Background Fludarabine (Flu) is a key conditioning chemotherapy agent for allogeneic hematopoietic cell transplantation (alloHCT). We hypothesized that excessive Flu pharmacokinetic (PK) exposure may lead to poorer outcomes in patients receiving post-transplant cyclophosphamide (PTCy)–based GVHD prophylaxis, and that an optimal exposure range exists. Methods We used a validated population PK model (Langenhorst et al, 2019) to estimate cumulative Flu exposure. Optimal Flu PK cutoffs were determined using maximally selected log-rank statistics for all survival outcomes. Baseline characteristics between groups were compared using the Wilcoxon rank sum test for continuous covariates and Pearson's Chi-squared test along with Fisher's exact test for categorical covariates. Results We included 399 alloHCT patients that received Flu-based conditioning regimens with PTCy from 2017-2023. The median follow-up was 35 months (IQR, 28-40). AML (30%) and MDS (32%) were the most common indications. Most received reduced-intensity conditioning (71%) regimens. Baseline characteristics are summarized in Table 1. The median estimated cumulative Flu AUC was 25.6 mg*h /L (IQR, 22.4-29.1). We defined two groups: optimal Flu exposure (<28 mgh/L, 71% of the cohort), and high Flu exposure (>28 mgh/L, 29%). The 1-year non-relapse mortality (NRM) in the optimal exposure group was 7.9% (95% CI 5.1-11%) compared to 23% (95% CI 16-32%) in the high exposure (p=0.006) (Fig.1A). One-year overall survival (OS) in the optimal exposure group was 82% (95% CI 77-86%) vs. 63% (95% CI 54-73%) in the high exposure (p=0.03) (Fig.1B). There was no difference in relapse, grade II-IV acute GVHD, grade III-IV acute GVHD, or chronic GVHD between the optimal vs. high exposure groups.In a multivariable Cox regression analysis adjusted for age, gender, HCT-CI, disease type, conditioning intensity, and donor type, high Flu exposure associated with increased mortality (HR, 1.65; 95% CI,1.11 to 2.45; p=0.014) due to higher NRM (HR, 2.26; 95% CI, 1.29 to 3.95; p= 0.004) without a difference in relapse.In the high vs. low exposure groups, respectively, infection was the second leading cause of death (25% vs. 16%) after relapse/progression (44% vs. 60%), followed by GVHD (15% vs. 9%). Conclusion High cumulative Flu exposure associates with higher risk for non-relapse mortality and lower survival. The use of model-based Flu dosing to define an optimal exposure may be an easily modifiable strategy to improve transplant outcomes in recipients of alloHCT receiving PTCy. External validation of these findings is planned.

Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P =.002) and fewer severe infections (2.5% vs 18.8%, P =.011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

Nonimmune effector cell-associated neurotoxicity syndrome neurotoxicities (NINTs) are serious, atypical toxicities associated with ciltacabtagene autoleucel (cilta-cel), a US Food and Drug Administration chimeric antigen receptor T cell (CAR T cell) therapy approved for relapsed/refractory multiple myeloma (RRMM). Risk factors contributing to the development of NINTs are poorly understood. In a cohort of 109 patients with RRMM treated with cilta-cel, we identify predisposing risk factors and propose strategies to mitigate NINTs. We show that high-peak absolute lymphocyte count is a strong NINT predictor, which directly correlates with flow cytometry-based peripheral blood CAR T cell quantitation. The observed CAR lymphocytosis was polyclonal with a bias toward CD4+ CAR T cells rich in memory marker expression. We then identified CAR lymphocytosis-associated CD4+ CAR T cell populations, which exhibited increased inflammatory pathway gene expression. Last, we characterize NINT-associated CD4+ CAR T cell populations, which are potential therapeutic targets for future exploration.

Bispecific antibody (BsAb) treatment in multiple myeloma can be associated with adverse events including cytokine release syndrome (CRS), cytopenias, and infections. While granulocyte colony-stimulating factors (G-CSF) can be used to treat neutropenia, little is known about their safety during the BsAb initiation period and whether G-CSF can increase the risk of CRS. To assess the impact of G-CSF on risk of CRS, we included all patients with multiple myeloma who received at least one dose (step-up doses [SUD] and first treatment dose [FTD]), of commercial teclistamab, elranatamab, or talquetamab between November 2022 and April 2024 at Memorial Sloan Kettering Cancer Center (N = 186). Exposure to G-CSF was defined as administration of at least one dose of filgrastim from 48 h before up to 7 days after BsAb SUD or FTD, or one dose of peg-filgrastim between 7 days prior to up to 7 days after BsAb SUD or FTD. Of the 186 patients, 22 were classified as G-CSF exposed. CRS occurred in 16/22 (73%) patients with G-CSF exposure vs 76/164 (46%) of non-exposed. All CRS was grade 1 (56%) or grade 2 (44%) and the majority occurred prior to G-CSF was given (16/22 patients). The median absolute neutrophil count (ANC) at time of G-CSF exposure was 0.5 × 109/L (0.4–0.7). There was a trend towards increased risk of CRS after G-CSF exposure, although not significant (hazard ratio [HR] 1.7, 95% confidence interval [CI] 0.6–4.7, p = 0.3). These results suggest that G-CSF administration can be considered for neutropenia during BsAb initiation.

BACKGROUND:Blinatumomab, a bispecific CD19 × CD3 antibody is effective for the treatment of B-cell acute lymphoblastic leukemia (ALL). Because of its immune toxicities, namely cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), the US Food and Drug Administration (FDA) recommends preemptive hospitalization for the initiation of cycle 1 (C1) and cycle 2 (C2). The necessity of this approach is unclear. METHODS:The authors conducted a retrospective cohort study among all patients treated with blinatumomab between 2012 and 2025 at two academic cancer centers: Memorial Sloan Kettering Cancer Center (MSK) and Dana-Farber Cancer Institute (DFCI). RESULTS:For C1, only nine of 308 (3%) patients initiated outpatient (OP) treatment. A total of 184 of 308 (60%) initiated C2: At DFCI, 10 of 83 (12%) initiated C2 OP and at MSK, and 74 of 101 (88%) initiated C2 OP. Demographic and clinical characteristics were similar between patients initiating C2 inpatient versus OP. No patients who initiated C2 (0 of 184) had Gr3+ CRS (across all cycles) and only two (1%) had Gr3+ ICANS; both were inpatient for C2. Of 84 patients treated without preemptive hospitalization for C2, 16 of 84 (19%) required hospitalization at some point during the cycle, largely for infections (50%). CONCLUSIONS:OP administration of C2 of blinatumomab can be administered safely with no unexpected, severe, or life-threatening toxicities. The ability to safely manage treatment without preemptive hospitalization may support the patient experience and limit costs of care.

Thrombopoietin receptor agonists (TPO-RAs), such as romiplostim, are commonly utilized to facilitate timely platelet recovery and administration of chemotherapy in patients with cancer and chemotherapy-induced thrombocytopenia (CIT). However, there are limited data on the effect of TPO-RAs on clinically important outcomes. A target trial emulation study was implemented to assess the effects of romiplostim in patients with solid tumors and persistent CIT, compared to controls. Patients were exact-matched on chemotherapy, cancer type, degree of thrombocytopenia, and 1:1 propensity-score-matched on clinical/laboratory variables on Day 1 of romiplostim treatment or quasi-index date for controls. Study outcomes included overall survival over 24 months and venous thromboembolism (VTE) at 6 months. This study included 165 romiplostim-treated patients and 165 controls. Baseline characteristics were well-balanced. The median age was 61 years and 52% were female. The median romiplostim duration was 1.38 months. Median overall survival was 13 months (95% CI: 9.9-23) in the romiplostim group and 9.5 months (95% CI: 7.1-14.0) in controls (hazard ratio [HR] 0.86 [95% CI: 0.65-1.13]). There was a numerical improvement in survival with romiplostim (0.80 [95% CI: 0.60-1.06]) which was statistically significant in the subgroup of patients with metastatic disease (HR 0.70 [95% CI: 0.52-0.95]). The 6-month cumulative incidence of VTE was 10.0% (95% CI: 6.3%-16.0%) in the romiplostim group and 8.0% (95% CI: 4.5%-13.0%) in controls (HR 1.31 [95% CI: 0.64-2.70]), with death as a competing risk. In conclusion, these results support the safety of romiplostim in CIT with observed numerical improvement in overall survival at 2 years.

Background: Multiple studies link dietary patterns to cancer risk and survivorship outcomes with cancer-specific guidelines focusing on fiber and plant-rich, minimally processed diets. Additionally, patients frequently report unmet needs for dietary counselling. There is limited data on oncologists' knowledge and attitudes towards this evidence and whether it influences their clinical practice. Methods: A 25-question survey was distributed to oncology professionals with 150 evaluable responses. The survey assessed respondents' demographics, personal dietary choices, knowledge of dietary guidelines, and practice behaviors. Responses were analyzed using descriptive statistics and Fisher's exact and Pearson's Chi-squared tests. Results: Most respondents considered dietary choices important for cancer risk reduction (77.4%), during treatment (66.7%) and for survivorship (76.6%), with 23.3% referring all patients to a dietitian. Barriers to implementing dietary counselling included lack of time (66.7%) or knowledge (54%), or resources (54.7%) or lack of reimbursement (22%). Oncologists following plant-based dietary patterns were more likely to value dietary counselling, engage in self-directed learning, and perceive diet as relevant throughout the cancer care continuum. Conclusions: Despite established dietary guidance, significant gaps in training and practice persist. Enhancing nutrition education, increasing access to resources, consistent reimbursement of dietitian appointments, and generating robust clinical evidence are essential to support oncologists.

The 5th Edition of the World Health Organization Classification of Haematolymphoid Neoplasms (WHO5th) and the 2022 International Consensus Classification (ICC) both recognize myelodysplasia-related acute myeloid leukemia (AML-MR) as a diagnostic entity increasingly defined by integrated genomic data. Although largely concordant, the two classifications differ in various ways that should be resolved to achieve future harmonization. To address the areas of uncertainty, we retrospectively analyzed 615 newly diagnosed AML cases from adult patients treated at two large cancer centers. We demonstrate that AML-MR, whether defined by gene mutations (MR-GM) or cytogenetic abnormalities (MR-CGA), constitutes a prognostically distinct group with inferior outcome compared to most AML subtypes, second only to TP53-mutated or EVI1-rearranged AML. Isolated RUNX1 mutations were not associated with antecedent myeloid neoplasia. Neither the number of mutated MR genes nor their variant allele frequency independently impacted outcomes. Trisomy 8 and del(20q) did not confer inferior outcomes and may warrant exclusion from MR-CGA. Complex karyotype without TP53 mutations did not worsen outcomes within AML-MR and may be considered equivalent to other MR-CGA. The adverse prognosis of AML-MR appeared to be at least partly driven by ASXL1 and/or EZH2 mutations. These findings provide evidence toward a unified schema across the WHO5th and ICC.

ABSTRACT:The incidence of venous thromboembolism (VTE) in patients with acute lymphoblastic leukemia (ALL) receiving asparaginase-based induction is high despite primary thromboprophylaxis. Our aim was to derive and externally validate a VTE risk prediction model in patients with ALL receiving asparaginase-based induction. We conducted a multicenter retrospective cohort study of patients (aged ≥18 years) with newly diagnosed ALL receiving asparaginase-based induction. The derivation and external validation cohorts included 306 and 94 patients, respectively. Primary outcome was VTE at any site. A cause-specific Cox proportional hazards model stratified by thromboprophylaxis and center was performed to identify VTE risk factors in the derivation cohort. A risk prediction model for VTE at 30 days was derived using variables with P value < .05 in the multivariable model and was tested in the validation cohort. VTE risk factors on multivariable analysis in the derivation cohort included D-dimer ≥1 μg fibrinogen equivalent unit per mL (hazard ratio [HR], 2.64; 95% confidence interval [CI], 1.07-6.5) and hemoglobin (HR for each 1 g/dL increment, 1.19; 95% CI, 1.06-1.34) at ALL diagnosis. A VTE risk score based on these variables distinguished between a 4% (95% CI, 0.72-12) and 20% (95% CI, 14-27) 30-day cumulative incidence of VTE in the derivation cohort, with similar findings in the validation cohort (area under the curve, 0.56). The negative predictive value for VTE at 30 days was 96% and 93% in the derivation and validation cohorts, respectively, and the positive predictive value was 20% in both. We derived and validated a model using D-dimer and hemoglobin, which stratifies VTE risk in patients with ALL receiving asparaginase-based induction.

While CAR T has shown superior efficacy in earlier line of therapy [1, 2] for functionally high-risk multiple myeloma (FHRMM), outcomes with its use in later lines (3+) for FHR disease remain unknown. We describe a single-center experience of FHRMM patients (pts), defined as those with progression of disease (POD) < 24 months of frontline therapy, receiving CAR T-cell therapy. Of the 208 pts treated with CAR T, 117 (56%) had FHR disease and had received median of 5 prior lines of therapy (LOT). FHR pts had higher rates of extramedullary disease (EMD) and progression within 12 months of transplant. Median PFS were 11 and 13 months (p = 0.15), and median OS were 34 and 55 months (p = 0.025) in the FHR and non-FHR groups, respectively. On multivariable analyses, EMD and high disease burden were associated with inferior OS. FHRMM pts receiving CAR T as late LOT had inferior survival outcomes compared to those with non-FHR disease, underscoring the poor prognostic impact of POD < 24 months from frontline therapy. This association was largely driven by active EMD and high disease burden at the time of CAR T, highlighting the potential benefit of utilizing CAR T as an early LOT for FHRMM.

Introduction: Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) are two chimeric antigen receptor (CAR) T-cell products targeting B-cell maturation antigen (BCMA) that have recently been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) with 1-2 prior lines of therapy, based on the results of CARTITUDE-4 and KarMMa-3 trials. While daratumumab (dara) refractoriness is predictive of inferior outcomes with subsequent therapies, not all patients enrolled in these pivotal trials were refractory to this anti-CD38 monoclonal antibody. Therefore, we conducted a single-center retrospective cohort study comparing the clinical outcomes of RRMM patients who received BCMA-directed CAR T-cell therapy based on their dara refractoriness status. Methods: Our analysis included all patients with RRMM who received ide-cel, cilta-cel, or orvacabtagene autoleucel (orva-cel) between April 2018 and November 2023. All patients were dara exposed and divided into two groups according to their dara refractoriness status: dara refractory (DR) and dara non-refractory (DN). Refractory disease was defined according to IMWG criteria as disease that did not respond to therapy (failing to achieve a partial response or better) or as progressive disease within 60 days of the last administered dose. Key outcomes of interest included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Survival outcomes were calculated from the date of infusion. Response categories were determined per IMWG consensus definitions. CRS/ICANS were graded based on ASTCT criteria. Results: Of 127 patients included (41% female, age range: 37-86 years) in the analysis, 28 (22%) were considered DN at the time of CAR T-cell infusion. In the DR group (n=99), 41.4% patients received cilta-cel, 31.3% patients received ide-cel, and 27.3% patients received orva-cel. In the DN group (n=28), 50% patients received cilta-cel, 32.1% patients received ide-cel, and 17.9% patients received orva-cel. All patients except one in the DN group were triple class exposed. The analyzed groups (DR vs DN) had comparable rates of patients with ECOG performance status >0 (68.7% vs 60.7%) and high-risk cytogenetic abnormalities (70.7% vs 71.4%), including del(17p)/TP53 mutation, t(4;14), t(14;16), t(14;20), 1q gain/amp and/or del(1p) by FISH analysis. In contrast, the DR group had higher rates of extramedullary disease (EMD) (46.5% vs 28.6%), prior BCMA-directed therapy (24.2% vs 7.1%), prior T-cell-redirecting therapy (13.1% vs 3.6%), high tumor burden (defined as ≥50% bone marrow plasma cells) (28.3% vs 14.3%), and a higher median number of prior lines of therapy (6 vs 4). With a median follow-up of 12 months (range: 1-72 months) for the entire population, best ORR was 77.7% (40% sCR/CR, 22% VGPR, 15% PR) in the DR group vs 85.7% (50% sCR/CR, 14% VGPR, 21% PR) in the DN group. The 12-month PFS was 38% (95% CI: 28-not reached [NR]) in the DR group vs 57% (95% CI: 37-NR) in the DN group (HR: 0.6, p=0.08). The 12-month OS was 74% (95% CI: 64-NR) in the DR group and 86% (95% CI: 68-NR) in the DN group (HR: 0.56, p=0.18). CRS and ICANS rates were similar between the two groups: 74.7% (4% grade ≥3) and 13.1% (2% grade ≥3), respectively, in the DR group, and 78.6% (4% grade ≥3) and 21.4% (0% grade ≥3), respectively, in the DN group. Conclusion: A majority of patients treated with BCMA-directed CAR T for RRMM in this single-center experience were dara refractory. Despite more prior lines of therapy and higher rates of EMD, high tumor burden, prior BCMA-directed therapy, and prior T-cell-redirecting therapy; the DR group showed comparable efficacy outcomes to DN group. Longer follow up with more patients, as well as details of efficacy and safety outcomes with univariate and multivariate analysis will be presented at the meeting.

Undetectable minimal residual disease (uMRD) at the end of first-line (1L) treatment (tx) with 12-cycles (C) of venetoclax (ven) + obinutuzumab (obin) is associated with prolonged survival for patients (pts) with chronic lymphocytic leukemia (CLL, Al Sawaf et al. Blood 2024). We hypothesized that MRD may be used to guide ven tx duration for CLL pts treated with 1L ven + obin. In this ongoing phase II, multicenter investigator-initiated study, pts receive ven + obin for 1L tx of CLL/small lymphocytic lymphoma (NCT04447768). Eligible pts have a CIRS score of ≤ 6 and require 1L tx per iwCLL 2018 criteria. Pts receive 6 x 28-day C of obin and initiate ven on C1D22. Ven duration is dependent on peripheral blood (PB) MRD status measured by ClonoSeq next generation sequencing. At C7, pts undergo MRD testing. Pts uMRD6 (<10-6 sensitivity) at both C7 and C9 dc ven after 9C and enter treatment free observation (TFO). Pts with detectable MRD6 (dMRD6) at C7 undergo repeat testing at C12; if uMRD5 (<10-5) pts dc ven after 12C. Pts dMRD5 at C12 continue ven for an additional 12C (24C total) prior to TFO. The primary study endpoint is 36-month PFS; the unpromising rate is set at 82% and will be tested by a nonparametric survival estimate (Kaplan-Meier) along with Greenwood's formula. RNA sequencing (RNAseq) was performed pre-tx on patient bone marrow (or PB if inaspirable) samples. Unsupervised clustering using machine learning (ML) based on consensus nonnegative matrix factorization was applied to the most variable genes to identify patient clusters. Clusters were then biologically characterized by gene signature scoring using xCell algorithm and assessed for association with uMRD6 at C7 using a Fisher exact test. Baseline characteristics of the 100 pts who initiated tx include: median age 58 (range 34-81); 71% male, 90% White, 3% Black and 2% Asian, 5% unknown; 49% IGHV unmutated, 16% TP53 mutation, 8% del17p (previously reported, Roeker et al. ASH 2024). 3 pts stopped tx prior to C7. 51 pts were uMRD6 at C7 and C9 and completed 9C ven. 46 pts were dMRD6 at C7; 6 pts stopped tx outside of meeting protocol requirements and are included in intention-to-treat (IIT) analyses. 32 pts were uMRD5 at C12 and dc ven after 12C. 8 pts were dMRD5 at C12: 5 continued ven per protocol (3 completed 24C ven, 2 ongoing tx as of 15 May 2025 data cut-off), 2 stopped ven outside of protocol requirements (included in ITT analyses), and 1 pt withdrew consent. At a median follow-up of 35 months, the 36-month PFS rate is 90% (95% CI: 84%, 97%). 36-month OS is 94% (95% CI: 89%, 99%). Landmark PFS analyses from EOT were performed for pts who dc ven after 9C due to uMRD6 (24-month PFS 92%, 95% CI: 85, 100%, n=51) and pts who dc ven after 12C due to uMRD5 (24-month PFS 96%, 95% CI: 89%, 100%, n=32). For pts dc ven after 9C due to uMRD6 (n=51), PB MRD at 12C after EOT was: 59% uMRD6, 12% uMRD5, 4% uMRD4, 8% dMRD4 and 18% unknown. For pts dc ven after 12C due to uMRD5 status (n=32), PB MRD at 12C following EOT was: 9% uMRD6, 31% uMRD5, 9% uMRD4, 25% dMRD4 and 25% unknown. Of the 5 pts with PD, 3 pts have had Richter Transformation to diffuse large B-cell lymphoma (all uMRD6 at C7 / 9). Two pts with PD have not met iwCLL tx criteria and remain in TFO. Five pts have died (suicide, West Nile encephalitis, COVID-19, complications of glioblastoma and RT DLBCL). Five C12 dMRD5 pts who continued ven have reached C18, with only 1 of 5 converting to uMRD5 in PB. However, all 5 maintained uMRD4 (<10-4). Of 3 pts that completed 24C ven (2 ongoing tx), 1 pt had deepening of response to uMRD5 at C24, and 2 pts had rising MRD on ven (dMRD4 at C24). To investigate patient heterogeneity at baseline and its relationship to uMRD, we clustered patient RNAseq samples into two clusters using artificial intelligence/ML based unsupervised clustering. The clusters associated with uMRD6 at C7 (Fisher exact test p=0.038), and patients in the cluster with significantly higher immunosuppressive cells such as T-regulatory cells and M2 macrophages were less likely to be uMRD6 at C7. At a median follow-up of 35 months, the estimated 36-month PFS rate is 90%. RNAseq transcriptomic analyses identified that patients with enriched immunosuppressive cells were less likely to be uMRD6 at C7. Additional follow-up is required to confirm the durability of this MRD-guided ven + obin tx strategy.

Introduction Recent evidence showing benefit of blinatumomab (blina), a CD19xCD3, in upfront treatment of B-cell acute lymphocytic leukemia (B-ALL) broadly expands its use (Litzow et al., NEJM 2024). Due to risks of cytokine release syndrome (CRS) and neurotoxicity (NTX), the FDA label for blina specifies that patients (pts) with B-ALL should be hospitalized for a minimum of 9 days for cycle 1 (C1) (or 2 days if in complete remission (CR)) and 2 days for cycle 2 (C2). However, Gr3+ NTX and CRS are rare, particularly after C1 (Topp et al., Lancet Oncology 2015). As our ability to recognize and treat toxicities has improved, we assessed if blina can be safely administered outpatient (OP) during C1/C2. Methods We conducted a retrospective cohort study of adult B-ALL pts treated with blina from 2012 to 2024 across 2 centers, Memorial Sloan Kettering Cancer Center (MSK) and Dana Farber Cancer Institute (DFCI). CRS and NTX were graded per ASTCT criteria (Lee et al., 2019). Hospital days were counted from the first dose of blina to 90 days after the last dose. Results Overall, 307 pts (188 at MSK and 119 at DFCI) were included. 29% had active BM disease (≥5% blasts) at time of blina initiation. Cycle 1: At DFCI, all pts received C1 inpatient, so this analysis focused on MSK pts. At MSK, 11 of 188 pts (6%) started C1 in the OP setting. Pts who started C1 as IP vs. OP did not differ in age (median 55 vs. 49 years, p = 0.8), proportion of Philadelphia positive (Ph+) ALL (34% vs, 45%, p = 0.4), CNS disease (3% vs. 0%, p > 0.9) at time of blina, or extramedullary disease (EMD) (20% vs. 17%, p > 0.9) at time of blina. No C1 OP pts had active BM disease, compared to 37% of C1 IP pts (p = 0.006). Six (55%) of C1 OP pts were MRD- at time of blina. C1 OP and C1 IP pts received a median of 2 vs. 2 cycles of blina (p = 0.7). Of the 11 pts who started blina while OP, 3 (27%) required hospitalization for during the cycle (1 for NTX, 1 for pulmonary edema, 1 for subdural hemorrhage). C1 OP pts were less likely to have CRS in C1 than C1 IP pts (18% vs. 49%, p = 0.046) but rate of C1 NTX did not differ (9% vs. 13%, p > 0.9). No Gr3+ CRS/NTX was observed in the C1 OP group. Healthcare utilization was numerically but not statistically lower for C1 OP vs. C2 IP pts: 6 vs. 14 median days of hospitalization per cycle (p = 0.4). Cycle 2: Across both sites, 184 received a 2nd cycle; 101 (54%) started C2 IP and 83 (45%) OP. At DFCI, 73 pts (88%) started C2 IP and 10 (12%) started OP, while at MSK, 28 (28%) started IP and 73 (72%) OP. Pts who received C2 IP vs. OP did not differ statistically with regards to median age (54 vs. 56 years, p = 0.3) or rates of Ph+ disease (38% vs. 49%, p = 0.2), CNS1 status (96 vs. 100%, p = 0.3), EMD (7 vs. 12%, p = 0.2), or rate of active disease (29% vs. 22%, p = 0.5) at time of blina initiation. C2 OP pts received more cycles of blina than C2 IP pts (median 4 vs. 2, p < 0.001). Of the 83 pts who started C2 OP, 11 (13%) were hospitalized during C2 (5 for infection, 2 for NTX, 2 for disease progression, 1 for possible bowel perforation, 1 for likely CRS). C2 OP pts were less likely to develop CRS at any time during blina compared to IP pts (43% vs 61%, p = 0.02) and rates of NTX did not differ statistically (16% vs. 8.4%, p = 0.12). Numerically more C2 OP pts from MSK had active disease compared to C2 OP pts at DFCI (25% vs 0%, p=0.11); despite this, no Gr3+ CRS/NTX was observed in C2 OP pts from either center, though Gr1 occurred numerically more frequently for the MSK C2 OP pts than DFCI (77% vs 40%, p=0.12). Healthcare utilization was lower among C2 OP vs. C2 IP pts: 3 vs. 14 median days of hospitalization per cycle (p < 0.001). This remained statistically significant after stratification by center. Conclusion In this large retrospective study across two major centers, blina was administered OP during C1 (to a small number of pts in CR) and C2 (to a significant number of pts with active disease or in CR before blina) without increased CRS or NTX compared to IP administration and was associated with lower healthcare utilization when given OP during C2. Our data suggests that C2 OP initiation may be a safe approach for most pts that may result in significant healthcare savings. As we gain experience with pts initiating blina in deep MRD- remissions and low total B-cell counts, our experience with C1 OP initiation of blina might help establish a safe pathway for this growing group of pts.

Background: Advantages of covalent Bruton Tyrosine Kinase inhibitor (cBTKi) treatment (tx), as compared to BCL2 inhibitor (BCL2i) containing regimens, include ease of initial administration without a requirement for frequent laboratory monitoring, even in patients (pts) with bulky disease. However, limitations of cBTKi monotherapy include acquired resistance, cumulative toxicity and the financial burden associated with continuous administration. CLL pts treated on the E1912 study who discontinued (dc) ibrutinib for reasons other than progression of disease (PD) had a median progression free survival (PFS) of ~2.7 years from ibrutinib dc, suggesting that a time-limited cBTKi strategy may be feasible for some pts(Shanafelt et al. Blood Advances 2025). We hypothesized that acalabrutinib (acala) and obinutuzumab (O) could be administered as a time-limited initial tx for CLL with duration guided by minimal residual disease (MRD). Methods: This is an ongoing phase II, multicenter, investigator-initiated study of acala and O for previously untx pts with CLL/small lymphocytic lymphoma (SLL) requiring tx per iwCLL 2018 criteria (NCT04722172). Pts with TP53 aberrancy are excluded. Pts receive acala 100 mg twice daily and O during 28-day cycles (C) 2-7. Undetectable MRD is defined with a 10-4 sensitivity in the peripheral blood (PB) by ClonoSeq next generation sequencing (uMRD4). Pts undergo MRD testing at C13; if uMRD4 at C13 with a complete response (CR) or partial response (PR), pts dc acala and enter tx free observation (TFO). If detectable MRD4 (dMRD4) at C13, pts continue acala until uMRD4, with repeat MRD testing occurring at C16, 19, 22 and 25. All pts dc acala after a maximum of 26C and enter TFO, even if dMRD4. If pts have PD meeting iwCLL criteria for tx during TFO, re-tx consists of acala + 6 cycles of O. Pts are followed for 13C of re-tx. Primary endpoint is 36-month PFS. Results: 55 pts initiated tx. Baseline characteristics include: median age 67, 64% male, 47% LN ≥ 5 cm, 73% IGHV unmutated. Best overall response rate (ORR) was 95% (CR: 4, PR: 48, SD: 0, PD: 1, unknown: 2). Best uMRD4 rate at any time during the study was 49% (n=27 pts, intention-to-treat, IIT). 5 pts dc tx prior to C13 MRD testing (2 pt decision, 2 AE, 1 due to PD after ~4C). At C13, 22 pts (40% of IIT) were uMRD4; 21 entered TFO after 13C and 1 pt had 19C tx prior to TFO. 28 pts had dMRD4 (51% ITT) at C13. Between C13 and 26, 2 pts became uMRD4 and entered TFO, 1 pt died (COVID-19), and 2 pts stopped acala for tx of other cancers. 21 pts completed 26C acala per protocol prior to entering TFO; 2 additional pts had PD at C25 and EOT. Median tx duration was 19C. In univariate analyses, age, del11q, del13q, IGHV mutational status and baseline LN ≥ 5 cm were not predictive of uMRD4 at C13. At a median follow-up of 38 months, the median PFS for the overall cohort is 42 months (95% confidence interval (CI): 37, not reached), with an estimated 36-month PFS of 69% (95% CI: 57%, 84%). At data cutoff, of 46 pts entering TFO, 29 pts remained in TFO without PD, 7 pts had PD during TFO but had not met iwCLL criteria for re-tx, and 10 pts had PD requiring tx (5 pts re-tx pe protocol, 5 came off study for non-protocol tx approach). The overall median TFO period (measured from acala dc to PD) was 25 months (95% CI: 21 – not reached, n=46 pts). 5 pts have initiated re-tx with acala + O (1 pt best response PR and uMRD4; 4 ongoing tx). Median time to re-tx was 18 months (range 6-34, n=5 pts). Conclusions: This study is proof-of-concept that cBTKi may be administered as a time-limited tx without the addition of a BCL2i. While the initial PFS is shorter than historical studies examining continuous cBTKi, of patients entering TFO after 1-2 years of acala, the median duration of TFO until PD is 25 months, and longer follow-up will provide re-tx outcomes. Potential advantages to MRD-guided, time-limited cBTKi tx include time off tx for pts, limiting acquired resistance, the ability to re-challenge with cBTKi at progression, and reserving BCL2i for third-line or later tx.

This cohort study examines barriers to access of CAR T-cell therapy among patients with hematologic cancer referred for this treatment.