Citations

We present a subset analysis on the adolescent cohort of the S1826 randomized phase three trial, comparing nivolumab, doxorubicin, vinblastine, dacarbazine (N-AVD) to brentuximab vedotin-AVD (BV-AVD) in newly diagnosed advanced-stage (AS, stages III and IV) classic Hodgkin lymphoma (cHL). Among 994 patients enrolled, 24% (n = 240) were age 12-17 years. The 3-year progression-free survival (PFS) was significantly higher in the N-AVD group (93% [95% CI, 87 to 96]) compared with the BV-AVD group (82% [95% CI, 73 to 88]; hazard ratio, 0.37 [95% CI, 0.17 to 0.80]). One N-AVD and two BV-AVD patients received protocol-specified residual site radiotherapy (RT). Rates of febrile neutropenia and sepsis were low in both groups. Severe immune-related adverse events were infrequent, although thyroid dysfunction was seen in 7% with N-AVD. Sensory neuropathy (grade ≥2) was more frequent with BV-AVD (14% v 7%) by clinician report. Although premature discontinuation of therapy was reported in 12 N-AVD patients and four BV-AVD patients, no PFS events were noted in the N-AVD group. Patient-reported outcomes indicated less toxicity with N-AVD. N-AVD demonstrated high 3-year PFS in adolescents with AS cHL, with minimal RT use. S1826 exemplifies the benefits of harmonized clinical trial protocols, resulting in timely access to novel agents for adolescents.

Abstract E1910 evaluated the addition of blinatumomab to chemotherapy in adults with B-acute lymphoblastic leukemia (ALL). The addition of blinatumomab in patients (pts) with measurable residual disease (MRD) negative (neg) B-ALL significantly improved both relapse-free and overall survival (NEJM 2024; 391: 320-33)1. Given the increasing use of blinatumomab and the E1910 backbone chemotherapy regimen, we evaluated > Grade 3 toxicities on this trial in further detail. We assessed toxicity among the MRD-neg pts by age, gender, body mass index (BMI), combined cytogenetic-molecular risk, and number of cycles of blinatumomab received. We also evaluated toxicities during induction since this trial used a modified chemotherapy backbone. Methods: The eligibility, combined cytogenetic-molecular risk, and treatment have been previously described.1 All toxicities were > Grade 3 by CTCAE version 4 with at least a possible relationship to treatment. Descriptive statistics were used to summarize the occurrence and rates of toxicities and Fisher's exact test was used to compare differences in proportions between groups. Analysis of induction included all pts who started treatment. Analysis of Step 3 toxicities included MRD-neg pts who started treatment on the blinatumomab (n=111) or chemotherapy only arm (n=112). Results: Pt characteristics: For induction (n=488), median age was 51 years (yrs) (range 30-70); 48.6% female. Combined cytogenetic-molecular risk: favorable (13.5%); intermediate (12.9%); no risk assigned (16.2%); unfavorable (57.4%). For induction, we compared toxicities for E1910 (n=488) to pts treated on a prior young adult study (n=289) (C10403) (Blood Adv 2021; 5(2): 504-12). The incidence of hyperglycemia (8% vs. 31.1%, p< 0.001), aspartate aminotransferase (AST) increase (6.1% vs. 12.8%, p=0.002), alanine aminotransferase increase (ALT) (11.7% vs. 28.7%, p< 0.001), and hyperbilirubinemia (11% vs. 19%, p=0.002) were significantly lower in E1910 pts. The incidence of pancreatitis (1.8%), thromboembolic events (4.5%), and febrile neutropenia (25.4%) in E1910 was similar to C10403. Toxicities in the MRD-neg pts in the blinatumomab arm (n=111): Despite a high incidence of neutropenia (74.8%) and thrombocytopenia (55.9%) in Step 3, there was a relatively low incidence of sepsis (7.2%), bacteremia (1.8%), cytokine release syndrome (CRS) (3.6%) and neurologic adverse events (0-6.3%). There was a higher incidence of neurological or psychiatric events in the blinatumomab arm (23%) versus chemotherapy arm (5%) (p < 0.001) when all events were combined. There was a numerically higher incidence of ataxia (4.4% vs. %, p=0.16) and dysphasia (11.1% vs. 3%, p=0.12) in pts > 55 yrs and a higher incidence of neutropenia (80.3% vs. 66.7%, p=0.12) and thrombocytopenia (62.1% vs. 46.7%, p=0.12) in the younger pts (age < 55 yrs). In pts with a BMI < 30 kg/m2 (vs. > 30 kg/m2), there was a significantly higher incidence of leukopenia (51.7% vs. 26.4%, p=0.007) and thrombocytopenia (65.5% vs. 45.3%, p=0.037). However, this did not translate into an increased incidence of bleeding or infectious complications. By gender, females had a higher numerical incidence of AST increase (8.8% vs. 0%, p=0.057) and CRS (7% vs. 0% p=0.12); whereas males had a higher incidence of catheter- related infections (7.4% vs. 0%, p=0.05) and hyperglycemia (11.1% vs. 3.5%, p=0.16). A little more than half (56.8%) of pts received 4 cycles of blinatumomab with the remainder of pts receiving 1 (10.8%), 2 (28.8%), or 3 cycles (3.6%). Pts receiving 3-4 cycles of blinatumomab vs. 1-2 cycles of blinatumomab had a statistically higher incidence of anemia (38.8% vs. 6.8%, p< 0.001), neutropenia (98.5% vs. 38.6%, p< 0.001), and thrombocytopenia (83.6% vs. 13.6%, p< 0.001), likely related to being on treatment for a longer period of time. Conclusions: Blinatumomab was well tolerated with no significant toxicity differences noted by age, gender, or number of cycles of blinatumomab received. Pts with a lower BMI did have an increased incidence of leukopenia and thrombocytopenia, possibly related to flat dosing of the drug. However, this did not translate into increased complications. Toxicites during induction were notably few, which suggests that this backbone with age adjustments may serve as a good backbone for future trials. Blinatumomab is being evaluated with low dose chemotherapy and other targeted agents in ongoing trials.

Abstract Background: MyeloMATCH is an NCI-sponsored initiative for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) employing a Master Screening and Reassessment Protocol (MSRP) to assign patients (pts) to a pt and disease biology-specific clinical trial. Several trials evaluating initial therapies are currently open, while subsequent trials dedicated to eradicating measurable residual disease during consolidation and including stem cell transplant are being developed. A pt enrolled at diagnosis may be followed longitudinally and be eligible for trials in sequential tiers throughout the treatment course. We report key data concerning the first cohort of pts enrolled on the MSRP. Methods: After pts with suspected AML or MDS consent for the MSRP, blood and marrow are sent to the myeloMATCH Molecular Diagnostics Network (MDNet) of central CLIA labs operating under a single Investigational Device Exemption to rapidly define molecular, cytogenetic, and immunophenotypic characteristics. These data are catalogued by a bioinformatics team (MATCHBox) and reviewed daily to assign participants to an available trial based on pt and disease features. A Tier Advancement Pathway (TAP) allows standard of care therapy with potential for assignment to subsequent myeloMATCH trials. Since activation in May 2024, 550 patients age≥18 were enrolled on the MSRP from 76 institutions: 48 Academic, 14 NCORP, 11 community, 3 VA. There are currently 4 open randomized AML trials (≥age 60 or unfit with mutant FLT3, ≥age 60 IDH2 mutant AML, fit age<60 ELN 2017 intermediate-risk AML, fit age<60 ELN 2017 adverse risk) and 1 MDS trial(IDH2 mutant). Patients not eligible for an open protocol were assigned to TAP. Results: Of the 550 pts consented, 491 completed screening assays; 49 had no or incomplete samples; 10 withdrew before completed analysis. Median cytogenetic turnaround time (TAT) was 69 hours (91% within 72 hours), and median Next Generation Sequencing (NGS) TAT from receipt was 49 hours (95% within 72 hours). Seventy-six pts (of 491 with assay data) were not assigned due to non-AML or non-MDS diagnoses, the most common being: B-ALL [n=11], MPN [9], benign marrow [9], APML [7], and MPAL [6]. The AML/MDS verified cohort was 415 pts, 366 (89.2%) patients with AML (45% age <60) and 49 (11.8%) with MDS. The median age at screening was 63 years (range:18-95) and 186 (45%) were female. Eighty-two percent identified as White, 7.5% Black, 3% Asian, 7% unknown, and 9% as Hispanic. The most frequent mutations in the AML pts were NPM1 (24.0%), DNMT3A (22.7%), TET2 (19.9%), NRAS (18.0%), FLT3 (18.0% ITD, TKD 7.1%), TP53 (14.5%), and CEBPA (8.7%); IDH1/2 mutation rates were 8.2% and 13.7%, respectively. Co-mutations include FLT3/NPM1 (9.8%), NPM1/IDH2 (4.4%), IDH1/2 and any RAS (3.8%). Karyotypes were normal in 40.4%, complex 20.8%, inv(16) 6.0%, MLL/KMT2A 4.6% and t(8;21) 1.9%. 29% had favorable risk disease, 29% intermediate, and 42% adverse (ELN 2017). In MDS, mutations included: TP53 (36.7%), RUNX1 (20.4%) ASXL1 (20.4%), TET2 (18.4%), spliceosome mutations (SRSF2, SF3B1, U2AF1 and ZRSR2, 28.6%) andIDH1/2 in 4.1% and 6.1%, respectively. Karyotypes were normal in 24.5%; complex in 40.8%. By IPSS-R, 2.4% were low, 73.8% intermediate, 2.4% high, and 21.4% very high risk. 82/415 (20%) pts were assigned to initial therapy protocol, with an increase in assignment rate to 44% in the most recent two months. 71/415 pts (16%) were enrolled in one of the MyeloMATCH studies. Three-hundred forty-four pts (80%) were assigned and enrolled to TAP (296 AML, 48 MDS) for potential assignment to subsequent tier trials. In the TAP AML pts, 99 (33%) have completed initial treatment, including intensive chemotherapy (IC) in 62% of pts and hypomethylating agents/venetoclax (HMA/VEN) in 38%. In pts <60 years of age, 87% received IC v. 13% with HMA/VEN, in >60 34% IC v. 66% HMA/VEN and in age 60-75 42% IC v. 58% HMA/Ven. Conclusion: MyeloMATCH has screened over 500 pts from academic and community sites in the US and Canada in 14 months, meeting the TAT goal of sample acquisition to results of <72 hours. Assignment to treatment protocols has substantially increased recently. As additional trials open (12 in development) we expect the percentage of pts enrolled on MSRP who go on to therapeutic trials will markedly increase, thereby allowing a personalized medicine approach for a broad group of US and Canadian adult pts with AML and MDS.

Abstract Introduction:A comprehensive integration of significantly mutated genes and pathways with molecular subgroups is lacking in adult B-ALL. Furthermore, the genomic drivers underlying each subgroup remain to be identified.We aimed to perform genomic analysis on a large cohort of patients with adult B-ALL, and to correlate genomic markers with achievement of MRD negativity enabling blinatumomab randomization, and with subsequent response to blinatumomab. Methods:For genomic analysis, we studied 569 adults with newly diagnosed B-ALL registered for initial screening on the ECOG-ACRIN-led E1910 trial (NCT02003222), which evaluated the addition of blinatumomab to standard consolidation chemotherapy. The median age was 52 yrs (range 30 to 71 yrs), with 52% males. Analysis was performed on tumor and matched-normal samples using whole transcriptome sequencing (RNA-seq; tumor only; n=569), whole exome sequencing (n=490), whole genome sequencing (n=131), and single nucleotide polymorphism array (n=445). B-ALL cases were classified into 22 molecular groups. Outcome analysis was limited to patients enrolled and treated on E1910 (n=319). Results: Driver genes (n=268) were identified by the mutation-significance detection tool dNdScv or by the presence of pathogenic variants in known cancer genes, with NUP188 identified as a novel driver gene. Recurrently mutated pathways included: B-cell development (46%), cell cycle (44%), epigenetic regulation (30%), other transcriptional regulation (27%), Ras signaling (25%), RNA machinery (17%) and JAK-STAT signaling (8%). A high frequency of high-risk subtypes was observed including BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A (12%). Using tSNE analysis, we identified a new cluster of cases (n=20, 3.5%) lacking a known subgroup driver, with overexpression of CEBPA (n=13) or CEBPB (n=7), distinct from CEBPE/ZEB2, termed “CEBP-altered” ALL (CEBPalt). Five of 13 cases with high CEBPA expression harbored an IGH::CEBPA rearrangement and one harbored a RXRA::CEBPA enhancer hijacking alteration. Of the 7 cases with high CEBPB expression, 5 harbored IGH::CEBPB, and two of these had concomitant clonal BCR::ABL1 fusions. To identify additional mechanisms of CEBP deregulation, in situ Hi-C coupled to H3K27 acetylation immunoprecipitation (HiChIP) was performed on 5 cases. Four cases showed evidence of de novo CEBPA enhancer activity. In two cases, we identified novel insertions (12 and 34nt) ~2kb downstream of CEBPA. A novel translocation and enhancer hijacking event between LINC00426 and the 5' UTR of CEBPB was identified in the remaining case. Overall, we confirmed genomic alterations of CEBPA or CEBPB in 16 of 20 cases with available material. Thus, we have identified a new molecular subgroup of adult B-ALL characterized by genomic alterations that drive enhancer hijacking and oncogenic deregulation of CEBPA/CEBPB. Several subgroups were enriched in patients that failed induction chemotherapy (n=62) or were MRD-positive (n=63) compared to those that achieved MRD-negative status (n=194): BCR::ABL1-like (30 vs 14%, p<0.001), KMT2A (18 vs 9%, p=0.03) and BCL2/MYC (5 vs 1%, p=0.06). Conversely, the following subgroups were enriched in patients that achieved MRD-negativity: PAX5alt (6 vs 18%, p=0.002), TCF3::PBX1 (0 vs 5%, p=0.01) and ZNF384 (2 vs 6%, p=0.08) Within each molecular subgroup we compared the survival of patients who achieved MRD-negative status after induction and were randomized to receive blinatumomab plus chemotherapy (n=93) or chemotherapy only (n=91). Although numbers were low, blinatumomab improved relapse-free survival for patients with hyperdiploid, PAX5alt, BCR::ABL1-like and KMT2A ALL compared to chemotherapy alone. Clonal hematopoiesis of indeterminate potential (CHIP)-related gene mutations were identified in 121 of 417 cases analyzed (29% total: somatic 74%, remission 31%, both 5%). TP53 mutations were most frequent (n=65 patients), with the majority identified in patients with low hypodiploid (n=52). Interestingly, patients with CRLF2 rearrangements collectively harbored the highest number of other CHIP gene mutations (n=13), including DNMT3A (n=4), TET2 (n=3) and ASXL1 (n=3). Conclusions:We provide a comprehensive landscape of genomic alterations in adult B-ALL and identify a new group characterized by deregulation of CEBPA/CEBPB (CEBPalt). We also provide insights into the efficacy of blinatumomab in different molecular subgroups of adult B-ALL.

Abstract Background: The addition of the CD19/CD3 bispecific T-cell engager, blinatumomab, to standard consolidation chemotherapy in adults with ALL who achieved a measurable residual disease negative (MRDneg) remission (CR), demonstrated an improvement in 3-year overall survival (OS, 85% vs 68%, HR 0.41, P=0.002) and 3-year relapse-free survival (RFS, 80% vs 64%, HR 0.53) compared to conventional chemotherapy in the ECOG-ACRIN E1910 study (Litzow et al, NEJM 2024). Given the complex therapy in this study, treatment delays and modifications are expected. We herein explored the impact of such delays on patient outcomes. Methods: In the phase 3 ECOG-ACRIN E1910 trial (NCT02003222), adults aged 30-70 years with newly diagnosedALL who had achieved MRDneg CR following induction and intensification were randomized to consolidation chemotherapy with blinatumomab (blina arm) or chemotherapy alone (chemo arm). We examined the association between the timing of the initiation of maintenance therapy and OS and RFS. The expected duration of consolidation was 252 days vs 126 days for patients on the blina and chemo arms, respectively. For this analysis, participants were classified into two groups (no/short delay or long delay) depending on whether they started on time/before or after the median time between the beginning of consolidation and start of maintenance therapy for their treatment group (medians: 335 days, range, 181-457 days vs 176 days, range, 139-265 days for blina and chemo arms, respectively). Multivariate analyses of OS and RFS were performed to examine the effect of no/short delay vs. long delay in starting maintenance. Patients were stratified according to their assigned consolidation treatment arm, and the models were further adjusted for age, sex, white blood cell count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status and genetic-genomic risk at diagnosis. Results: Of the 488 patients enrolled, 224 MRDneg patients were randomized to consolidation chemotherapy with or without blinatumomab and 135 of the 224 went on to maintenance therapy on study (N= 66 on blina arm and 69 on chemo arm, respectively). The median follow-up from the time of maintenance registration was 43.4 months. There were no significant differences in baseline characteristics between patients in either arm who experienced no/short delay or long delay. In the blina group, 60 of 66 patients (90.9%) received all 8 cycles of consolidation therapy of which 31 (45.6%) had long delays. Sixty-eight of 69 patients on the chemo arm (98.5%) received all cycles of consolidation therapy, of which 34 (50%) had a long delay. Strikingly, patients who had a long delay before initiation of maintenance had a significant improvement in OS in multivariate analysis compared to patients who had no/short delay (HR 0.31, 95% CI: 0.11-0.91; P =0.03). However, within each treatment group, OS benefit did not reach statistical significance (blina arm: HR 0.04, 95% CI: 0.001-1.64; P =0.09; chemo arm: HR 0.32, 95% CI: 0.08-1.38; P =0.13). Similar results were observed for RFS in multivariate analysis (HR 0.40, 95% CI: 0.16-1.01; P =0.05), though this impact on improved RFS was noted in the chemo arm but not in blinatumomab treated patients (blina arm: HR 0.56, 95% CI: 0.10-3.24; P =0.52; chemo arm: HR 0.19, 95% CI: 0.04-0.83; P=0.03). Additionally, patients who had no/short delay before starting maintenance experienced a longer median duration of maintenance treatment (blina arm, 548 days; chemo arm, 708 days) compared to patients who had a long delay (blina arm 488 days; chemo arm 598 days) before initiation of maintenance (P=0.0008). Conclusion: In the phase 3 randomized ECOG-ACRIN E1910 clinical trial, long delays between initiation of consolidation therapy and start of maintenance therapy were associated with improved OS compared to no/short delays. However, within each treatment group (blina or chemo), no significant difference of OS was observed. We postulate that these longer delays allowed more patients to receive all of the recommended protocol-assigned therapy thereby resulting in improved survival. Furthermore, patients who had no/short delays had a significantly longer duration of maintenance therapy. These data indicate that treatment delays during consolidation do not worsen survival. Further studies are being done to better understand why patients with long delays had better overall survival.

Abstract Background. Uproleselan (GMI-1271) is an antagonist of E-selectin, an adhesion molecule expressed on endothelial cells in the vascular niche of the bone marrow. Engagement of E-selectin by acute myeloid leukemia (AML) blasts, which express E-selectin ligand, activates cell survival pathways and promotes resistance to chemotherapy. In multiple preclinical AML tumor models, blockade of E-selectin with uproleselan enhanced the efficacy of chemotherapy. Methods. We conducted a phase (P) 2/3 study in which subjects age ≥ 60 years with untreated, FLT3 unmutated AML were randomized to receive conventional chemotherapy with or without uproleselan. Induction chemotherapy consisted of 7+3 (cytarabine + daunorubicin) +/- uproleselan with a second induction cycle with 5+2 +/- uproleselan administered for residual AML. Uproleselan 800 mg IV was administered as a single dose 24 hours before the first dose of chemotherapy and then every 12 hours until 48 hours after the completion of chemotherapy. Post-remission therapy consisted of up to 3 cycles intermediate-dose cytarabine 2 gm/m2 IV d1-5 +/- uproleselan. Allogeneic transplant was performed at the discretion of the treating physician. The primary endpoint was event-free survival (EFS) for P2 and overall survival (OS) for P3. Results. The study enrolled 267 patients between March 2019 and November 2021, with a median age of 66.9 years (IQR 63.8-69.9). 32% were classified as 2017 ELN intermediate risk, 41% as adverse risk, with 62 (29%) having complex karyotype / mutated TP53. The P2 analysis was to be performed when at least 191 events were observed. However, as the required events had not been observed > 5 years after study initiation and 3 years after completion of P2 enrollment, an independent statistician was consulted, and the analysis plan was amended to conduct the P2 EFS analysis in November 2024. With a median follow-up of 53.1 months, the EFS was not significantly different between the two arms (HR 0.90, 95% CI 0.70-1.23, P=0.58). As the study did not meet its P2 EFS endpoint, enrollment in the P3 was not initiated. There was no significant difference in OS between the 2 arms (HR 0.99, p=0.94) with a median OS in the uproleselan arm of 23.6 months (95% CI 15.1-35.4 mo) vs 19.8 months (14.6-36.3) for the control arm. The overall rate of CR/CRi after induction was 65% (CR: 60%) in the uproleselan arm versus 63% (CR: 55%) in the control. MRD results by either local or central assessment in patients achieving a CR/CRi were available for 129 patients with the MRDneg rate of 81 % (95% CI 69.5-89.9%) in the uproleselan arm vs 67% (54.3-78.4%) in the control arm (p=0.053), The 30-day mortality was 5.3% for uproleselan vs 8.1% in the control. Forty-eight (36%) patients in the uproleselan arm and 55 (40%) in the control arm underwent alloHCT, including 37 (27%) and 29 (22%) in CR1, respectively (p = 0.34). In patients undergoing alloHCT in CR1, those randomized to uproleselan and allografted in CR1 had an HR 0.71 (95% CI 0.34-1.47; P=0.35) compared to the control arm. Expression of E-selectin ligand on AML blasts was performed by flow cytometry, with subjects having an E-selectin ligand expression above the median having a trend towards worse median OS 16.2 (95% CI 11.4-24.3) vs 32.2 (15.9-57.8) months, but was not affected by treatment arm. In both univariate and multivariate analyses, WBC at baseline, ELN genetic risk group, and TP53/complex karyotype were found to be associated with EFS. A subgroup analysis identified an improvement in EFS favoring uproleselan in patients with mutated ASXL1 (HR 0.25, 95% CI 0.08-0.78, p<0.017). Conclusions. Although the addition of uproleselan to intensive chemotherapy was associated with a higher rate of MRDneg CR/CRi in older adults with AML, uproleselan failed to improve EFS or OS and did not overcome the adverse outcomes associated with higher E-selectin expression on AML blasts. The median OS of 20-24 months with an overall 3-year OS of almost 40% for patients treated on this study exceeds previous CALGB / US Cooperative Group studies (median OS ~12 months, 3-year OS ~20%) and continues to support a role for intensive chemotherapy in the management of older adults with AML. Furthermore, this study suggests a potential benefit for uproleselan in patients harboring ASXL1 mutations, which may warrant further investigation. ClinicalTrials.gov Identifier: NCT03701308

Abstract Introduction: MyeloMATCH (mM), is an National Cancer Institute (NCI)-sponsored precision medicine initiative for newly diagnosed AML/MDS. It consists of an initial screening study (Master Screening and Reassessment Protocol, or MSRP) that involves centralized testing of bone marrow/whole blood, leading to assignment into several genetically driven treatment subprotocols within the mM portfolio. MSRP employs karyotype, 8-15 probe fluorescence in situ hybridization (FISH) and NCI-myeloid (NMAv2) assays to determine ploidy, translocations and mutational status needed for accurate disease subclassification, risk stratification as well as for theragnostic determination. NMAv2, a rapid next generation sequencing assay (TAT<48 hrs), interrogates 45 DNA and 35 RNA fusion driver genes to report 1661 hotspot DNA mutations and 779 targeted RNA fusions, including all relevant fusions in AML except Inv3/t(3;3)/MECOM rearrangement (Yeung et al, 2025). The initial mM MSRP workflow relied on karyotype and FISH assay results to identify fusion positive AML/MDS as per the current testing guidelines/ recommendations as well as to abide by the FDA's requirements under the investigational device exemption (IDE). Here we present concordance analysis between karyotype, FISH and NMAv2 assay to identify relevant fusions in AML/MDS. Methods: First 400 participants enrolled in the mM MSRP were included in this analysis. We examined the results from karyotype analysis analyzing 20 metaphase cells, 8-15 probe FISH analyzing 500 nuclei per probe, and NMAv2 curating fusion read counts greater than 100, performed at the mM labs to determine the prevalence of fusions in this cohort. Concordance analysis was performed to determine clinical utility of the NMAv2 assay to report relevant fusions at the time of initial diagnosis. The concordance analysis excluded biomarkers including Inv3/t(3;3)/MECOM rearrangement, KMT2A-PTD and other rare fusions that are beyond the scope of detection by NMAv2 and/or FISH assay. Results: Of the 400 patients analyzed in this cohort (median age 64, [range 20-95]; 43% female; 15.5% non-white; 9.5% Hispanic), translocations/fusions were reported in 67, 73 and 95 patients by karyotype, 8-15 probe FISH and NMAv2, respectively. The karyotypic analysis reported inv(16)/t(16;16) [15], t(11q23) [13], t(9;22) [10], inv3/t(3;3) [9], t(8;21) [6], t(15;17) [5], t(6;9) [4], t(21q22) [3], t(9q34) [1] and t(10;11) [1]. The FISH reported inv(16)/t(16;16) CBFB::MYH11 [15], t(11q23) KMT2A rearrangement [14], t(9;22) BCR::ABL1[10], inv3/t(3;3) MECOM rearrangement [10], t(8;21) RUNX1::RUNX1T1 [7], t(15;17) PML::RARA [5], t(6;9) DEK::NUP214 [5], t(21q22) RUNX1 rearrangement [3], t(11p15.4) NUP98 rearrangement [3], and t(9q34) ABL1 rearrangement [1]. The NMAv2 reported KMT2A-PTD [26], CBFB::MYH11 [15], KMT2A fusion [14], BCR::ABL1[12], RUNX1::RUNX1T1 [8], PML::RARA [5], DEK::NUP214 [5], RUNX1 fusion [4], NUP98 fusion[3], t(9q34) ABL1 fusion [1], PICALM::MLLT10 [1] and ETV6::MECOM [1]. The concordance analysis between NMAv2 and karyotype assay demonstrated positive percent agreement(PPA) of 100%, negative percent agreement(NPA) of 96.81% and overall agreement (OA) of 97.25% when using karyotype as reference. The concordance analysis between NMAv2 and FISH assay demonstrated PPA of 100%, NPA of 98.81% and OA of 99% when using FISH as reference. Of the 12 cases with discrepant results, 7 were due to presence of cryptic translocations missed by karyotype assay, 3 had suboptimal specimen submitted for karyotype/FISH analysis, 1 had false positive BCR::ABL1 fusion reported by NMAv2 due to low level contamination and 1 had minor subclonal population of leukemic blast with BCR::ABL1 fusion detected only by NMAv2. Conclusion: NMAv2 shows high concordance with karyotype and FISH assays which are the most commonly utilized assays to identify fusions/translocations in AML/MDS. NMAv2 is a faster, relatively cheaper and sample conserving method to identify fusions and is less prone to false negative results than karyotype/FISH assay from suboptimal specimen acquisition and testing. Based on the results above, mM MSRP workflow has been amended with FDA concurrence such that a combination of NMAv2, karyotype and MECOM breakapart FISH assay will be used to identify relevant fusion variants in all patients enrolled in mM, whereas additional specific FISH assay will be limited to cases where discrepant results between karyotype and NMAv2 are reported.

Abstract Introduction: Standardized reporting of clinical trials results for MDS is essential to improve clinical interpretation and cross-study comparison. However, reporting of patient characteristics, response criteria, and endpoints in publications is often inconsistent; there is no systemic analysis of MDS trial reporting available. We conducted a systematic review of published MDS trial manuscripts on behalf of the international consortium for MDS (icMDS) to assess variability in reporting practices. Methods We searched ClinicalTrials.gov to identify all clinical trials registered for adults (≥18 years) with MDS that reported results between 2015-2024. Clinical trials that included acute myeloid leukemia (AML) or MDS/myeloproliferative neoplasms (MPN) were included if they enrolled ≥5 MDS patients. We excluded trials without an MDS cohort; non-therapeutic trials; trials focused on transplant interventions; or those which enrolled solid malignancies or other hematologic malignancies (chronic myeloid leukemia or lymphoid diseases). Finally, trials were required to have a manuscript available on Larvol, PubMed, or Google Scholar. Trials were categorized by disease risk (lower-risk [LR] vs. higher-risk [HR]) and trial phase (early phase [EP] vs. late phase [LP]). Results We identified 502 MDS trials on ClinicalTrials.gov, of which 351 did not meet inclusion criteria and 79 lacked a manuscript. A total of 72 trials (32 EP, 40 LP) with 80 publications (34 EP, 46 LP) were analyzed. Frequently reported baseline characteristics included age (100% EP, 100% LP), disease risk (74% EP, 74% LP), Eastern Cooperative Oncology Group performance status (85% EP, 72% LP), prior treatments (71% EP, 67% LP), and RBC transfusion dependency (32% EP, 70% LP). Less frequently reported characteristics included blood counts (hemoglobin [Hb; 38% EP, 54% LP], platelet count [38% EP, 54% LP], neutrophil count [24% EP and LP]) and bone marrow blasts (29% EP, 43% LP). Although disease risk was widely reported, definitions varied: IPSS and IPSS-R were each reported in 54% of manuscripts, while IPSS-M appeared in only 3%. Cytogenetic risk was separately reported in 39% of manuscripts (38% EP, 39% LP), and mutational data in 45% (47% EP, 43% LP). Responses per IWG 2006 criteria were reported in 84% of manuscripts. The primary endpoint involved safety/tolerability in 85% of EP manuscripts, though definitions were variable; recommended phase 2 dose was the most common (26% of EP manuscripts). In LP trials, primary endpoints were risk-specific: transfusion independence (TI) in 77% of LR, overall response rate (ORR) in 28% of HR, and complete remission (CR) or overall survival (OS) in 22% of HR. In HR manuscripts, CR was reported in 100%, ORR in 73%, hematologic improvement (HI) in 48%, RBC-TI in 23%, and OS in 80%. However, seven different definitions were used for ORR: CR + marrow CR + partial remission + HI per IWG 2006 was most common (35%). Event-free survival was reported in 25%; progression-free survival and relapse-free survival in 13%; and leukemia-free survival in 5%. Early mortality rate was reported in 35% (18% EP, 56% LP) and transplant rate in 58% (50% EP, 67% LP). Only 47% of HR and 90% of LR manuscripts identified HI-eligible patients. In LR-MDS, RBC-TI was reported in 72% of manuscripts but used six definitions. The most common were RBC-TI ≥8 weeks at any time during treatment (24%), ≥8 weeks within 28 weeks of treatment (13%), ≥8 weeks with Hb increase ≥1.0 (4%), ≥12 weeks with Hb increase ≥1.5 (4%), and ≥16 weeks within 24 weeks of treatment (12%). The remainder did not report RBC-TI, did not define it, or used a custom definition not used in another trial. HI was reported in 80% of LR papers with most of those reporting HI using IWG 2006 criteria (90%). Conclusion Reporting of baseline characteristics, response criteria, and outcomes is inconsistent in MDS clinical trials, with wide variability in response definitions, including ORR and TI. This heterogeneity limits interpretability, hampers historical comparisons and may obscure efficacy signals. Our findings highlight the need for standardized reporting guidelines to ensure clarity and consistency in MDS trial publications. As a next phase of this effort, we will conduct a formal Delphi process among icMDS experts to establish consensus recommendations for minimal and optimal MDS clinical trial reporting in manuscripts by disease risk (LR/HR) and trial phase (EP/LP).

Abstract Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly phase 3 trials, have unnecessarily restrictive eligibility criteria. This study aims to evaluate the most common eligibility criteria according to phase of trial and to determine whether criteria correspond with drug safety signals. We identified MDS clinical trials registered on ClinicalTrials.gov from 1 January 2000 to 1 September 2023 and analyzed the eligibility criteria of 191 therapeutic MDS trials. We found that categorical inclusion and exclusion criteria are remarkably similar in representation across trial phases. Additionally, only 13% of trials are concordant with drug safety signals, suggesting that the eligibility criteria are often arbitrary. On behalf of the icMDS (International Consortium for Myelodysplastic Syndromes), an association of international MDS experts, we provide a position statement on restrictive eligibility criteria for MDS clinical trials that should be avoided with the aim of removing barriers to clinical trial enrollment.