CRS were similar, with any-grade (grade ≥3) CRS seen in 74% vs 78% (0% vs. 0.8%) of cilta-cel recipients and 86% vs. 87% (3.1% vs. 1.5%) of ide-cel recipients in the older vs younger groups, respectively. ICANS rates were 21% vs. 20% for cilta-cel (p = 0.79) and 29% vs 20% for ide-cel (p = 0.07), with similar rates of grade ≥ 3 ICANS. In the cilta-cel cohort, Parkinsonian delayed neurotoxicity (DNT) occurred in 3/62 (4.8%) older patients and 6/128 (4.7%) younger patients. Similarly, other non-Parkinsonian DNT rates were similar across age groups, with 6.4% vs 5.5% in older vs younger cilta-cel cohort and 0% vs 1% in the older vs younger ide-cel cohort. Rates of IEC-HS, and infections were comparable across the cohorts. There was no difference in hospital length of stay and ICU admission rate between products within either age cohort. The overall non-relapse mortality (NRM) was 6.7% for patients ≥ 75 years and 6.2% in patients < 75 years. For cilta-cel, NRM in older vs younger cohort was 9.4% vs 4.7% (p= 0.96) and for ide-cel it was 5.4% vs 6.9%, respectively (p= 0.65). Conclusion: Appropriately selected older adults (≥75 years) receiving CAR-T therapy for RRMM can derive a similar efficacy benefit with CAR-T as a propensity-matched younger cohort, without any increased signal of toxicity including CRS, ICANS or delayed NT. NRM was numerically greater, but not statistically significant, in older adults receiving cilta-cel. Median PFS with cilta-cel and ide-cel in older adults were 28.7 months and 16.4 months with median OS not reached and 40 months, respectively. Older adults, ≥75 years old, should not be excluded from CAR-T therapy solely due to advanced age. Overall, cilta-cel was not associated with worsened toxicities in older adults and may offer better PFS.

Abstract Introduction: Multiple myeloma (MM) significantly contributes to global disease burden. To facilitate tailoring of treatment strategies and improved patient (pt) management according to regional differences, there is a need for research on geographical distribution of clinical characteristics that may influence tumor expression and treatment response in RRMM. This study aimed to describe the distribution of prognostic characteristics of pts with RRMM in Europe and the US. Methods: Data were drawn from the Adelphi Real World MM III Disease Specific ProgrammeTM(DSP), a cross-sectional survey, with retrospective chart review, of physicians and their pts with RRMM. The survey was administered to hemato-oncologists and hematologists in EU4 (France, Germany, Italy, Spain) from July to Nov 2021, the UK (May to Nov 2021), and the US (Sep 2020 to Sep 2021). Physician-reported data (collected via DSP pt record forms) for consulting RRMM pts (second-line or later [2L+]) were analyzed to capture demographics, clinical characteristics, and treatment history. Descriptive analyses were performed to assess key variables. Results: In total, 236 physicians provided data on 2037 pts with 2L+ RRMM (n=259 US; n=1778 EU4+UK). Demographic characteristics in the US and EU4+UK were generally similar except there were more White pts in EU4+UK than the US (93%/59%). The mean (standard deviation [SD]) age at diagnosis was 65.8 (7.9) years in the US and 65.9 (9.2) years in EU4+UK, and at the time of data collection (i.e., at the most recent RRMM consultation) mean (SD) age was 69.1 (8.1) years in the US and 70.8 (9.1) years in EU4+UK. Most pts were male (62% in the US and 56% in EU4+UK). Most clinical characteristics were similar between the US and EU4+UK and within regions between White and non-White pts. International Staging System (ISS) stage I/II/III at the time of data collection was 10%/37%/53% in the US and 11%/26%/63% in EU4+UK. There was some variation in other clinical characteristics: ECOG performance status 0–1 at the time of data collection was 80% in the US and 68% in EU4+UK. Bone lesions were experienced by 58% in the US and 65% in EU4+UK, and high-risk cytogenetics were present in 39% in the US and 26% in EU4+UK. The most frequent comorbidities reported at the time of data collection in the US and EU4+UK were hypertension (47%/46%), anemia (24%/26%), hyperlipidemia (19% in both), diabetes (19%/24%), and mild renal disease (12%/18%). Despite some differences in populations, prescribed therapies were broadly similar between regions and between White and non-White within regions. Common 1L therapy classes prescribed in the US and EU4+UK were proteasome inhibitors (PIs) (22%/27%), immunomodulatory drugs (IMDs) (18%/15%), and PI/IMD (59%/51%). Common 2L therapies prescribed in the US and EU4+UK were PIs (15%/18%), IMDs (4%/21%), PI/IMD combination (28%/20%), and IMD/anti-CD38 combination (25%/20%). Common 3L+ therapies in the US and EU4+UK were PIs (24%/14%), IMDs (8%/20%), PI/IMD (26%/21%), and IMD/anti-CD38 (15%/16%). Minor variations in prescribed therapies included rates of stem cell transplantation (22% US/30% EU4+UK), exposure to anti-CD38 (63%/71%), exposure to lenalidomide (88%/92%), and exposure to both lenalidomide and anti-CD38 (56%/66%). The US had higher rates of pts refractory to treatments: anti-CD38 refractory (43% US/31% EU4+UK), lenalidomide refractory (32%/27%), and refractory to both lenalidomide and anti-CD38 (40%/13%). Conclusion: Our study provides critical insights into pts with RRMM across different regions, aligning closely with results from other published large population-based studies. Demographic/clinical characteristics were generally similar across the regions (except proportions of White pts) and between White and non-White pts within regions, including age of diagnosis, ISS staging, and comorbidity burden. Pts were also treated with similar combinations of classes in frontline and second line therapy during the time the study was conducted. Minor variations were seen in level of refractoriness to common therapies, including lenalidomide and anti-CD38. Similarities between the populations enable extrapolation across the regions, to inform treatment strategies.

Abstract Introduction: Brexucabtagene autoleucel (Brexu-cel) is a CD19-targeted chimeric antigen receptor (CAR-)T cell therapy approved for treatment of relapsed/refractory (r/r) B-ALL. Brexu-cel's approval was founded on data from the ZUMA-3 trial, in which 78 patients (pts) were treated at the pivotal dose of 1x10e6 CAR-T cells/kg, resulting in a complete remission (CR) rate of 73%. Three-year follow-up from ZUMA-3 demonstrated median relapse-free and overall survival (RFS/OS) of 11.6 and 25.6 months (mos) for all treated pts. Amongst responders, the median OS was 60.4 mos for those who did not receive a subsequent allogeneic hematopoietic cell transplant (HCT) (n=43), but only 36.3 months for those who did (n=14). This has led some to conclude that HCT may not be beneficial following brexu-cel therapy for r/r B-ALL; however, it must be noted that 29 (37%) of the pts treated on ZUMA-3 received brexu-cel for post-HCT relapse. T cells collected from individuals who relapse in the post-HCT setting are largely of donor origin, making the CAR-T product comparable to a genetically modified donor lymphocyte infusion (DLI). The immunology at play in this scenario may be different from that in which CAR-T cells are of truly autologous origin. Methods: The Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database includes pt characteristics and outcomes of brexu-cel therapy given as standard-of-care across 41 US institutions. We identified pts who achieved an MRD negative (neg) CR by either flow cytometry (minimum sensitivity 10e-4) or NGS following brexu-cel for r/r Ph neg B-ALL and categorized them into three groups with regard to use of HCT: Never HCT, Pre-CAR HCT, or Post-CAR HCT. Pts who received second HCT following brexu-cel for post-HCT relapse (n=9) were excluded. Pt/disease characteristics, RFS, and OS were assessed for each group, landmarked at 73 days after brexu-cel infusion (the median time to consolidative allogeneic HCT). Results: In the ROCCA database we identified 165 pts who achieved MRD neg CR following brexu-cel, amongst whom 69 never underwent HCT, 49 were transplanted pre-CAR (ie, brexu-cel served as a genetically modified DLI), and 47 underwent post-CAR consolidative HCT while in CR. The median follow-up is 373 days. The median age was higher in the Never HCT group (49, range 19-83) in comparison with the Pre-CAR HCT (40, 24-72) and Post-CAR HCT (34, 18-70) groups. Thirty-five percent were >60yo in the Never HCT group vs 20% in the Pre-CAR HCT and 9% in the Post-CAR HCT groups. Ph-like disease was present in 38%, 29%, and 43% of the Never HCT, Pre-CAR HCT, and Post-CAR HCT groups, respectively (p=0.35). No significant differences were observed in pre-apheresis bone marrow blasts, presence of CNS disease at apheresis, prior blinatumomab or inotuzumab treatment, or use of bridging therapy across the groups, though there was a higher prevalence of non-CNS extramedullary disease in the Pre- and Post-CAR HCT groups (32, 39%) vs the Never HCT group (13%) (p=0.004). A minority of pts in all groups were deemed to be in MRD neg CR prior to apheresis (6-20%). Median RFS was 260 days in the Never HCT group and not reached in the Pre- and Post-CAR HCT groups (p=0.002), with respective 1-yr RFS of 38%, 64%, and 67%. Median OS was not reached in any group and was similar for all at 1-yr at 68-79% (p=0.13). Characteristics of those in the Never HCT group who were least likely to relapse included age >60 (OR 0.22, CI 0.07-0.73 vs age 18-39, p=0.024) and those with non-Ph-like B-ALL (OR 0.33, CI 0.12-0.94, vs Ph-like, p=0.037) in univariate analyses. Conclusions: Real-world data regarding outcomes following brexu-cel therapy allow evaluation of the role for consolidative allogeneic HCT, which remains one of the most important unresolved questions in the use of CAR-T therapy for r/r B-ALL. This analysis demonstrates that a first consolidative HCT after achieving MRD neg CR with brexu-cel is associated with a significant decrease in relapse. Additionally, use of brexu-cel for post-HCT relapse is also associated with a significantly lower risk of relapse compared with those who never received an allogeneic HCT. With the current duration of followup, OS is not significantly different across the three groups. These data suggest there is a benefit for relapse-free survival in pts receiving an allogeneic HCT at some point in the course of treatment for r/r Ph neg B-ALL.

Abstract Background: Chronic graft-versus-host disease (cGVHD) is a leading cause of non-relapse mortality following allogeneic hematopoietic cell transplantation (allo-HCT). Further investigation is needed to understand cGVHD risk, diagnostic features, and outcomes. Patient-reported outcomes (PROs) are important for characterizing the direct and indirect impact of cGVHD on patients, caregivers, and the healthcare system. THRIVE (NCT05919511) is a prospective, longitudinal observational study of patients at risk for cGVHD to describe the clinical course, burden, and practice patterns for cGVHD. THRIVE uses a novel app-based platform designed for rigorous collection of PROs related to symptoms, quality of life, and indirect costs to the healthcare system. We report preliminary patient demographics and clinical characteristics at study enrollment. Methods: THRIVE includes adults aged ≥18 years in the United States who were enrolled 90–180 days after allo-HCT. Follow-up is for 36 months at intervals determined by clinician standard practice; a virtual site is available for patients who return to community sites for follow-up. Presence or absence of GVHD symptoms, cGVHD therapies when applicable, and adverse events are captured in medical records at clinical visits every ~3 months. In all, 13 PROs are assessed (Cutaneous GVHD Questionnaire [CuGQ], General Anxiety Disorder [GAD-7], Lee Total Symptom Scale [TSS; 7-day], modified Frenchay Activities Index [mFAI], modified Patient-Generated Subjective Global Assessment [mPG-SGA], Oral Health Impact Profile [OHIP-14], Ocular Surface Disease Index [OSDI-12], Patient Health Questionnaire [PHQ-9], Patient-Reported Baseline Data [PRBD], Patient-Reported Caregiver Assessment [PRCA], Patient-Reported Economic, Income, and Insurance Data [PREIID], Patient-Reported Outcomes Measurement Information System–Sexual Function [PROMIS-SF], and Pulmonary GVHD Questionnaire [PulmGQ]). Patients are randomized to sequence groups to complete rotating sets of 4–5 PRO measures via digital platform, monthly (Year 1) then every 2 months (Years 2–3). Recruitment is ongoing (target, 1500 patients). Results: This interim report includes the first 340 patients enrolled in THRIVE (data cutoff: June 17, 2025) at 22 sites across the United States since August 1, 2023. Median (range) age was 60.5 (19–83) years (>70 years, n=60 [18%]). Most patients were male (n=190, 56%), White (n=276, 81%), and had college/graduate education (n=219, 64%). Underlying disease was malignant in 328 (96%) patients; most common malignancies requiring allo-HCT were acute myeloid leukemia (n=129, 38%), myelodysplastic syndrome (n=50, 15%), and acute lymphocytic leukemia (n=37, 11%). Most patients (n=212, 62%) were in complete remission at time of allo-HCT, 282 (83%) enrolled after their first allo-HCT, and median (range) time from allo-HCT to enrollment was 111 (77–211) days. Transplant source was most commonly peripheral blood stem cells (n=272, 80%) from unrelated (n=229, 67%) donors, of whom 169 (50%) were male. Overall, 188 (55%) patients had human leukocyte antigen identical HCT, 72 (21%) had mismatched HCT, and 55 (16%) had haploidentical HCT. Conditioning regimens were myeloablative for 177 (34%) patients, reduced intensity for 164 (48%), and non-myeloablative for 16 (5%). At data cutoff, 296 (87%) patients were continuing in THRIVE; 18/44 (41%) patients who discontinued were alive at discontinuation. There were 107 patients (31%) who developed acute GVHD before enrollment (grade I, n=52; grade II, n=35; grade III, n=9; grade IV, n=0; missing/unknown, n=11); 85 (79%) received systemic treatment for acute GVHD. Overall, 28 (8%) patients had cGVHD at enrollment (mild, n=25; moderate/severe, n=3). Organs affected by cGVHD were skin (n=13), eyes (n=4), and gastrointestinal tract (n=3). Conclusions: THRIVE aims to report on clinical practice for managing risk and treatment of cGVHD after allo-HCT in a prospective cohort of ~1500 patients in the United States for ≤3 years. Although real-world assessment of PROs can be associated with challenges including willingness to participate in an observational study and the collection of data without routine clinical visits, the virtual hybrid design is intended to improve patient access and facilitate data collection. In the 22 months since initiation, 340 patients have been enrolled at 22 sites, and the discontinuation rate is low.