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Background Endpoints for GVHD treatment trials use early response (i.e, day (D)28 of treatment) as a surrogate for long term survival. Overall response (OR) that combines complete (CR) and partial responses (PR) at day (D) 28 is the conventional endpoint for primary acute GVHD trials because of similar survival outcomes between CR and PR. D28 OR ignores symptom severity at baseline and D28, however, and the PR category encompasses a wide range of responses from minimal improvement to near complete resolution of symptoms. D28 OR is the only endpoint currently approved by the FDA for efficacy, but it has not been re-evaluated as an endpoint for primary treatment (1L) in fifteen years and little is known regarding the prognostic value of D28 OR as an endpoint for second line treatment (2L) of GVHD. We hypothesized that refinement of the current D28 OR criteria, particularly through recategorization of PR in the GI tract, the main driver of nonrelapse mortality (NRM), would more accurately reflect disease control and better predict survival outcomes than current D28 response. Methods The Japanese Society for Transplantation and Cellular Therapy (JSTCT) collaborated with the Mount Sinai Acute GVHD International Consortium (MAGIC) to develop and validate D28 refined response (RR) criteria for 1L and 2L treatment (tx) in patients with Grades II-IV acute GVHD. To maximize the correlation between treatment success (i.e, response) with long term survival, our primary measured metric was the negative predictive value (NPV). We first randomly divided the 1L tx cohort of JSTCT into the training (n=2341) and validation sets (n=1156). In the training set we used a classification and regression tree (CART) algorithm to generate RR criteria that predicted 6-month (mo) NRM based on symptoms both at tx onset and D28. We then compared the two D28 response endpoints (RR vs OR) as surrogates for 6-mo NRM in two validation sets of both 1L tx (JSTCT: n=1156; MAGIC: n=1141) and 2L tx (JSTCT: n=510; MAGIC: n=196). Results The CART algorithm defined a RR as GVHD Grades 0/I at D28 without additional tx; all other D28 grades were considered refined nonresponses. As expected, RR successfully stratified the risk of 6-mo NRM in both 1L tx validation sets (JSTCT: 8% vs 38%, p<0.01; MAGIC: 9% vs 37%, p<0.01). We defined a discordant nonresponse as a nonresponse by RR criteria but a response by OR criteria, which accounted for the majority (~75%) of differences between RR and OR. 6-mo NRM in discordant nonresponders was four fold higher than in responders (JSTCT: 35%; MAGIC: 30%). The large majority (>80%) of discordant nonresponders had persistent GI GVHD at D28. Because the proportion of discordant nonresponders was small (<7% of the total population) in the 1L setting, the improvements of an already high NPV were small (JSTCT: 93% vs 91%; MAGIC: 91% vs 90%). In the 2L tx validation sets, RR also stratified the risk of 6-mo NRM (JSTCT: 26% vs 56%, p<0.01; MAGIC: 13% vs 55%, p<0.01). At the time of 2L tx, the discordant nonresponders are more common and half of the discordant nonresponders experienced 6-mo NRM (JSTCT: 45%; MAGIC: 59%); as a result, RR achieved much higher NPVs than OR (JSTCT: 75% vs 66%; MAGIC: 87% vs 76%). Deaths in responders from acute GVHD (vs. other causes such as infection) were more frequent in OR than RR in both 2L tx validation sets (JSTCT: 41% vs 20%; MAGIC: 41% vs 13%) and 1L tx validation sets (JSTCT: 25% vs 18%; MAGIC: 32% vs 29%). D28 RR is superior to OR because it more accurately reflects control of serious GVHD in four independent validation cohorts, particularly in patients with GI disease. Conclusion We conclude that RR is a more accurate endpoint than OR in patients with grade II-IV GVHD primarily because it classifies persistent GI GVHD at D28 as a non-response instead of a response, which correlates with 6-mo NRM and achieves a higher NPV. This validated RR metric can serve as a better endpoint than OR in assessing treatment efficacy in both primary treatment trials that enrich for high risk GVHD, e.g. GI involvement, and second line treatment trials.

Introduction Poor diet quality, elevated body mass index (BMI), insulin resistance, microbiome dysbiosis, inflammation as well as immune dysfunction have all been implicated in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to multiple myeloma (MM). Plant-based diets have been associated with reduced risk of MGUS and MM in epidemiological studies. Whether a dietary intervention can impact these modifiable risk factors and delay disease progression has not been investigated. Methods We conducted a pilot, single-arm trial providing controlled high fiber plant based dietary (HFPBD) intervention for 12 weeks and health coaching for 24 weeks in 20 patients with MGUS/SMM with BMI≥25 (NCT04920084). The primary endpoint was feasibility (adherence and BMI reduction). Secondary and exploratory endpoints included quality of life, metabolic markers (insulin, adiponectin, leptin, LDL cholesterol), microbiome (diversity and composition by 16S and shotgun sequencing) and immune profiling in peripheral blood (flow cytometry and Olink inflammation panel) and bone marrow (scRNAseq and ATACseq). We also conducted an in vivo study in transgenic Vk*MYC mice fed a high fiber or control diet at the phase of mouse(m)SMM. The mice were monitored for the progression to active mMM. Differences in microbiome and immune response profiles between high fiber- and control-treated mice were assessed via microbiome 16S sequencing and flow cytometry. Results The HFPBD intervention was safe, feasible, improved quality of life and addressed modifiable risk factors - metabolic profile (improved BMI, insulin resistance, adiponectin leptin ratio), microbiome profile (increased alpha-diversity and butyrate producers) and immune (decreased inflammation and increased anti-inflammatory classical monocyte) subsets. A reduction in long-term progression trajectory was observed in 2 patients. Consistently, the high fiber diet delayed progression from mSMM to mMM in Vk*MYC mice increasing median progression-free survival from 12 weeks in the control arm to 30 weeks in the high fiber diet intervention arm. Additionally, in the intervention arm 40% of mice did not progress to mMM during the study period whereas all mice in the control arm progressed. Both human and mouse data showed that HFPBD modulated gut microbiota composition favoring the expansion of butyrate-producing bacteria. Additionally, short-chain fatty acids were increased in the feces of mice fed a high fiber diet. Integrated analysis from human bone marrow and peripheral blood analysis indicated that the dietary intervention reduced inflammatory biomarkers and skewed the immune response towards T helper and CD14+ monocytes. Consistently, the bone marrow of Vk*MYC mice fed high fiber diet was more infiltrated by IFNg-producing T lymphocytes while displaying less exhausted T cells and immunosuppressive myeloid cells. Conclusion This is the first interventional clinical trial and in vivo study to show that a HFPBD intervention may delay progression from MGUS/SMM to MM. To our knowledge there has been no similar dietary interventional study in hematological cancers or solid tumors. Together our in vivo and clinical data support the beneficial anti-inflammatory role of a HFPBD providing a link between diet, microbiota, and immune modulation to delay disease progression in MGUS/SMM.

Background: Acute promyelocytic leukemia (APL) is one of the most treatable leukemias in the current era, with cure rates upwards of 90%. Early mortality due to coagulopathies often seen at diagnosis is a major driver of adverse outcomes. Prompt initiation of all-trans retinoic acid (ATRA) is crucial for suspected APL, as it is known to reverse these coagulopathies. Chemotherapy-free protocols consisting of arsenic trioxide (ATO) and ATRA have become the standard of care for low-risk APL with high cure rates and reduced hematologic toxicities. For high-risk disease, there are multiple treatment options that have not been compared. Since APL is rare, there is a lack of real-world data for this disease. This retrospective review aimed to assess the outcomes of APL patients (pts) across multiple institutions and to examine the most common induction regimens, characteristics linked to early (30-day) mortality, and supportive care strategies. Methods: This retrospective study involved 9 institutions in the US and was conducted through the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND). Data included pts admitted from 8/5/2006 through 2/3/2024 with a confirmed diagnosis of APL. Each institution received a data-collection form and contributed data on APL pts from presentation to last follow-up. Key data categories included patient demographics, presenting laboratory and molecular data, treatment regimen, supportive care, and patient outcomes. Results: Data for 412 pts were identified with a median age of 51 (range 17-90) and 49% were female. Cardiovascular comorbidities were present in 44% of pts and 16% had a known pulmonary comorbidity. At presentation 109 (27%) had high risk-disease, defined as a white blood cell count (WBC) greater than 10 x 109/L. A FLT3 mutation was seen in 50% of tested pts, WT1 (22%), KRAS (3.6%), and NRAS (6.5%). The median WBC at presentation was 2 x 109/L (range: 0-166 x 109/L) and the median platelet count was 27 x 109/L (range: 2.0-315 109/L). Twenty-six percent presented with grade 2+ thrombosis, bleeding, or both. A higher percentage of pts with high-risk vs. low-risk disease presented with grade 2+ thrombosis, bleeding, or both (43% vs. 20%), DIC (60% vs. 36%), and mutated FLT3 (81% vs. 37%). The majority of pts received a chemotherapy-free induction regimen consisting of ATRA plus ATO. It was determined that 36 (8.7%) pts received induction with intermittent ATO plus ATRA (Burnett AK, Lancet Oncol 2015), 276 (67%) received daily ATO plus ATRA (Ravandi F, J Clin Oncol 2009 and Lo Coco, NEJM 2013), and 70 (17%) received a regimen inclusive of an anthracycline plus ATRA. Eleven pts did not start an induction regimen other than single-agent ATRA due to early death, while 19 had their regimen classified as “other” because they did not follow a conventional induction path. In total, 295/358 (82%) received ATRA within 24 hours of admission. At least 1 dose of gemtuzumab ozogamicin was given to 58 (14%) pts, of which 35 (60%) were considered high risk. The incidence of differentiation syndrome (DS) was 37% (n=154). Among the 243 pts who received steroid prophylaxis, 30% developed DS, compared to 52% of those who did not receive prophylaxis. Among the 360 pts with at least 1 available PCR result after starting induction, 94% achieved PCR-negativity. The 30-day mortality rate was 6.6%. On univariate analysis, presenting variables associated with a higher 30-day mortality include older age, diabetes, cardiovascular comorbidities, thrombosis or bleeding, DIC, eGFR < 60, elevated total bilirubin and D-dimer levels, and high-risk disease. The median overall survival (OS) of the cohort was not reached, and the 5- and 10-year OS was 88% (95% CI: 84-91%) and 79% (95% CI: 72-87%) respectively. The cumulative incidence of relapse at 3 years was 2.7% (95% CI: 1.4 - 5.1%), with no additional relapses observed. The incidence of CNS relapse at 3 years was 0.9% (95% CI: 0.3% - 2.8%), with 2 of the 4 pts classified as high-risk. Conclusion: This is the largest real-world evidence data collection in the US evaluating the outcome of pts with APL in the current era, inclusive of ATO as front-line induction. Outcomes for this disease remain extremely positive, with low 30-day mortality rates noted in this study along with durable OS rates and low incidence of relapse. Additional information on outcomes, safety, and supportive care will be presented at the meeting.

Introduction BCL-2 inhibition with venetoclax (ven) was a major advance in CLL treatment, but the 5-week dose ramp-up to mitigate the risk of tumor lysis syndrome and drug-drug interactions (DDIs) challenge treatment optimization. Lisaftoclax is an investigational, oral BCL-2i with a short half-life, allowing it to be ramped-up on a daily schedule. We present updated results of a phase 1b/2 study of lisaftoclax alone or combined with acalabrutinib or rituximab in pts with treatment-naïve (TN; lisaftoclax-acalabrutinib arm), relapsed/refractory, or prior ven-treated CLL/SLL (NCT04215809). Methods Pts were treated with a rapid 4- to 6-day daily ramp-up of lisaftoclax from 20 mg to a target dose of 400, 600, or 800 mg, receiving daily oral lisaftoclax alone or, plus continuous acalabrutinib or 6 cycles of rituximab in 28-day cycles, starting on Cycle 1 Day 8 (C1D8) until disease progression, complete response by C24, or unacceptable toxicity. Intensive blood samples were collected for pharmacokinetic (PK) and exposure-response (E-R) analyses. Results From March 20, 2020, to June 27, 2024, 176 pts were enrolled: 46 in monotherapy and 39 and 91 in rituximab and acalabrutinib combination cohorts, respectively; 154/176 (87.5%) were R/R and 22/176 (12.5%) TN. The median (range) age was 63 (34-80) years; 67% were male; 25.6% had del(17p) and/or TP53 mutation; and 70.6% had unmutated IGHV. Median (range) duration of treatment with lisaftoclax was 16.5 (1-54; monotherapy), 24 (3-39; rituximab), and 27 (1-43; acalabrutinib) months. In R/R pts, the median (range) number of prior lines of therapy was 2 (1-15), and 14 (9%) pts had been treated with ven. Prior ven pts had a median (range) age of 65 (51-78); 79% were male; of evaluable pts, 50% had del(17p), 36% TP53 mut, 64% del(11q), 38% complex karyotype (≥ 3 abnormalities), and 92% unmutated IGHV; 57% were BTKi naïve; and the median (range) number of prior therapies was 3 (1-6). Incidence and severity of TEAEs were similar across cohorts. Common (>10%) any-grade TEAEs in all cohorts combined were neutropenia (59 [33.5%]), diarrhea (38 [21.6%]), anemia (27 [15.3%]), and thrombocytopenia (26 [14.8%]). Grade ≥ 3 TEAEs were neutropenia in 15 (32.6%), 10 (25.6%), and 22 (24%) pts and anemia in 10 (21.7%), 5 (12.8%), and 12 (13.2%) pts in monotherapy, rituximab, and acalabrutinib combination cohorts, respectively. Comprehensive E-R analyses indicated that lisaftoclax had similar systemic exposure as monotherapy or when combined with acalabrutinib or rituximab; lisaftoclax had no DDI when combined with acalabrutinib or rituximab. No discontinuations were attributed to lisaftoclax TRAEs. Forty-four (95.7%) pts in monotherapy discontinued treatment. Most discontinuations were due to progressive disease (n = 41 [23.3%]) and 13 (7.4%), AEs; 9 (5.1%) pts withdrew consent; 7 (4%) achieved complete response or MRD negativity after ≥ 24 cycles; 5 (2.8%) died; and 18 (10.2%) discontinued for other reasons. Clinical (n = 2) and laboratory (n = 3) TLS was observed in 5 (2.8%) pts on lisaftoclax (by Howard/Cairo-Bishop criteria), with cases rapidly resolving to resume lisaftoclax safely. ORR for lisaftoclax plus acalabrutinib in 87 pts was 96.6%, and the median DOR (95% CI, 23-NR) and median PFS (95% CI, 34-NR) were not reached. The 12- and 18-month PFS rates were 89% and 86%, respectively. Fourteen R/R CLL ven-exposed pts received lisaftoclax plus acalabrutinib, of whom 9 had progressed on ven, 3 relapsed after completing ven, and 2 discontinued due to ven intolerance. Median (range) duration of treatment was 16 (3-25) months. Safety profile was similar to that of other study cohorts. ORR was 85.7% (12/14), 100% (8/8), and 66.7% (4/6) in the ven-exposed, ven-exposed but BTKi-naïve, and ven- and BTKi-exposed pts, respectively. The median duration of response (DOR) and progression-free survival (PFS) were not reached. The 12- and 18-month PFS rates were 84% and 73%, respectively. Conclusions Our data suggest that lisaftoclax combined with acalabrutinib is effective for pts with prior ven exposure, including those with progression on ven. In this updated analysis with longer follow-up, no DDIs or new safety findings were observed in TN or R/R CLL/SLL pts treated with lisaftoclax monotherapy/combinations. We continue to accrue pts with prior ven exposure to further evaluate this promising signal. A global registrational phase 3 study GLORA (NCT06104566) is recruiting.

Background: Randomized studies in newly diagnosed (ND) AML patients with a FLT3 mutation show that adding 14 days of a FLT3 inhibitor to each intensive chemotherapy cycle improves overall survival. For patients unsuitable for intensive chemotherapy due to older age or comorbidities, the presence of a FLT3-ITD mutation is associated with high rates of early relapse and short remission duration. There is a limited survival benefit of venetoclax (ven) plus azacitidine (aza) compared to aza alone among patients with AML with a FLT3-ITD mutation. Accordingly, there is significant interest in adding FLT3-targeted therapy to lower intensity chemotherapy for patients with ND AML and FLT3 mutations, but to date no randomized data have demonstrated a survival benefit for this approach.Gilteritinib (gilt) is a highly potent and FLT3-selective oral tyrosine kinase inhibitor that is the standard therapy of relapsed/refractory FLT3-mutated AML, based upon superior survival in randomized studies. Gilt can also be combined safely with ven and/or aza, though myelosuppression remains a concern. Despite this, single institution studies of ven, aza, and gilt therapy of ND AML patients with FLT3-mutations show that this three-drug regimen is associated with near-universal complete remission rates (CR 90%, CRi 6%) and a majority of studied patients eliminate detectable FLT3-ITD (<1 x10-5) within four cycles by an ultrasensitive, amplicon-based NGS assay (Short, et al. JCO 2024). Rates of CR with full count recovery and survival appear superior to historical comparisons, but myelosuppression is potentially increased with the triplet regimen. These data demonstrate a need for multi-institutional comparative trials, not only to determine whether adding FLT3-inhibitors to ven and aza improve deep remission rates, but also to refine schedules of the triplet combination that improve tolerability for widespread use.Methods: This tier 1 MyeloMATCH substudy is an open-label, randomized phase 2 trial that will enroll ND AML patients older than age 60 or individuals judged by their treating physician to be best served by azanucleoside + ven-based therapy due to comorbidity. Subjects provide samples to the central MyeloMATCH Master Screening and Reassessment Protocol (MSRP, NCT05564390 ) and are assigned to the MM1OA-EA02 substudy (NCT06317649) based upon the presence of a FLT3-ITD or FLT3-TKD (D835) mutation by NGS. Subjects are randomized to one of three arms (regimens 1, 2, or 3), stratified by age (<70 years vs. older) and FLT3-ITD burden (ITD VAF>33% vs. lower VAF or D835). All study arms contain aza and ven administered in 28-day cycles with two study arms also including gilt. Regimen 1 is ven and aza administered as per the pivotal VIALE-A study. Regimen 2 adds gilt 80 mg once daily on days 1-28 and regimen 3 adds gilt on days 8-21 only. A marrow biopsy is performed during the first cycle (day 14-21, depending on study arm) and all chemotherapy is held until count recovery if a morphologic leukemia-free state or aplasia is seen. Patients receive up to two induction cycles to achieve remission and then receive ongoing consolidation cycles of therapy with a similar pattern of gilt administration up to 2 years. To minimize risk of cumulative myelosuppression, during consolidation azacitidine administration is reduced to days 1-5 on regimens 2 and 3 and ven limited to days 1-7 on regimen 2 and days 1-14 on regimen 3. For all arms, treatment-related adverse events prompt further reduction in ven, aza, or gilt dose or duration. Response will be measured after cycles 2 and 4, including centrally-performed MRD by flow cytometry. The primary endpoint is the rate of MRD(-) CR (<1 x 10-3) after up to 4 cycles. Key secondary endpoints include safety data, response rate, EFS, and OS. The study is powered to detect a 25% absolute improvement in MRD(-) CR rate in either triplet arm from a target accrual of 147 patients. A safety run-in for regimens 2 and 3 to confirm tolerability and feasibility will be performed after 20 subjects enroll to these arms; an interim futility analysis will be performed once response assessment of 50% of all planned accrual occurs. Study was activated on June 6, 2024 and is expected to continue until December 2025.

Introduction The pathogenic role of somatic non-coding (nc) single nucleotide variants (SNVs) is underexplored in multiple myeloma (MM) and additional characterization of these regions has the potential to provide significant new insights into disease progression. To investigate the role of ncSNVs and their relationship with MM pathogenesis, we have characterized a novel series of WGS from 294 cases of MGUS, SMM, and MM using computational tools optimized to identify functional driver SNVs in these regions. We hypothesize the ncSNVs that co-localize to sites of super-enhancers (SEs) active in plasma cells (PC) are sites of high functional impact SNVs and these mutations lead to the dysregulated expression of genes that should be silent at the terminally differentiated stage of PCs, providing a selective advantage that shapes the fitness of the MM genomic landscape. Methods We analyzed 294 high-coverage matched tumor/normal pairs (80x tumor and 40x normal) derived from 21 MGUS, 86 SMM, 167 NDMM and 40 RRMM. In addition to previously sequenced samples, newly sequenced patients were obtained from NYU Langone Health, Memorial Sloan Kettering Cancer Center, University of Alabama at Birmingham and University of Miami following IRB-approved informed consent. DNA was extracted from CD138+ purified bone marrow plasma cells using standard approaches. We used the MGP1000 (https://github.com/pblaney/mgp1000) to process sequencing data which employs a union-consensus mechanism for determining the final set of variants. We collected enhancer elements (E/SEs) active in GC B-cells, ABC-DLBCL and GBC-DLBCL (Bal, et al. Nature, 2022) and PC specific E/SEs (Loven, et al. Cell 2013). FunSeq2 was used to score ncSNVs. GRAM was used to predict how variants alter TF binding and gene expression in a subset of 6 cases with paired WGS in our series and will expand this analysis on a validation set of 263 NDMM and 93 RRMM cases from University-Hospital Heidelberg enrolled in the GMMG-HD6 clinical trial. Results We identified 1,952,232 high-quality SNVs with 18,199 (0.93%) accumulating in 280 focal sites we termed “mutationally enriched regions” or MERs. To discern SNVs in MERs with the highest potential for imparting a selective advantage, we clustered mutations based on the density of FunSeq2 impact scores which uses reference data contexts on sequence conservation, modification of transcription factor (TF) binding, and gene linkage to regulatory elements and network hubs from pan-cancer studies. We show that MERs are enriched for ncSNVs with high impact scores (mean=2.57) compared to random similarly-sized regions of the genome (Fisher's exact test P<9.7e-12, OR=10.10 [3.88-37.40]). The high impact ncSNVs (hi-ncSNVs) in MERs (n=220) account for 8.09% of all hi-ncSNVs and are present in 46.3% of cases (136/294) with some patients having up to 7. The proportion of cases carrying a MER hi-ncSNVs was similar across disease stages (MGUS=42.9%, SMM=46.5%, MM=40.7%, and RR=47.5%). Analysis of the VAF of MER hi-ncSNVs shows a minor shift towards more clonal versus subclonal mutations (53.6% vs 46.4% VAF>=0.25) suggesting some high impact mutations are acquired in the GC but additional hi-ncSNV are acquired later in PC development, providing evidence that hi-ncSNVs accumulate in MERs throughout disease progression. We mapped these hi-ncSNVs to associated genes then intersected the loci with E/SEs active in GCBs and PCs to determine their functional context. This approach identified 12 genes affected by hi-ncSNVs including the previously identified nc-drivers NEAT1, MIR142, ZCCHC7, and IGLL5 as well as the PC differentiation genes IRF8, BACH2, proliferation genes RHOH, SPRED2, known coding MM drivers CCND1, ZFP36L1, and chr1q genes BTG2 and CROCC. We predicted the effect of ncSNVs on expression through modulation of TF binding at this set of putative nc drivers in MM and identified a trend towards increase in expression of SPRED2, CCND1, NEAT1, and IGLL5 compared to non-mutated cases (P=0.089). We will present data on the validation of this set of genes on a larger set of data derived from the Heidelberg group. Conclusions We identified a set of 12 putative nc driver genes in MM that modify expression and have the potential to significantly alter the pathogenesis of MM by providing a selective survival advantage. We will present the impact of these by clinical stage and on outcome.

Background: Proven salvage therapies for pts with triple-class refractory MM who progress on BCMA-targeted therapies are lacking.Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage. Cevostamab is a FcRH5xCD3 BsAb that facilitates T cell-mediated killing of MM cells. In an initial Phase I study (GO39775), cevostamab monotherapy was clinically active and had manageable toxicity in pts with heavily pretreated relapsed/refractory MM (Trudel et al. ASH 2021). In Cohort A1 of the subsequent Phase I/II CAMMA 2 study (CO43476; NCT05535244), cevostamab was highly active and had manageable safety at the 160mg target-dose (TD) level in pts with triple-class refractory MM who had received a prior BCMA-targeted antibody-drug conjugate (ADC; overall response rate [ORR]: 60%, 6/10 pts) or chimeric antigen receptor T-cell (CAR-T) therapy (ORR: 73%, 8/11 pts) but had not received a prior BCMA-targeted BsAb (Kumar et al. EHA 2024). We present initial results from Cohort A2, which enrolled pts with triple-class refractory MM who had received prior BCMA-targeted therapies, including ≥1 BCMA-targeted BsAb. An exploratory analysis of baseline patient and tumor-related factors is also presented. Methods: Cevostamab was initiated with step dosing (Cycle [C] 1 Day [D] 1: 0.3mg; C1D2, D3, or D4 depending on the emergence of cytokine release syndrome [CRS] after the initial administration: 3.3mg) and continued at the 160mg TD on C1D8 and on D1 of each subsequent 21-day cycle until disease progression (PD) or unacceptable toxicity. Cytokine, tumor antigen, T-cell function/activation, and inhibitory immune checkpoint expression were assessed in blood and tumor samples collected at baseline and during treatment. Results: As of February 23, 2024, 21 pts (median age: 64 years, range: 46-84) had been enrolled into Cohort A2. Seven pts (33%) had extramedullary disease and 5/12 pts (42%) with a conclusive assay result had high-risk cytogenetics (t(4;14), t(14;16), or del(17p)). All pts were heavily pretreated (median prior lines of therapy: 8, range: 5-14); 62% had received ≥2 prior BCMA-targeted therapies (median time since last: 122 days, range: 68-558) and 33% had received ≥2 prior BsAbs (median time since last: 139 days, range: 68-782). Most pts (86%) were refractory to their last line of therapy; 62% were penta-drug refractory. Median follow-up was 173 days (range: 20-360). Grade (Gr) 3-4 adverse events (AEs) occurred in 71% of pts (15/21). Gr 3-4 AEs in >3 pts were neutropenia, anemia, thrombocytopenia (38% each), and infections (29%). CRS occurred in 76% of pts (16/21) and was mainly Gr 1 (43%) or Gr 2 (29%); 1 patient had Gr 3 CRS. One treatment-related Gr 5 (fatal) AE of pneumonia was reported in the context of PD. No treatment-related AEs leading to cevostamab discontinuation occurred. Objective responses (partial response [PR] or better) were observed in 2/21 pts (ORR: 10%). Both pts achieved a very good PR and had ongoing responses at cut-off. Stable disease was observed in 10 pts (48%). Pts in the prior BsAb group had received more prior lines of therapy than those in the prior ADC and CAR-T groups (median 8 vs 5 and 6, respectively) and more prior BCMA-targeted therapies (median 2 vs 1 and 1). The percentage of pts with low levels (<4.5 ng/mL) of soluble BCMA in plasma was also higher in the prior BsAb group (47% vs 0% and 18%). At baseline, inhibitory immune checkpoint expression across T-cell subsets was more common in the prior BsAb group. Notably, the median frequency of PD1+CD8+Tnaive and TIGIT+CD8+Tnaive cells in blood was higher in the prior BsAb group (21% and 29%, respectively) than in the prior ADC (3% and 6%) and CAR-T groups (4% each). Peak median IL-6 and IFN-γ levels were delayed until the first TD in the prior BsAb group, suggesting a different pharmacodynamic profile. Conclusions: Cevostamab has manageable safety in pts with triple-class refractory MM who have received prior BCMA-targeted therapies, including ≥1 BCMA-targeted BsAb. Clinical responses were less frequent in the prior BsAb group than in the prior ADC and CAR-T groups, which could be explained by the higher number of prior lines of therapy and T-cell exhaustion due to multiple prior exposures to BsAbs. Notably, the high frequency of CD8+ T-cell subsets expressing inhibitory immune checkpoints in the prior BsAb group suggests a level of T-cell dysfunction that could prevent effective T-cell activation.

Introduction: The development of increasingly sensitive tests for the detection of measurable residual disease (MRD), such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) assays, has changed clinical practice in acute lymphoblastic leukemia (ALL). IGH V(D)J-based NGS MRD is the most sensitive assay to predict relapse in patients (pts) with B-ALL (Short, Blood Adv 2022). However, data regarding the use of T-cell receptor (TR) NGS MRD in T-ALL are limited and recent reports from pediatric cohorts suggest that persistent TR MRD may not predict relapse in T-ALL (Roy, ASH 2023, abstract 2976). With limited options for the treatment of relapsed/refractory T-ALL, accurate prediction of high relapse risk may provide an opportunity for early intervention. In this study, we evaluated the prognostic utility of TRB/TRG NGS MRD and its correlation with MFC MRD in adult patients with T-ALL. Methods: We retrospectively evaluated the MRD data and clinical outcomes of precursor T (pre-T) and early T precursor (ETP) ALL patients treated at four academic centers in the US. MRD was evaluated using MFC in CLIA-certified labs at individual sites with a sensitivity of 10-4, and the clonoSEQ (Adaptive Technologies, lnc) NGS assay, with a sensitivity of 10-6. Pts were included if they had a trackable TR clone and NGS MRD remission assessment in at least one time point. The correlation between the percentage of MRD by MFC vs NGS was calculated with the Pearson correlation coefficient, using every available MRD assessment for T-ALL pts in complete remission. Relapse-free survival was stratified based on NGS MRD level at the time of post-induction and post-consolidation assays, and comparisons were made with the log-rank test. The positive predictive value (PPV) for relapse of NGS MRD was calculated for pts with MRD > 10-6 at the post-induction and post-consolidation period. Results: A total of 19 pts who met our inclusion criteria, with a median age of 30 years (range, 18-65). 9 pts (47%) had ETP-ALL, 10 pts had pre-T ALL. Pts had a trackable TRB/TRG clone in 76% of cases, with 66% having a trackable TRG clone and 38% having a trackable TRB clone. 10 pts (53%) were treated with a modified AALL0434 regimen as first line therapy, 6 pts (32%) were treated with CALGB10403, 1 pt (5%) was treated with hyperCVAD, 1 pt (5%) was treated with a BFM regimen, and 1 pt (5%) was treated with CALGB9511. Out of 11 T-ALL pts with MRD data available post-induction, 6 pts (55%) had detectable MRD by NGS and no detectable MRD by MFC. Out of 13 pts with available post-consolidation MRD data, 2 pts (15%) had undetectable MRD by both NGS and MFC and 9 pts (69%) had detectable MRD by NGS only. There were no pts with detectable MRD by MFC and undetectable MRD by NGS at either timepoint. A total of 64 MRD data points from 19 pts were available to evaluate MRD correlation by MFC vs NGS, for which the Pearson correlation coefficient showed a statistically significant linear correlation (p < 0.01). At post-induction, 9 pts had NGS MRD > 10-4 and 2 pts had NGS MRD < 10-4. With a median follow-up time of 19.8 months, pts with NGS MRD > 10-4 had a median RFS of 19.8 months and pts with NGS MRD < 10-4 had a median RFS of 14.8 months. The log-rank test comparing RFS between these two groups was not statistically significant (p= 0.18). Persistent NGS MRD at post-induction had a PPV for relapse of only 18%. At post-consolidation, 7 pts had NGS MRD > 10-4, 4 pts had NGS MRD < 10-4, and 2 pts had undetectable MRD by NGS. With a median follow-up time of 17.3 months, pts with NGS MRD > 10-4 had a median RFS of 15.3 months and pts with NGS MRD < 10-4 or undetectable had a median RFS of 20.6 months. The log-rank test comparing RFS between these two groups was not statistically significant (p= 0.6). Persistent NGS MRD at post-consolidation had a PPV for relapse of only 27%. Conclusion: Despite statistically significant linear correlation between MFC and NGS MRD testing, there were no RFS differences between pts with NGS MRD > 10-4 vs NGS MRD < 10-4. All patients had persistent NGS MRD post-induction, which is markedly lower than the reported 20-25% NGS undetectable MRD rate in B-ALL post-induction. Persistent NGS MRD has low PPV for relapse in T-ALL, which limits its utility in clinical decision making for this population.

Background: SAR442257 (SAR'257) is a trispecific antibody that targets CD38, CD3 and CD28. Simultaneous CD3 and CD28 binding triggers T cell co-signaling, and additional CD38 recognition directs the T cells to CD38+ cancer cells such as multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). This is a first-in-human phase 1 study investigating the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) profile of SAR'257 in patients (pts) with refractory and relapsed (rr) MM and rrNHL. Methods: This is a multicenter, international, open-label, dose-escalation study (NCT04401020) of SAR'257 in pts with rrMM refractory to standard-of-care (SOC) options, including anti-CD38 monoclonal antibodies, and in pts rrNHL without any SOC options. SAR'257 was administered intravenously with lead-in doses (Day 1−5) in the first week, followed by twice weekly (BIW) or once weekly (QW) dosing; 11 target dose levels (TDLs) in pts with rrMM (9 TDLs: 0.06-11 µg/kg BIW; 2 TDLs: 18-27 µg/kg QW), and 2 TDLs in pts with rrNHL (2 µg/kg BIW and 4 µg/kg QW). Results: As of February 19, 2024, 47 pts (rrMM, n=40; rrNHL, n=7) received SAR'257. The median ages (years) were 64 (rrMM; range: 40−84) and 70 (rrNHL; range: 18−75). The median number of prior lines was 5 (range: 3−12) for rrMM and 5 (range: 2−7) for rrNHL cohort. In rrMM cohort, all (100%) pts had prior exposure to an anti-CD38 monoclonal antibody (MAb) and were refractory to anti-CD38 and in rrNHL cohort all were anti-CD38 naïve. The median time from last anti-CD38 dose was 2.7 (range: 1−65) months for rrMM cohort. Safety analysis revealed that 68% (n=32) pts had treatment-emergent adverse events (TEAEs; 26 pts in rrMM and 6 pts in rrNHL); 21.3% pts (n=10) Grade (G) ≥3 TEAEs (7 in rrMM and 3 in rrNHL). Cytokine release syndrome (CRS) was the most common TEAE, occurring in 52.5% of rrMM pts across all TDLs (n=21; G≥3 in 1 pt from 11 µg/kg BIW TDL) and in 57.1% of rrNHL pts (n=4; no G≥3) at the two TDLs tested. Repetitive CRS episodes (>1 episode) were more frequent at higher TDLs. Infusion-related reactions (IRRs; any G) were observed in 22.5% pts with rrMM (n=9; no G≥3) and in 28.5% pts with rrNHL (n=2; G≥3 in 1 pt). Epstein-Barr virus (EBV) infection/reactivation was reported in 17.5% (n=7; G≥3 in 4 pts) and 28.6% (n=2; no G≥3) pts with rrMM and rrNHL respectively. Further, 15% (n=6, G≥3 in 2 pts) from rrMM and 14.3% (n=1; G2 CMV reactivation) pts from rrNHL cohort reported cytomegalovirus (CMV) infection/reactivation. One case of immune effector cell-associated neurotoxicity syndrome (ICANS) was reported (G4) in the rrNHL cohort. Four dose-limiting toxicities (DLTs) were observed in the rrMM cohort [1 at 4 µg/kg BIW (G3 hepatotoxicity); 1 at 11 µg/kg BIW (G5 CRS−EBV reactivation; and 2 at 27 µg/kg QW (G3 CMV infection reactivation and G3 febrile neutropenia in same pt)]. Three DLTs were observed in the rrNHL cohort (2 at 2 µg/kg BIW [G4 neutropenia and G4 thrombocytopenia; same pt] and 1 at 4 µg/kg QW [ICANS G4]). For pts with rrMM, the maximum plasma concentration of SAR'257 reached within or above the theoretical efficacious range (0.1−1nM; extrapolated from ex vivo models), starting at 8 µg/kg BIW and 18 µg/kg QW in the first treatment cycle. As of July 08, 2024, the overall response rate (ORR), defined as partial response (PR) or better, was 5% (n=2) in the rrMM cohort: 1 pt exhibited stringent complete response (duration of response [DOR]=8.1 months, on-going) and 1 showed a complete response (CR) at 27 µg/kg QW TDL. In rrNHL cohort, the ORR was 14.3%, 1 pt achieved PR (DOR=7.1 months) at 2 µg/kg BIW TDL. The disease control rate (stable disease or better for >8 weeks) was 60% (n=24) and 28.6% (n=2) in the rrMM and rrNHL cohorts respectively. For both cohorts exploratory biomarker analysis revealed that: (1) SAR'257 treatment activated peripheral blood T cells and reduced regulatory T cell numbers and CD4/CD8 ratio; (2) CD38 expression on plasma cells positively corelated with time since the last anti-CD38 MAb dose; (3) Among the pts experiencing CRS, the peak values of cytokines (Interleukin (IL)-6, IL-8, and C-reactive protein) were significantly higher during the first cycle in comparison to subsequent cycles. Conclusion: This Phase 1 study of SAR'257 showed an anti-tumor response in a small number of pts from the rrMM and rrNHL cohorts. Due to safety concerns, in particular high rates of EBV and CMV reactivation and recurrent episodes of CRS in the higher dose levels, the study was terminated during dose escalation.

Background: The addition of midostaurin (M), an oral multi-kinase inhibitor, to intensive chemotherapy (IC) prolongs survival in newly diagnosed (ND) FLT3 mutated (m) AML. It is not known if there is a benefit to more potent and selective FLT3 inhibitors. Among these is Gilteritinib (G), now approved as a single agent in relapsed/refractory FLT3m AML. Combined with IC, G also leads to high measurable residual disease (MRD)negative (-) composite complete remission (CRc) in FLT3 Internal Tandem Duplication (ITD)m AML. The aim of the PrECOG 0905 study was to compare FLT3m clearance and CRc rates of G vs M with IC in adults with ND FLT3m AML. Methods: We conducted a randomized, open-label, phase 2 trial comparing G to M in combination with IC during induction and consolidation in ND AML pts with centrally PCR detected FLT3 ITD or TKD mutations. Pts age 18-70 with non M3 AML and no known core binding factor rearrangement were eligible. Pts were stratified by mutation type (TKD only vs. ITD (+/- TKD)), NPM1 mutation status, and FLT3-ITD allelic ratio. Induction consisted of cytarabine 100 mg/m2 by continuous infusion daily, on day (d) 1-7 and daunorubicin 90 mg/m2 IV on d 1-3. G 120 mg daily or M 50 mg twice daily was given orally on d8-21. Consolidation (up to 4 cycles) began within 60 d of induction with Cytarabine (1.5-3 g/m2 IV) X 6 doses and G or M (as per randomization) on d8-21. Pts could proceed to transplant (HCT) at any time. Maintenance was not included. The primary outcome was FLT3m MRD (-) CRc after induction. MRD for TKD mutations was tested by PCR (sensitivity 10-2); ITD MRD was tested by amplicon-based NGS (sensitivity 10-4). Safety and efficacy were analyzed in all eligible pts who received treatment. Secondary endpoints included comparison of CRc, MRD by flow cytometry (sensitivity 10-3), and survival. Results: From 11/2019 to 11/2022, 722 pts were screened at 37 centers, 180 pts randomized, and 177 pts (58% female, 77% white, 8.5% black, 8.5% hispanic) treated on the G (n=90) or M (n=87) arm. Median age was 54, with 27.7% > age 60. FLT3-ITD was present in 80% in the G arm and 78.2% in the M arm. Of those with FLT3-ITD, NPM1 was detected in 56.9% pts in G arm and 58.8% in M arm. 24.4% G and 20.7% M pts had co-occuring FLT3-ITD, NPM1 and DNMT3A mutations. Adverse karyotype was seen in 3.4% G and 9.3% M while 10% G and 13.8% M were ELN 2022 adverse risk. For pts on G arm, 85.6% achieved CRc compared to 72.4% for M (p=0.042). 5 (5.6%) pts on G arm and 6 (6.9%) on M arm received 2 cycles in induction. Post induction, the FLT3m- CRc rate was 40% for G vs 47.1% for M (p=0.366). FLT3-TKD only mutated pts achieved CRc in 88.9 % with G and 63.2% with M and FLT3m- CRc in 72.2% and 63.2% respectively. FLT3-ITDm (+/- TKDm) pts achieved CRc/FLT3m- CRc in 84.7%/31.9% with G and 75%/42.6% with M, respectively. In pts with FLT3-ITD, NPM1 and DNMT3A mutations, 95.5% G and 72.2% M achieved CRc and 50% G vs 33.3% on M achieved FLT3m- CRc. Flow cytometry MRD negative CRc was documented in 64.4% on G arm and 59.8% on M arm after induction (p=0.539). On G arm 67 (74%) patients received at least one cycle of consolidation compared to 53 (61%) pts on M arm. On exploratory analysis, 54 (66%) G and 40 (46%) M were reported to proceed to HCT in first remission. FLT3m testing was done post consolidation cycle 1 in 27 pts in FLT3m+ CRc after induction and 15/18 (83%) on G and 4/9 (44.4%) on M converted to FLT3m-. On multivariate logistic regression analysis for FLT3m-CRc post-induction, FLT3-ITD allelic ratio, NPM1m, WBC and hemoglobin at baseline were significant at the 0.10 two-sided level, while treatment arm, and 2017 ELN risk were not. There were no deaths from treatment-related (TR) adverse events (TRAEs) while grade >=3 TRAE was reported in 73%G vs 70% M during induction and 79%G vs 73%M pts during consolidation. Conclusion: Induction therapy with daunorubicin 90 mg/m2 X 3 days, cytarabine 100 mg/m2 and gilteritinib results in an excellent CRc rate with no TR deaths in pts with ND FLT3m AML up to age 70. Compared to M, G increased the CRc but not the FLT3m- CRc rate after induction. More post induction FLT3m+CRc pts who received G became FLT3m- after consolidation cycle 1 and more G pts succeeded in proceeding to HCT. Future survival data will help evaluate the clinical impact of G and MRD assessments in ND FLT3mAML. Larger studies will be needed to establish most predictive timing of MRD and for definitive comparisons of these drugs in patients with specific mutation profiles ( ie TKD, ITD/NPM1/DNMT3).