Prior Lines Of Treatment Research Articles

Final Results of the Phase Ib/II Study Evaluating Enasidenib in Combination with Venetoclax in Patients with IDH2-Mutated Relapsed/Refractory Myeloid Malignancies

BACKGROUND: Theisocitrate dehydrogenase 2 ( IDH2) gene is mutated in ∼10-15% cases of acute myeloid leukemia (AML) and ∼5% cases of myelodysplastic syndromes (MDS). Enasidenib (ENA) is an oral selective IDH2 inhibitor used for treatment of IDH2-mutated (m IDH2) relapsed/refractory (R/R) AML. Preclinical studies showed that m IDH2 AML cells are particularly sensitive to BCL2 inhibition with venetoclax (VEN) and combination of ENA and VEN is more effective than single agents in patient-derived xenograft models of m IDH2 AML. Based on this rationale, we conducted a phase Ib/II trial evaluating the safety and efficacy of ENA plus VEN in patients (pts) with m IDH2 R/R AML or MDS (NCT04092179). METHODS: This single-arm phase Ib/II trial was conducted at the Princess Margaret Cancer Centre and the University of Alberta Hospital in Canada. Pts ≥ 18 years with m IDH2 R/R AML or MDS, adequate organ function and ECOG performance status ≤ 2 were eligible. Participants were not eligible if they had prior exposure to IDH2 or BCL2 inhibitors. Pts were treated continuously by 28-day cycles of VEN 400 mg daily starting with a 3-day ramp-up on cycle 1 day 1 and with ENA 100 mg daily starting on cycle 1 day 15. The primary endpoints were safety, tolerability and recommended phase 2 dose (RP2D) for the phase Ib part and overall response rate (ORR) for the phase II part. ORR included complete remission (CR), CR with partial hematological recovery (CRh), CR with incomplete hematological recovery (CRi), morphologic leukemia-free state (MLFS) and partial remission (PR) as defined by the European Leukemia Network (ELN). Duration of response (DOR), overall survival (OS), pharmacokinetic (PK) analysis for VEN and bone marrow (BM) IDH2 variant allele frequency (VAF) by droplet digital PCR (ddPCR) were also evaluated. RESULTS: From November 2020 to July 2022, 27 pts were enrolled: 12 in the phase Ib and 15 in the phase II. Almost all pts had AML, except one with MDS who progressed on treatment with azacitidine. The data cutoff date was June 30, 2023. The median age was 70 years (range, 23 - 84) ( Table 1). Patients had a median of 1 prior line of treatment (range, 1-2) including 5 (19%) who had previously undergone allogeneic stem cell transplant (HSCT). Fifteen (56%) and 12 (44%) pts had R140Q and R172K/W IDH2 mutation (mut), respectively. The median BM IDH2 VAF at baseline was 23.4 (range 2.3 - 49.9). The most common (≥ 20%) grade 3-5 treatment emergent adverse events (TEAEs), regardless of attribution, were febrile neutropenia (41%), lung infection (22%) and thrombocytopenia (26%). Nausea, vomiting and diarrhea occurred each in 41% of pts, but were primarily grade 1-2 (only 1 pt with grade 3 diarrhea). Hyperbilirubinemia of any grade occurred in 48% pts, including grade 3 in 15%. No case of IDH inhibitor associated differentiation syndrome (IDH-DS) occurred in this study. Grade 3 leukocytosis without IDH-DS occurred in 2 (8%) pts. No patient discontinued ENA because of an adverse event and no treatment-related death was reported. The PK profile of VEN was not altered by ENA, and the RP2D was VEN 400 mg daily plus ENA 100 mg daily. Among 23 pts with R/R AML evaluable for response, the ORR was 70% (16/23), including 57% (13/23) CR ( Figure 1). In pts with R172 mut, the ORR and CR rates were 83% (10/12) and 67% (8/12), respectively, versus 55% (6/11) and 45% (5/11) in pts with R140 mut. m IDH2 VAF at baseline was similar between responders and non-responders. On follow-up BM samples, there was an association between response and decrease in m IDH2 VAF. Clearance of m IDH2 was observed in 47% (7/15) of analyzed responders. The median time to initial response was 1 month (range, 0.9 - 5.7), and the median time to best response was 2.8 months (range, 0.9 - 12.5). The median DOR was 16.6 months (95% CI 5.0 - NR) and pts received a median of 7 cycles of treatment (range, 1 - 32). With a median follow-up of 17.1 months (range, 0.9 - 31.4), 10 (38%) pts were alive, including 9 (35%) in ongoing remission. The median OS was 9.4 months (95% CI, 8.2 - NR) and the 2-year OS rate was 42% (95% CI, 27 - 66). Four pts proceeded to HSCT after achieving remission, of whom 2/4 (50%) are alive in remission on last follow-up. CONCLUSIONS: The combination of ENA and VEN is safe and well tolerated in pts with R/R m IDH2 myeloid malignancies. The ENA-VEN combination compares favorably to ENA single-agent in this patient population. Further studies of targeted combination therapies using IDH2 and BCL2 inhibitors are warranted.

Realmind: A Prospective and Retrospective Study to Characterize Real-World Use of Tafasitamab Plus Lenalidomide in US Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma, with a Focus on Patients from Minority Groups

Background The combination of the anti-CD19 monoclonal antibody tafasitamab and the immune modulatory drug lenalidomide (LEN) has been commercially available in the US for adult patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) not otherwise specified, including DLBCL arising from low-grade lymphoma, and who are ineligible for autologous stem cell transplant (ASCT) since August 05, 2020. It was granted accelerated FDA approval and EU conditional marketing authorization after the primary analysis of Phase II L-MIND study (NCT02399085) demonstrated safety and efficacy in this setting. To complement clinical data, it is important to assess real-world safety and effectiveness given the heterogeneity of routine clinical care. Furthermore, focusing on patients from racial and ethnic minorities, who may face challenges in receiving optimal access to care, may help to identify and address inequities. realMIND is an observational study of the real-world safety and effectiveness of tafasitamab + LEN for the treatment of R/R DLBCL among patients in the US by race and ethnicity. Using prospective and, where necessary, retrospective data collection, this non-interventional study will also provide a deeper understanding of treatment patterns of US patients with R/R DLBCL treated with tafasitamab, and its use in a real-world setting in terms of treatment duration, dose modifications, and post-tafasitamab + LEN combination partners and monotherapy use. Methods realMIND (NCT04981795) is a multicenter, observational, prospective and retrospective Phase IV trial-in-progress study targeting ≥100 US patients with R/R DLBCL treated with tafasitamab + LEN. To ensure diversity, Group 1 will enroll patients from racial and ethnic minorities (n≥50), while Group 2 will comprise non-Hispanic White (NHW) patients (n≥50) (Figure 1). Eligible patients are ≥18 years old with histologically confirmed R/R DLBCL, ≥1 prior line of treatment, and have initiated or will be initiating tafasitamab treatment (except in the context of an interventional study). Prospective data collection began at study sites in September 2021, and retrospective data (from study sites or vendor databases) may include patients with a tafasitamab start date (index date) from August 05, 2020, onwards. The primary endpoints include safety and effectiveness outcomes (Table 1). Serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) will be reported. Effectiveness will be assessed in terms of tumor response rates and time-to-event endpoints, while secondary endpoints include treatment line and dose information (Table 1). Patient data for this observational study will be collected by prospective follow-up of patients included at study sites, or by retrospective collection of data from patient records, at study sites or from vendor databases. Prospective and retrospective data will be analyzed separately, as well as pooled. No formal sample size calculation was performed due to the descriptive nature of the study and no hypothesis testing is planned. Study status The in-progress non-interventional realMIND study is expected to end by approximately December 2025, or earlier, when: ≥50 patients treated with tafasitamab + LEN have been recruited into each of Group 1 and Group 2 with either prospective or retrospective data collection; and all prospectively-followed patients have ≥6 months follow-up after starting tafasitamab treatment, or have discontinued from the study for any reason, whichever occurs earlier. The results are anticipated to describe the real-world safety and effectiveness of tafasitamab for R/R DLBCL in US patients, with a focus on underrepresented racial and ethnic minorities, to help optimize outcomes of treatment and identify opportunities for further studies.

Roginolisib a Highly Selective Allosteric Modulator of the Phosphoinositide 3-Kinase Delta (PI3Kδ) in Patients with Refractory/Relapsed Follicular Lymphoma

Introduction PI3Kδ inhibitors are active in patients (pts) with lymphomas, but their clinical development has been hampered by toxicity (Brown et al, Lancet Oncol 2022). Roginolisib (IOA-244) exerts an allosteric modulation of the PI3Kδ C-terminus and functions as a non-ATP competitive PI3Kδ inhibitor, delivering a selective inhibition without off-target effects typically seen with other PI3K inhibitors (Johnson et al, Cancer Res Commun 2023). Using the recommended phase 2 dose (RP2D) of 80 mg QD established in solid tumors patients, patients with refractory/relapsed (r/r) follicular lymphoma (FL) were treated to investigate its safety profile in pts with hematologic malignancies (NCT04328844). Methods In Part A of the FiH dose escalation study, roginolisib was investigated at 20 and 80 mg QD in pts with r/r FL. Primary objective: safety of the RP2D established in solid tumor pts. Secondary objectives: PK; PD (e.g., changes in immune cell subsets in peripheral blood); Lugano-based responses; PFS and OS. Results In Part A for pts with r/r FL, there were two cohorts: (a) Cohort 1: 20 mg QD daily (4/4; 2 female, 2 male); (b) Cohort 2: 80 mg QD (4/4; 3 female, 1 male). There were no DLT observed and no dose modifications were needed. The mean time on treatment was 1.9 months (20 mg QD) and 4.3 months (80 mg QD), with one patient at the 80 mg receiving Roginolisib for 9 mo. More than 4 prior lines of treatment were in 3/8 pts. Transient (lasting less than 48 hrs) platelet reduction (G3) and AST/ALT elevation (G3) were observed in 2/8 pts, which improved while pts continued without a treatment intervention, such as dose modification or medical treatment with steroids. Lugano-based PRs were observed in 2/4 pts at the 80 mg QD dose and none at the 20 mg QD. At the 80 mg QD dose a third pt had a clinical response manifested by improvement in night sweats and fever, reduction in cervical palpable lymph nodes and relief from chronic pleural effusion. This clinical improvement lasted less than 5 weeks. While Overall Survival (OS) is still ongoing, the median has not been reached in this study and is currently at 14.3 mo. Subsequent to ending Roginolisib treatment, patients received at least one additional therapy (6/8), one patient was able to undergo autologous transplant with a complete metabolic response (CMR). Biomarker evaluation using flow cytometry showed low counts of T regulatory cells (Treg) in peripheral blood in all 8 r/r FL patients compared to solid tumor patients at baseline and throughout the treatment. Myeloid derived suppressor cells in peripheral blood remained unchanged during the course of treatment with Roginolisib. Conclusions The safety profile of roginolisib in pts with r/r FL appears to match that in pts with solid malignancies. In contrast to other PI3Kδ inhibitors, roginolisib is highly selective for binding to PI3Kδ, favoring an inactive confirmation of PI3Kd and functions as a non-ATP competitive inhibitor.

Clinical Outcomes in Real-World Patients (RW) with Triple-Class Exposed (TCE) Relapsed/Refractory Multiple Myeloma (RRMM): A Retrospective Study Using Electronic Health Records from Flatiron Health and COTA Vantage Databases

Introduction: With rapid treatment advances in multiple myeloma (MM), more patients receive the 3 main classes of MM treatments (immunomodulatory imide drug [IMiD] agents, proteasome inhibitors [PIs], and anti-CD38 monoclonal antibodies [mAbs]) in earlier lines of therapy and become TCE. This is a prerequisite for subsequent treatment with some novel therapies eg, anti-B-cell maturation antigen (BCMA) agents. Published evidence of RW clinical outcomes in patients with TCE MM is scarce in the evolving RRMM treatment landscape. The objective of this study was to assess RW clinical outcomes in patients with TCE RRMM who received treatment post-TCE. Methods: In this observational study, we analyzed de-identified patient data derived from electronic health records (EHRs) from 2 key United States (US) MM longitudinal databases (Flatiron Health MM [FHMM] and COTA Vantage MM [CVMM]). We identified patients who became TCE between November 2015 and March 2021 and received a subsequent treatment post-TCE; the earliest available end date of the 3rd treatment class was considered the date patients became TCE. The start date of the 1st treatment post-TCE (index treatment) was defined as the index date. We analyzed patient demographics, disease characteristics, prior treatment exposure, refractory status, and index treatments patterns/classes. Clinical endpoints assessed were response rates (overall and complete), overall survival (OS), progression-free survival (PFS), and time to progression (TTP). Results: The FHMM and CVMM databases included 1,319 and 1,118 TCE patients, respectively, of whom 897 and 795 received an index treatment post-TCE. Median (range) follow-up for patients who received an index treatment was 18.1 (0.1-82.0) and 15.5 (0.03-72.3) months for FHMM and CVMM cohorts, respectively. Median age for both RW cohorts was 68 years, more than half of patients were men and the majority were White. Patients received a median of 3 lines of prior treatment (range, 1-14 and 1-12 for FHMM and CVMM cohorts, respectively). In both RW cohorts, >75% of patients who received an index treatment were triple-class refractory and approximately 10% were penta-refractory, having received treatment with 2 IMiD agents, 2 PIs, and an anti-CD38 mAb. Approximately 67% and 79% of patients in the FHMM and CVMM cohorts, respectively, had ECOG performance status 0 or 1. Approximately 54% and 61% had received prior stem cell transplantation. IMiD agents either alone or in combination with a PI and/or anti-CD38 mAb constituted the main regimens for index-treated patients. In the CVMM cohort, the overall and complete response rates were 15.2% and 1.7%, respectively; response data were not available in the FHMM cohort. Median OS (22.3 and 20.4 months), median PFS (4.8 and 4.9 months), and median TTP (5.9 and 5.9 months) were comparable for both FHMM and CVMM cohorts. Conclusions: In this observational cohort study of 2 US RW EHR databases, patients became TCE with a median of 3 prior lines of therapy. Post-TCE, most patients with RRMM still received the same 3 treatment classes with poor response and survival outcomes on their treatments. Despite advances in MM management, this study highlights the need for more efficacious novel treatments for patients with TCE MM and serves as a RW benchmark in the literature for appraising emerging data from novel agents in patients with RRMM.

Outcomes in Patients with Acute Myeloid Leukemia Treated with CLAG (cladribine, cytarabine, filgrastim) and/or Mitoxantrone with Venetoclax

Introduction: CLAG (cladribine, cytarabine, filgrastim) with or without M (mitoxantrone) has anti-leukemic activity in newly diagnosed (ND) and relapsed/refractory (R/R) AML (Wierzbowska et al. 2008, Jaglal et al. 2014, Seiter et al. 2016). Venetoclax (Ven) with hypomethylating agents (HMA), approved for patients (pts) who are not candidates for intensive chemotherapy (IC), is increasingly being employed even for pts who are fit for IC. R/R disease remains a major cause of mortality in fit pts with AML, and thus improved IC regimen is an area of active research. Various combination of IC with Ven are ongoing with promising early findings (DiNardo et al. 2021, Reville et al. 2022). In this study, we examined the outcomes of AML patients treated with CLAG and/or mitoxantrone with Ven, CLAG(M)/Ven. Methods: This was a retrospective study of pts with AML who received CLAG(M)/Ven (Days 2-8) in 2022-2023. Clinical responses were reported using ELN 2022 criteria. Kaplan-Meier analyses were used to estimate overall survival (OS) from the date of CLAG(M)/Ven initiation. Results: This cohort of 19 pts (8M/11F with median age of 60 [23-74] at diagnosis) is comprised of 68.4% (13/19) R/R and 31.6% (6/19) ND AML who had prior MDS directed therapy. There were 57.9% (11/19) with secondary/therapy-related AML and when including de novo AML pts who had mutations highly specific for secondary AML ontogeny, it increased to 78.9% (15/19). Most of the pts (68.4%, 13/19) had adverse risk disease by ELN 2022. Common mutations being TP53 (26.3%, 5/19) followed by IDH1/2 (21.1%), ASXL1 (15.8%), and RUNX1 (15.8%). There were 36.8% (7/19) who had received allogeneic hematopoietic cell transplant (alloHCT) (Table 1). Similar number of pts received CLAG/Ven (47.5%) and CLAG-M/Ven (52.6%). Pts received on average 2.6 lines of treatment prior to CLAG(M)/Ven with 1 pt received 5 prior lines of treatment after AML diagnosis. Most of the pts, 78.9% (15/19), had prior HMA/Ven. The 30-day and 60-day morality was 5.3% (1/19) (disease status unknown at the time of death) and 26.3% (5/19) (disease status: 3 yes, 1 no, 1 unknown), respectively. Among these 5 early deaths within 60 days, 3 were ND AML that were heavily pretreated for prior MDS (average 3 lines of prior therapy) and 2 were R/R AML. All of them had prior HMA/Ven. Eighty percent (4/5) had adverse risk disease and received CLAG-M/Ven. Forty percent (2/5) had TP53 mutation. Objective response rate (ORR) of the entire cohort was 26.3% (5/19) (2 CR, 1 CRi, and 2 MLFS). Among those with evaluable response (n=10), ORR was 50%. Two CR/CRi pts achieved undetectable MRD by flow cytometry. MRD was not tested in the other 3 pts. Notably, ORR was higher in pts who received CLAG/Ven (44.4%, 4/9) compared to CLAG-M/Ven (10%, 1/10). No response in ND AML and 38.5% (5/13) ORR in R/R AML. Of the 47.4% (9/19) nonevaluable pts, 6 had aplastic marrow (2 died while getting induction, 2 transitioned to alloHCT, 1 moved onto next line of treatment, and 1 lost to follow up) and 3 had recovery marrow pending. For pts who achieved a response, 60% (3/5) underwent alloHCT (all of them alive without disease at data cutoff). The median time to count recovery was 42.5 days (27 days to never recovered). Prior HMA/Ven failure, high dose cytarabine failure, and mutations did not significantly impact response in this small cohort. The median OS from the time of CLAG(M)/Ven initiation was 5.5 months with a median follow up of 8.6 months (Figure 1). OS from the date of CLAG(M)/Ven was significantly shorter in pts with TP53 mutation vs. wild-type (2 vs. 11.2 months, p=0.031). Conclusions: Our findings showed the combination regimen CLAG(M)/Ven is feasible in pts with AML. It also provided better characterization in terms of early mortality and survivals in these pts, which can help inform future clinical trial design. ORR was similar to what was previously reported with CLAG(M); however, it is encouraging that those who achieved CR/CRi and had MRD testing also achieved MRD negativity. Outcomes of TP53-mutated subset is dismal suggesting IC-based approach in this setting is limited. Larger cohort and longer follow up is needed to confirm the impact of factors such as specific regimen, mutations, and prior therapies on outcomes.

Covalent Menin Inhibitor Bmf-219 in Patients with Relapsed or Refractory (R/R) Acute Leukemia (AL): Preliminary Phase 1 Data from the Covalent-101 Study

Background: Menin, a protein involved in transcriptional regulation, plays a role in the genesis of multiple cancers. Preclinical data from BMF-219, an investigational, highly selective, oral small-molecule inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling. BMF-219 is the first and only covalent menin inhibitor in clinical development and is being evaluated in multiple hematologic malignancies, solid tumors, and diabetes mellitus. COVALENT-101 (NCT05153330) is a Phase I dose-escalation and -expansion study of BMF-219 in R/R AL (Cohort 1), DLBCL (Cohort 2), MM (Cohort 3), and CLL (Cohort 4). Here we report preliminary safety, PK and anticancer activity data from Cohort 1 (AL). Methods: Doses of BMF-219 are escalated independently for each indication, initially in single-subject cohorts followed by a “3 + 3” design. Eligible patients (pts) include adults with R/R AL ineligible for standard therapy. Initially pts were enrolled agnostic to molecular status. A subsequent amendment introduced quotas for KMT2Ar (MLL1r), NPM1 and other known menin-dependent mutations: CEBP/A, MLL1-PTD, MN1, NUP98, NUP214, PICALM-AF10, SETBP1. Prior exposure to reversible menin inhibitor therapy is permitted. Subjects receive BMF-219 daily for continuous 28-day cycles until progression/intolerability. There are 2 parallel dose-escalation arms: pts not taking (Arm A) or taking (Arm B) moderate or strong CYP3A4 inhibitors. The study is ongoing and accruing in the escalation. Expansion cohorts will enroll pts to obtain further safety and efficacy data at the OBD/RP2D. Results: As of data cutoff of 7/24/2023, 26 pts with R/R AL (24 AML; 2 ALL) are enrolled; 7 remain on study treatment. Baseline characteristics include 17(65%) males and 9(35%) females with a median age of 57.5 years (range 33-84). There is a median of 4 (range 1-8) prior lines of therapy and 11 (42%) with prior HSCT(s). Six pts (23%) had KMT2Ar, 3 (12%) KMT2A-PTD, 4 (15%) NPM1, and 13 (50%) WT for KMT2A and NPM1. Dosing began with single-patient cohorts at 100 mg QD (Arm A) and 25 mg QD (Arm B) and has been escalated through 4 dose levels. Thus far, pts have been dosed up to 500 mg QD (Arm A) and 125 mg QD (Arm B). BMF-219 exposures were comparable between arms, with ~2-4-fold higher exposures observed with co-administration of a moderate or strong CYP3A4 inhibitor. At the highest dose (DL4) in which PK was evaluated, Arm A (500 mg QD) and Arm B (125 mg QD), pts on average achieved ~50% of target exposure (2000 ng*hr/mL) with some pts surpassing it. Higher QD dosing or corresponding BID dosing is expected to achieve desired exposure. BMF-219 has generally been well tolerated with no DLTs observed and no discontinuations due to treatment-related toxicities. No related QTc prolongation was observed. At the time of data cutoff, 23 of 26 pts were included in the safety population. Common TRAEs (≥10%) include vomiting 13% (3) and Differentiation Syndrome (DS) 13% (3). No Grade 5 TRAEs were reported. The only common Grade ≥3 TRAE (≥5%) was DS 13% (3). The efficacy evaluable population includes AML pts who meet the following criteria: dosed at or near predicted efficacious dose (500 mg or above [Arm A]; 125 mg or above [Arm B]), had known menin-dependent mutations, and completed at least one scheduled response assessment (or had a minimum of 7 doses if discontinued prematurely). Thus far, 2 of 5 efficacy evaluable patients achieved a complete remission (1 CR; 1 CRi) and both continue BMF-219 treatment. Patient A: 39/M, NUP98-NSD1, ECOG=0, 500 mg QD, Arm A, 4 prior lines of treatment including intensive chemotherapy and allo-HSCT. At C1D27, marrow blasts were reduced to 6% from 13% at study entry. The patient achieved CR at C2D28 with 0% blasts.Patient B: 70/F, NPM1m, ECOG=1, 125 mg QD, Arm B, 1 prior line of treatment with decitabine and an investigational agent. At C1D28, marrow blasts were reduced to 34% from 52% at study entry. The patient achieved CRi with 3% blasts at C2D28. Conclusion: BMF-219 is generally well tolerated with no DLT observed (and able to be taken with and without CYP3A4 inhibitors) with no pts discontinuing therapy due to toxicity. BMF-219 dose escalation is ongoing and approaching target exposure. BMF-219 demonstrates early signs of clinical activity in different genomic subgroups. The trial is ongoing and includes enrollment for pts diagnosed with AL, DLBCL, MM and CLL.

Efficacy and Safety of a Third Generation CD20 CAR-T (MB-106) for Treatment of Relapsed/Refractory Indolent B-Cell Non-Hodgkin Lymphoma: Phase-1 Results from a Multicenter Trial

Background: Indolent B-cell non-Hodgkin lymphomas (NHL) remain incurable despite multiple therapeutic options, including chemoimmunotherapy, targeted therapies, bispecific antibodies, and CD19-targeted chimeric antigen receptor T (CAR-T) cells. MB-106, a fully human 3 rd-generation CD20-targeted CAR-T product with both 4-1BB and CD28 costimulatory domains, had high overall response rate (100%) and complete response (CR) rate (91%) in follicular lymphoma (FL) patients at doses ≥ 3.3×10 6 cells/kg in a single institution trial (Shadman et al., 17-ICML, 2023). We seek to replicate the favorable efficacy and safety profile of MB-106 in a multicenter trial with centralized manufacturing. Methods: MB-106 is being evaluated in a Phase 1/2, open label, multicenter study utilizing a 3+3 dose-escalation design in R/R B-cell NHL patients with confirmed CD20 expression. Prior treatment with CD19-targeted CAR-T therapy is permitted. Following lymphodepletion (cyclophosphamide 300 mg/m 2/day and fludarabine 30 mg/m 2/day for 3 days), MB-106 is administered to patients with indolent B-cell NHL at one of two dose levels (DL): DL1, 3.3×10 6; and DL2, 1.0×10 7 cells/kg. MB-106 is infused in the outpatient setting if allowed by the institution, except for the first patient in each dose level cohort (overnight observation). Dose-limiting toxicities (DLT) are monitored through day 28. The treatment response is assessed on day 28 and on subsequent visits, and best overall response is reported here. CAR-T persistence is assessed by both flow cytometry and qPCR in peripheral blood mononuclear cells. Results: Three patients with indolent NHL (2 FL, 1 Waldenström macroglobulinemia [WM]) received MB-106 at DL1. In addition, one patient with hairy cell leukemia variant (HCL-v) received non-conforming material (drug product that failed to meet release criteria) at DL1, following FDA authorization. These four patients were heavily pre-treated with a median of 5.5 prior lines of treatment. High-risk features included progression of disease within 24 months of first-line treatment (POD24, n=1), prior autologous stem cell transplant (n=1) and prior CD19-targeted CAR-T therapy (n=1). No DLTs were observed at DL1. Three patients experienced Grade 1 cytokine release syndrome. There have been no occurrences of immune effector cell-associated neurotoxicity syndrome (ICANS). The 2 FL patients achieved CR by both PET-CT and bone marrow biopsy, one of whom had been previously treated with CD19-targeted CAR-T. The WM patient, who had nine prior treatments, including autologous stem cell transplant, and high disease burden, achieved very good partial response, with complete metabolic response by PET-CT, morphologic clearance of lymphoma in bone marrow, and resolution of the IgM paraprotein. The patient with HCL-v, who had been transfusion dependent, continues to have stable disease with decreased disease in the bone marrow, and achieved complete transfusion independence which is ongoing at 6 months. All patients displayed MB-106 expansion with peak levels between 7-14 days post-infusion. Persistence of CAR T-cells is ongoing at 6 months. Conclusion: Treatment with MB-106, a third generation CD20 targeting CAR-T, resulted in responses, including CRs, and CAR-T persistence in patients with R/R indolent NHL and was associated with favorable safety profile with no occurrence of Grade 3 or Grade 4 cytokine release syndrome and no ICANS of any grade. CRs have been observed in patients previously treated with CD19-targeted CAR-T in both this multicenter trial and the original single institution trial. Dosing is ongoing in the final dosing level (1.0×10 7 cells/kg) to establish the recommended Phase 2 dose for a planned pivotal trial in WM. It is anticipated that the complete data set from the Phase 1 indolent NHL arm will be presented.

Randomized Phase 3 Study of Pomalidomide Cyclophosphamide Dexamethasone (PCD) Versus Pomalidomide Dexamethasone (PD) in Relapse or Refractory Myeloma: An Asian Myeloma Network (AMN) Study

Introduction Patients with multiple myeloma (MM) who relapse or are refractory to (RRMM) lenalidomide and bortezomib have survival of less than 1 year. Pomalidomide (pom) is an immunomodulatory drug shown to improve survival in this group of patients 1. Optimal drugs to combine pom with are not known; patients tend to be triple class refractory by the time they require pom. We aim to compare pom, cyclophosphamide and dexamethasone (PCD) with pom and dexamethasone (PD) in Asian patients with RRMM 2. Methods This was a randomized, two arm, multicentre, multinational, prospective phase 3 study. RRMM patients with prior exposure to proteasome inhibitor (bortezomib, carfilzomib or ixazomib) and lenalidomide were recruited. Other inclusion criteria were: measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, satisfactory organ function (neutrophil count ≥ 1 000/mm 3, platelet ≥ 50 000/mm 3, bilirubin ≤ 1.5 x upper limit of the normal range (ULN), alanine aminotransferase and aspartate aminotransferase ≤ 3 x ULN and creatinine clearance ≥ 30ml/min). Patients with plasma cell leukaemia, > 6 lines of treatment or prior exposure to pom were excluded. Patients were randomized in a 1:1 ratio to receive PCD or PD. Dosing schedule was 4-weekly: pom 4mg day 1 - 21, dexamethasone 40mg twice a week and, for patients on PCD, cyclophosphamide 400mg weekly for 3 weeks. Patients received treatment until disease progression, unacceptable toxicity determined by treating physician, consent withdrawal or death. A modified intention-to-treat population was used for analysis, which included all randomized patients receiving at least 1 dose of study drug. Primary endpoint was progression free survival (PFS), defined as time from start of treatment to disease progression or death from any cause. Secondary endpoints were overall response rate (ORR, percentage of patients achieving partial response (PR) or better), overall survival (OS), duration of response (DOR, time from first evidence of PR or better till disease progression or death, whichever occurred first) and safety, assessed by frequency and percentage of adverse events by severity. PFS, OS and DOR were presented using Kaplan-Meier curves. Comparison between 2 arms was performed by Cox proportional hazard model for PFS, OS and DOR, using generalized linear model with binomial distribution for ORR. Results 124 patients were recruited, of whom 122 received at least 1 dose of study drug (62 PCD, 60 PD). Baseline characteristics were comparable between treatment arms (Table 1). Median age was 68.5 (range 47 - 88) years in the PCD arm; 67.2 (range 48 - 85) years in the PD arm. Patients in both arms received median of 3 (range 1-6) prior lines of treatment. At a median follow-up of 13.5 (IQR 8.7 - 24.0) months, median PFS was 10.9 months (95% CI, 7.1 - 27.7) in the PCD arm versus 5.8 months (95% CI, 4.4 - 6.9) in the PD arm (hazard ratio (HR) 0.43, 95% CI, 0.27-0.69); p < 0.001). ORR was 55.4% (95% CI, 41.0 - 69.7) in the PCD arm and 32.0% (95% CI, 19.5 - 44.5) in the PD arm; difference 23.3% (95% CI, 6.5 - 40.2, p = 0.007). Median DOR was 12.0 months (95% CI, 7.2 - not reached, NR) in the PCD arm and 5.7 months (95% CI, 3.7 - 9.7) in the PD arm (HR 0.41, 95% CI, 0.20 - 0.87). Although not statistically significant, median OS was numerically greater in the PCD arm (41.5 months, 95% CI, 24.5 - NR) in comparison with the PD arm (27.5 months, 95% CI, 27.5 - NR). Median treatment duration for pom was 7.8 (IQR 4.4 - 13.4) months in the PCD arm and 5.1 (IQR 2.8 - 8.7) months in the PD arm. Adverse events rates were similar in both arms. 51 patients (82.3%) in the PCD arm had 346 treatment emergent adverse events (TEAEs); 164 (47.4%) relating to study treatment. 49 patients (81.7%) in the PD arm had 241 TEAEs; 136 (56.4%) relating to study treatment. Most common grade 3/4 TEAEs in both arms were neutropaenia, anaemia and pneumonia. 34 deaths occurred during the study (17 PCD, 17 PD), 12 (35.2%) were due to disease progression. 3 (1 PCD, 2 PD) were deemed to be related to study treatment (2 infections, 1 fluid overload). Conclusion This study demonstrated that PCD significantly prolonged PFS, improved ORR, and DOR over PD in patients with RRMM and previous exposure to a proteasome inhibitor and lenalidomide. PCD treatment presents a therapeutic option in this population of patients, with acceptable and manageable safety profile.

In Vivo Anti-BCMA CAR T-Cell Expansion Kinetics Correlate with Early IMWG Response in RRMM: A Single Institution Study with Comparative Analysis of Idecabtagene Vicleucel and Ciltacabtagene Autoleucel

Introduction: The most recent breakthrough in the treatment of relapsed/refractory MM (RRMM) is chimeric antigen receptor (CAR) T-cell (CAR T) therapy which led to high overall response rates with acceptable toxicity. Here we present our single-institution experience with MM-specific CAR T performing a comparative analysis of clinical data and expansion kinetics after infusion of two commercially available myeloma CAR-T products. Methods: Out of 76 RRMM patients treated with CAR T, 23 patients provided consent, enrolled, apheresed and treated with commercial CAR-T between 6/20/2022 and 4/24/2023. Majority of patients had relapsed and multi-refractory MM. 11 patients received idecabtagene (idecel) and 12 received ciltacabtagene (ciltacel). Manufacturing slot availability was the primary deterministic factor for CAR T-type assignment. Study was IRB approved and informed consent was obtained to collect blood and clinical data. Blood samples were obtained at apheresis, pre-lymphodepleting (LD) chemotherapy, and on days 0, +7, +14, +21, +28 and +3 months post CAR T-cell infusion. PBMCs were generated from whole blood using density gradient centrifugation and were stained using BCMA or control CAR detection reagents and monoclonal antibodies against T-cell surface antigens. Samples were analyzed using MacsQuant-10 flow cytometer, gating on CD3+ and CAR+ cells. Fisher's Exact Test and Pearson Chi-Square tests were used for assessment of categorical variables whereas Independent-Samples Median Test was employed for non-categorical variables. Mann-Whitney U test was used for CAR T cell expansion analyses at individual timepoints. Results: As of July 10, 2023, 23 commercial patients were enrolled. Baseline clinical characteristics were comparable between the idecel and ciltacel cohorts with regard to age (median 66, p=0.827), prior lines of treatment, ASCT history (Table 1). Two patients in each cohort were penta-refractory. Three patients in each cohort had EMD (27.3%). There was balanced distribution of del 17p and t(4;14) across cohorts (p=1.000, p=0.175). Each cohort had 1 RISS-3 patient (p=0.476). Seven patients (30.4%) were previously treated with belantamab. Pre-apheresis and pre-LD absolute lymphocyte count (ALC) were comparable across cohorts. (Table 1). There were no G3 CRS events whereas G1/2 CRS events were not statistically significant between cohorts (p=0.256). Three G3 ICANS were observed, 2 in idecel and 1 in ciltacel cohorts (18.2% and 8.3%). Distribution of all-grade ICANS across cohorts were not statistically significant (p=0.676). Post-CAR T ferritin max correlated with the baseline b2m (p<0.001) and tocilizumab dose number (p=0.009) but none correlated with peak CAR T expansion (p=0.315). Responses were assessed by IMWG criteria at months 1,3,6,9 for efficacy-evaluable patients at that timepoint (n=19,14,8 and 2 in grand cohort (82.6%, 60.9%, 34.8% and 8.7%)). Global cohort ORR was 78.3% (n=18) and 60.9% (n=14) at days 30 and 90 respectively. +1 month IMWG responses were comparable with 72.7% (8/11) in idecel and 83.3% (10/12) in ciltacel cohort (p=0.625). Similarly, there was no statistically significant ORR difference between cohorts at 3, 6, and 9 months. Two-way ANOVA revealed a trend towards an effect of treatment type on CAR-T expansion (p=0.0595) (Figure 1A). Time-to-peak analysis reached statistical significance (p=0.0127) between two products (Figure 1B). Despite its delayed peak, ciltacel had significantly higher magnitude of expansion (p=0.043) (Figure 1C). Peak CAR-T expansion was associated with clinical responses across cohorts at +1 (p=0.034) and +3 months (p=0.050) but not at +6 months (p=0.449). Day +30 responses were indicative of Day +90 and Day +180 responses (p<0.001, p=0.011). Conclusions: In our single-center study of comparative analysis of commercial BCMA targeting CAR T-cell treatments, peak CAR T-cell expansion showed a positive correlation with +1 and +3 month post-CAR-T clinical responses. Despite the delayed peak expansion with ciltacel, the expansion was more robust with a higher level of circulating CAR T-cells. Baseline ALC or fludarabine dose reduction did not have an impact on overall CAR T expansion in combined cohort. Studies are underway at our institution investigating anti-BCMA CAR T cell responses in more detail and larger numbers of patients and functional studies will be further presented.

A Matching-Adjusted Indirect Comparison of the Efficacy of Elranatamab and Teclistamab in Patients with Triple-Class Exposed/Refractory Multiple Myeloma

BACKGROUND Elranatamab, a novel B-cell maturation antigen (BCMA)- and CD3-directed bispecific antibody, recently demonstrated efficacy and safety in patients with triple-class exposed/refractory multiple myeloma (TCE/R MM) in the phase 2, single-arm MagnetisMM-3 trial (NCT04649359). Teclistamab (TEC) is a BCMA-CD3 directed bispecific antibody which was recently approved in the US for patients with TCE/R MM who received 4+ prior lines of treatment, based on response rates in the MajecTEC-1 trial (NCT04557098). In the absence of comparative trials of elranatamab and TEC, an unanchored matching-adjusted indirect comparison (MAIC) was conducted to assess their relative efficacy. METHODS Individual patient data (IPD) from the 14.7 month follow- up of MagnetisMM-3 Cohort A (BCMA-naïve, N = 123), were reweighted to match published summary data from ~23 month follow-up in MajesTEC-1 (N=165) in Sidana et al (2023). Overall, the inclusion and exclusion criteria of the trials were similar; however, MajesTEC-1 excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status >1; therefore, patients with ECOG 2 in the MagnetisMM-3 trial were removed from the analysis (resulting N=116). To adjust for cross-trial differences, patients from MagnetisMM-3 were reweighted to match the baseline characteristics of the TEC trial patients. Weights were determined using a propensity score-type logistic regression via the method of moments (Signorovitch et al. 2012) based on age, median time since diagnosis, International Staging System disease stage, high-risk cytogenetics, extramedullary disease, number of prior lines of therapy, ECOG performance status, and penta-exposed and penta-refractory status. In the analysis for the overall survival (OS) endpoint, sex was also included. The adjusted variables were obtained based on univariate Cox regressions using the MagnetisMM-3 IPD, a systematic literature review of prognostic variables and effect modifiers in relapsed or refractory MM, a review of the prognostic variables identified in clinical studies for TCE/R MM, and a review of the recent relevant indirect comparisons, and were confirmed by clinical experts. A sensitivity analysis was conducted in which missing values of the adjusted baseline characteristics for elranatamab were imputed by a random sample of the observations in MagnetisMM-3 to potentially increase the effective sample size (ESS). Unanchored MAIC analyses were conducted in R studio following the code provided in the National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) 18 by Phillippo et al (2016). The efficacy outcomes included objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and OS. Kaplan-Meier curves of DoR, PFS, and OS from MajesTEC-1 were digitized according to Guyot et al (2012). Results were reported as rate difference (i.e., the difference between the ORR of elranatamab and TEC) and odds ratios (ORs) for binary endpoints or hazard ratios (HRs) for time-to-event endpoints, with 95% confidence intervals (CIs). RESULTS After adjustment in the MAIC, the selected key baseline characteristics were comparable between elranatamab and TEC. For all endpoints except OS, the post-matching ESS for elranatamab was 75 in the base case and 89 in the sensitivity analysis. For OS, the ESSs were 73 and 87 for the base case and scenario analyses, respectively. Compared with TEC, elranatamab was associated with significantly better ORR (rate difference: 12.30; 95% CI: 0.70-23.90; OR: 1.79; 95% CI: 1.01-3.19) and PFS (HR 0.59; 95% CI 0.39-0.89). Patients treated with elranatamab had numerically better DoR (HR: 0.64; 95% CI: 0.33-1.23) and OS (HR: 0.66; 95% CI: 0.42-1.03) compared to those who received TEC (Table 1 and 2). Results in the sensitivity analysis were consistent with the base case. CONCLUSIONS In this MAIC, elranatamab demonstrated significantly better ORR and PFS than TEC, and numerically better DOR and OS in both the base case and the sensitivity analysis. These results suggest that elranatamab is an effective option for treating patients with TCE/R MM.

Immunohistochemical Tumor Expression Predicts Response to CD3xCD20 Bispecific Antibodies in Patients with Relapsed/Refractory B Cell Lymphoma

Introduction Several studies show that CD3xCD20 bispecific antibodies show promising results in relapsed or refractory B-cell lymphomas and may have a milder adverse effect profile compared to chimeric antigen receptor T cell therapy (CAR-T). Tumor loss of antibody target (i.e. CD19 or PD1) have shown to negatively affect treatment outcomes in CD19-CAR-T cell therapy in DLBCL, and anti-PD1 therapy in Hodgkin lymphoma. It has, to our knowledge, not been reported how loss of CD20 expression and other immunohistochemical (IHC) expression patterns affects treatment outcomes in patients treated with CD3xCD20 antibodies. Methods We collected data on all patients in Denmark who received CD3xCD20 bispecific antibodies from 2017 to 2023. Electronic health records were assessed for general baseline characteristics and response according to Lugano criteria. Pathology reports on pre- and post-CD3xCD20 therapy lymphoma samples were collected and assessed on IHC analysis of CD20, Ki67, CD10, Bcl2, Bcl6, MUM1, germinal center B-cell (GCB) subtype and non-germinal center B-cell subtypes (non-GCB) according to Hans algorithm, as well as reports on cytogenetic FISH analysis regarding MYC with BCL2 and/or BCL6 rearrangements. To determine whether an expression was weak, negative, or strong the assessment of the original pathology reports was used. Results Pre-treatment IHC assessments were available in 122 patients. These were distributed across 81 patients with DLBCL, 32 with FL and 9 with other lymphoid neoplasms (MZL, HL, CLL). Of these, 109 had a strong CD20 expression, 10 had a weak CD20 expression, while 3 had no expression of CD20. Patients with a weak CD20 expression before treatment had an overall survival (OS) rate after 12 months at 40% (95% CI, 9.5-70) compared to 69% in patients with strong CD20 expression (95% CI, 45-61) (Figure 1, p=0.08). In a univariable Cox regression, we found that negative CD20 expression and higher Ki67 was significantly associated with inferior OS (Table 1, respectively HR=2.11 and HR=1.02 (per %-change in Ki67)). Worse performance status and a higher number of previous lines of treatment were also significantly associated with inferior overall survival (respectively HR=1.85 and HR=1.20). Surprisingly, BCL6 rearrangement was significantly associated with superior OS (HR=0.46). In a multivariable cox regression using OS as the endpoint, weak and negative IHC expression of CD20 was significantly associated with inferior OS (respectively HR=3.29, 95% CI 1.32-8.23, p=0.011 and HR=6.79 95% CI 1.25-36.76, p=0.026). Positive BCL6 compared to negative was associated with increased OS (HR =0.48, 95% CI 0.24 - 0.94, p=0.032). Analyzing only patients with DLBCL (n=81), weak and negative IHC expression of CD20 were the only factors to remain significantly associated with inferior overall survival (respectively HR=3.01, 95% CI 1.10-8.28, p=0.032 and HR=7.26, 95% CI 1.35-43.35, p=0.026). BCL6 rearrangement was associated with an increased overall survival, however only borderline statistically significant (HR=0.53, 95% CI 0.26-1.08, p=0.082). With regards to treatment response weak CD20 expression, worse performance status, higher Ki67 and a higher number of prior lines of treatment was in univariable analysis significantly associated with not being in a complete remission (CR) (respectively HR=2.28, HR=1.73, HR=1.01(per %-change in Ki67), HR=1.23 (per prior line of treatment). In a multivariable cox regression only weak and negative CD20 expression remained significantly associated with not being in CR (respectively HR=2.40, 95% CI 1.1-5.25, p=0.028 and HR=5.7 95% CI 1.14-28.58, p=0.034). Of the 48 patients who had biopsy-confirmed relapse, 29 had a weak or negative IHC CD20 expression (24 with a negative expression and 5 with a weak expression). Of these 29 patients, 24 had a strong pre-treatment IHC CD20 expression. Conclusions To our knowledge, we here present the first long-term analysis of the prognostic effect of tumor immunohistochemistry properties in patients treated with CD3xCD20 bispecific antibodies. We find that CD20 expression before treatment is an important prognostic factor, as patients with lymphomas with weak CD20 expression yield significantly poorer responses and decreased overall survival. Additionally, we find that BCL6 rearrangement is associated with superior overall survival in patients treated with CD3XCD20 bispecific antibodies.

A Phase 2 Study of Daratumumab in Combination with Thalidomide and Dexamethasone in Relapsed and / or Refractory Myeloma: A Report from the Asian Myeloma Network

Introduction Myeloma is a plasma cell dyscrasia characterised by a relapsing remitting course. Patients with relapsed / refractory myeloma (RRMM) with prior exposure to proteosome inhibitor and an immunomodulatory agent have a poor prognosis. In the last few years, CD38 antibodies such as daratumumab and isatuximab have revolutionised the treatment of multiple myeloma. They appear synergistic with immunomodulatory drugs; triplet combinations with lenalidomide 1 (DRd) or pomalidomide 2 (DPd) and dexamethasone have been approved for treatment of RRMM. However, patients face high out-of-pocket costs when attempting to access these drugs. There is hence a pressing need to develop combinations which harness the therapeutic potential of CD38 antibodies while preserving synergistic action of triplet combinations. Methods This was a multi-national, multi-centre, single arm, phase 2 trial of daratumumab in combination with thalidomide and dexamethasone. Patients with myeloma diagnosed according to the International Myeloma Working Group criteria with measurable disease and relapsing after / refractory to at least one prior line of treatment were eligible for enrolment. Satisfactory organ function (neutrophil count ≥ 1,000/mm 3, platelet ≥ 50,000/mm 3, bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN and creatinine clearance ≥ 30ml/min) were pre-requisites for inclusion. Patients with plasma cell leukaemia and those with prior CD38 antibody exposure were excluded. Patients received daratumumab IV 16mg/kg weekly for weeks 1 - 8, every 2 weeks from weeks 9 - 24 and every 4 weeks from week 25 onwards, thalidomide 100mg daily and dexamethasone 20mg twice a week. Treatment was continued for as long as tolerated and clinically indicated, based on physician assessment, or until disease progression. Thromboprophylaxis was allowed but not mandated. The primary outcome measure was progression-free survival (PFS), defined as the time from commencement of treatment to disease progression or death from any cause, whichever occurred first. Secondary outcome measures included overall response rate (ORR, the percentage of patients achieving a partial response (PR) or better), overall survival (OS), duration of response (DOR, the time from first evidence of PR or better till disease progression or death, whichever occurred first) and safety, assessed by the frequency and severity of adverse events. Results 70 patients were recruited. The median age was 66.8 (range 39 - 81) years with 62.7% males. 95.5% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The median number of prior therapies was 2 (range 1 - 6). 91% of patients had prior exposure to bortezomib, while 88% had prior exposure to thalidomide, lenalidomide or both. 50.7% had a prior autologous stem cell transplant. 67 patients completed at least one cycle of treatment. Two died prior to completion of the first cycle, while one withdrew consent and was excluded. Patients were treated for a median of 15.9 (interquartile range, IQR 5.1 - 23) months. 67 (95.7%) patients suffered 544 adverse events, of which 256 (47%) were related to the study treatment, 103 (19%) grades 3-4 and 8 (1%) were fatal. The most common adverse event was infection, which occurred in 26 patients; 4 were fatal. 27 patients had peripheral neuropathy, 25 of which were grade 1 - 2. 14 patients had an infusion reaction, 3 of which required hospitalisation. One patient had a deep vein thrombosis. At a median follow-up of 22.0 (IQR, 9.9 - 31.0) months, the median PFS was 16.3 (95% CI, 12.8 - 24.6) months (Figure 1). The median OS was 32.5 (95% CI, 25.4 - not reached) months. The ORR was 82.1% (95% CI, 70.8 - 90.4). This ORR was comparable to DRd and DPd (Table 2). Of these, 43 (78%) of patients achieved a very good partial response (VGPR) or better, with 9 (16%) of patients achieving a stringent complete response (sCR). The median DOR was 19.3 (95% CI, 12.2 - 36.5) months. Conclusion The combination of daratumumab, thalidomide and dexamethasone is effective in RRMM patients. Thalidomide and dexamethasone are cost-effective drugs which can improve the accessibility of daratumumab-based triplet combinations.

1-Year Data Analysis from a Cancer Center Molecular Tumor Board Dedicated to Clonal Hematopoiesis

Background Nearly 25% of cancer patients harbor clonal hematopoiesis of indeterminate potential (CHIP). Detection of clonal hematopoiesis (CH) in routine clinical practice is increasing due to incidental findings during sequencing analysis of circulating cell-free DNA (cfDNA) or exploration of unexplained cytopenia. To improve clinical management of these patients in our institution, we set up a multidisciplinary molecular tumor board (MTB) dedicated to patient cases with CH, CHIP, and clonal cytopenia of undetermined significance (CCUS) in 2022. Methods Between June 2022 and June 2023, our MTB reviewed a total of 345 cases, of which 212 referred by the solid tumor MTB and 133 referred by hematologists. The former 212 cases with CH were identified through cfDNA sequencing (FoundationOne Liquid CDx) within the Gustave Roussy Cancer Profiling study (NCT04932525), which includes some genes recurrently mutated in hematologic malignancies ( ASXL1, DNMT3A, IDH1, IDH2, JAK2, MPL, MYD88, SF3B1, TET2, U2AF1). A variant allele frequency (VAF) of at least 10% for the CH mutation was required to refer cases to the MTB, except for JAK2, MPL, and MYD88 mutations. The latter 133 cases were screened for CH mutations on peripheral blood leukocytes using a next-generation sequencing (NGS) assay targeting 174 genes recurrently mutated in hematologic malignancies. In addition to molecular data, standard clinical and biological parameters were recorded for each individual case. Results Patients referred by the solid tumor MTB In this cohort of 212 patients, median age was 72 years old (range, 48-91), sex ratio (M/F) was 1.4, median prior anticancer treatment lines was 2 (0-9), and time between MTB and cancer diagnosis was 2.3 years (0.2-34). The most frequent tumor types were lung (23%), colorectal (20%), prostate (19%), gynecological (12%) and breast (9%) cancers. The most frequently mutated genes were DNMT3A (59%), TET2 (30%), ASXL1 (24.5%), JAK2 (23%), SF3B1 (7.5%), and MYD88 (6%), with a median VAF of 4.2%, 3.0%, 8.5%, 1.0%, 5.0%, and 0.20%, respectively. Fifty percent of patients harbored more than 1 mutation. Six patients had a known history of myeloproliferative neoplasm (MPN). The proportion of cases with CH, CHIP, and CCUS was 15%, 59%, and 17%, respectively. The CH risk score of myeloid malignancy (CHRS, Weeks et al.) could be calculated in 126 cases but may underestimate risk due to the limited gene list considered, and revealed 69 (55%) low-risk, 52 (41%) intermediate-risk, and 5 (4%) high-risk patients. Our MTB recommended hematologic consultation for additional investigations in 58 patients, of which 22 were actually referred (main reason for not referring patients was advanced cancer disease). Four patients were diagnosed with hematologic malignancy (1 MPN, 1 chronic myeloid leukemia, 2 myelodysplastic syndromes [MDS]). Patients referred by a hematologist In this cohort of 133 patients, median age was 69 years old (53-89), and sex ratio (M/F) was 0.6. Eighty-six percent of patients had a cancer history, median prior anticancer treatment lines was 2 (0-7), time between MTB and cancer diagnosis was 3.5 years (0.2-34). The most frequent tumor types were lymphoid disorders (39%), breast cancer (15%), and gynecological cancer (15%). The proportion of CH, CHIP, and CCUS was 11%, 33%, and 41%, respectively. The most frequently mutated genes were DNMT3A (48,5%), PPM1D (24%), TET2 (22%), TP53 (17%), ASXL1 (6%), JAK2 (4.5%) and CHEK2 (4.5%), with a VAF of 2.5%, 2,3%, 4.0%, 2.0%, 8.0%, 1.0%, and 2.5%, respectively. Sixty percent of patients harbored more than 1 mutation. The CHRS could be calculated in 98 cases and revealed 34% low-risk, 50% intermediate-risk, and 16% high-risk CH patients. No need for a specific follow-up was recommended by the MTB in 33 patients. Among the 85 patients with hematologic follow-up, 3 (for which the CHRS was intermediate in 2 cases and high in 1 at the time of MTB evaluation) rapidly progressed to a myeloid malignancy ( Figure 1) (2 MDS and 1 MDS/MPN). Conclusions Our study highlights the utility of a MTB dedicated to CH, CHIP and CCUS for the identification of high-risk patients, early detection of hematologic malignancies, and appropriate therapeutic management. Long-term follow-up is needed to validate the CHRS but the design of a specific score for patients with cancer may be helpful due to the specific features of this population (high prevalence of PPM1D mutations, post-treatment cytopenia).

Efficacy and Safety of Asciminib in Chinese Patients with Philadelphia Chromosome(Ph)-Positive Leukaemias

Background Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) tyrosine kinase inhibitor (TKI). Its efficacy and safety profile in patients with chronic-phase chronic myeloid leukaemia (CML) have been shown in the Phase 3 ASCEMBL study, comparing asciminib 40 mg twice daily versus bosutinib 500 mg once daily. However, asciminib use in Chinese patients has hitherto not been reported. Moreover, the safety of high-dose asciminib (≥150 mg twice daily) in the Asian population is yet to be addressed. Here we present the real-world clinical outcomes of Chinese patients with Ph+ leukaemias in Hong Kong who received asciminib through a Managed Access Program (MAP). Methods Queen Mary Hospital (QMH) is a university-affiliated tertiary hospital in Hong Kong. Patients with Ph+ leukaemias under the care of QMH for whom asciminib was requested through MAP were included. Details on patient demographics, disease history, prior treatment lines, asciminib usage, adverse events, efficacy and death were collected. Results At data cut-off for analysis on 30 June 2023, 13 patients for whom asciminib was approved had data available. One patient passed away before the commencement of asciminib, and thus was excluded (Table 1). There were 7 patients with CML, who on diagnosis were all in chronic phase at a median age of 53 (22-70) years. All had received imatinib and at least one newer generation TKI, with 5 patients (71%) having received ponatinib. The majority (5 patients, 71%) received asciminib because of lack of efficacy of prior treatment, with 4 patients also having the T315I mutation. The median age at asciminib treatment (median dose: 400 mg, 80-400 mg) was 64 (28-76) years, with a median time from diagnosis of 81 (13-314) months. Two patients received imatinib concomitantly. The median duration of treatment was 12 (6-38) months. Two patients were already in at least major molecular response (MMR) before treatment, and have maintained that response. Two patients had ≥ 1-log reduction of BCR::ABL1 transcript level. Three patients had stable disease. There was one death unrelated to CML (Figure 1). There were 5 patients with Ph-positive acute lymphoblastic leukaemia (ALL), at a median age of 57 (18-68) years at diagnosis. All had received prior chemotherapy in combination with a TKI (imatinib, N=3; dasatinib, N=5; ponatinib, N=5), with 3 patients having undergone allogeneic haematopoietic stem cell transplantation (allo-HSCT). Three patients had detectable kinase domain mutation (T315I, N=2; E255K + E459K, N=1). The majority (3 patients, 60%) received asciminib because of lack of efficacy of prior treatment. The median age at asciminib treatment (median dose: 240 mg, 80-400 mg) was 58 (19-72) years, with a median time from diagnosis of 22 (7-47) months. The median duration of treatment was 16 (2-19) months. Four patients received another ATP-competitive TKI concomitantly (imatinib, N=1; dasatinib, N=1; ponatinib, N=2). For patients receiving asciminib due to prior treatment failure (N=3), complete molecular response (CMR) was achieved in 2 patients with measurable residual BCR:: ABL1; 1 patient with frank leukaemia achieved complete remission with incomplete hematologic recovery with molecular response at 0.06%. For two patients receiving asciminib because of intolerance to prior treatment, one further improved from MR4 to CMR while pre-existing CMR was maintained in the other patient. There were 3 deaths; 2 due to COVID-19 and 1 due to refractory leukaemia (Figure 1). Asciminib showed an acceptable safety profile, with raised lipase leading to dose reduction only in 1 patient. Grade 3 or above toxicities were all haematological, observed in 5 patients, 2 of whom had previous allo-HSCT. One patient on asciminib-ponatinib treatment developed grade 2 renal impairment. Conclusion Asciminib demonstrated promising clinical efficacy with satisfactory tolerance in this cohort of Ph+ leukaemias failing multiple lines of therapy. Further investigation of its therapeutic role in Ph+ ALL is warranted.

Real-World Clinical Outcomes in Patients with Relapse and Refractory Multiple Myeloma Received VTD-PACE Treatment in the Era of Monoclonal Antibody

The treatment outcomes of multiple myeloma (MM) have drastically improved with the use of novel agents, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies. However, ultimately, the disease relapses and results in a fatal outcome. Even in cases of relapse, treatment outcomes have improved with the use of novel agents. However, in situations where novel agents have been exhausted or when the disease rapidly progresses, bortezomib (Velcade), thalidomide, dexamethasone, platinum (cisplatin), adriamycin (doxorubicin), cyclophosphamide, and etoposide (VTD-PACE) is frequently utilized, with reported effectiveness. However, its outcomes in the era of monoclonal antibodies remain unclear. Therefore, this retrospective cohort study assessed the clinical outcomes of 60 patients with RRMM (median four prior treatment lines) administered VTD-PACE at the Japanese Red Cross Medical Center between June 2016 and April 2023. The characteristics of the 60 patients are shown in Table 1. The VTD-PACE regimen consisted of 1 mg/m 2 of bortezomib on days 1, 4, 8, and 11 administered subcutaneously; 200 mg of thalidomide administered orally on days 1-4; 40 mg of dexamethasone administered orally on days 1-4; and a 4-day continuous intravenous infusion of 10 mg/m 2 cisplatin, 40 mg/m 2 cyclophosphamide, 40 mg/m 2 etoposide, and 10 mg/m 2 doxorubicin. The cisplatin dose was adjusted based on renal function, as determined by the treating physician. The responses were evaluated according to the International Myeloma Working Group response criteria. High-risk cytogenetic abnormalities (HRCA) included del (17p), t(4;14), and t(14;16). Double-class refractory disease was defined as refractoriness to PIs and IMiDs, whereas triple-class refractory disease was defined as refractoriness to PIs, IMIDs, and anti-CD38 monoclonal antibodies. Penta-drug refractory disease was defined as refractoriness to bortezomib, carfilzomib, lenalidomide, pomalidomide, and anti-CD38 antibodies. The median follow-up period was 11.1 months (range, 0.5-72.0 months), during which they received a median of two cycles of VTD-PACE. The overall response (ORR), stringent complete response, complete response, and very good partial response rates were 66.7% (40 patients), 13.3% (8 patients), 5% (3 patients), and 20% (12 patients), respectively. The results of univariate analysis for factors associated with response rate are shown in Table 2. The ORRs in patients with ≥4 and ≤3 prior lines were 53.1% and 82.1%, respectively ( P = 0.027). Extramedullary disease (EMD), refractoriness to anti-CD38 antibody, HRCA, and triple-class/penta-drug refractory disease did not significantly reduce the ORR. The median overall survival (OS) was 17 months with a median progression-free survival (PFS) of 9.8 months. The median PFS in patients with and without receiving hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell therapy (CART) following VTD-PACE were 9.8 and 5.1 months, respectively ( P = 0.023). The median OS in patients with and without renal dysfunction were 10.7 months and 21.5 months, respectively ( P = 0.0091). A trend for longer OS was observed in patients with HSCT or CART following VTD-PACE (P = 0.18). Therefore, VTD-PACE is useful as a bridging therapy for HSCT or CART, as a response is expected regardless of organ damage, disease risk, or history of anti-CD38 antibody use. However, the response rate decreased in late lines; therefore, its use in early lines is recommended.

Early Prediction of Treatment Response By Circulating Tumor DNA Profiling in Patients with Diffuse Large B-Cell Lymphoma Receiving CAR T-Cell Therapy

Introduction Patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) are characterized by a particularly poor prognosis. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has improved outcomes of patients with r/r DLBCL, yet a substantial proportion of patients still experiences relapse or progression after CAR T-cell treatment. Identifying patients at high risk of CAR T-cell therapy resistance or future lymphoma progression remains challenging. Here, we explored the value of circulating tumor DNA (ctDNA) as a prognostic biomarker at baseline and early into treatment in DLBCL patients undergoing standard-of-care CAR T-cell therapy, without the need for matched tumor genotypes. We further investigated associations between ctDNA and other known clinical risk factors. Methods We applied targeted next-generation sequencing (NGS) to a total of 53 samples from r/r DLBCL patients receiving CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel, n=16) at the University Medical Center Freiburg (Germany), using a modified version of the AVENIO ctDNA analysis workflow (Roche; Research Use Only) that covered ~314kb and targeted 466 distinct genes recurrently mutated in DLBCL (based on the CAPP-Seq workflow, Kurtz DM et al. J Clin Oncol 2018). Tumor genotypes were assessed noninvasively from plasma samples obtained at baseline before lymphodepletion with matched germline controls. Concentrations of ctDNA were quantified at baseline and early after CAR T-cell therapy at day 7-10. Initial treatment response was assessed by conventional PET-CT obtained 4-6 weeks after treatment based on the Lugano criteria. Results At baseline prior to lymphodepletion, we detected somatic mutations in 100% of plasma samples by noninvasive genotyping, with a median of 19.5 mutations per patient (range: 3-97). The most frequently mutated genes were IGHV, IGLL5, BCL2, MYC, BTG1, CREBBP, and TP53. Patients with high baseline ctDNA concentrations (mean allele frequency [AF] >= 1%) showed shorter progression-free survivial (PFS) and overall survival (OS) than patients with ctDNA levels below this threshold (median PFS: 86.5 days vs. not reached, p=0.04, HR: 6.3, 95% CI: 1.7-23.6; median OS: 219 days vs. not reached, p=0.048, HR: 4.1, 95% CI 1.0-16.6, Figure 1). Pretreatment ctDNA levels were significantly correlated with LDH concentrations ( p=0.049, r=0.5). We further found significantly higher ctDNA concentrations in patients with transformed DLBCL (vs. non-transformed, p=0.008) and in those with 3 or more prior treatment lines (vs. 1-2, p=0.04). At day 7-10 after CAR T-cell therapy, ctDNA levels dropped a median of 10-fold compared to the pretreatment time point ( p=0.008). Patients achieving a complete (CMR) or partial metabolic response (PMR) by PET-CT after 4-6 weeks showed a significant decrease of ctDNA ( p=0.001), while those with a stable (SD) or progressive disease (PD) had no significant ctDNA reduction at day 7-10 after CAR T-cell infusion. Vice versa, while 100% of patients with a >1.5-log-fold drop of ctDNA level between the pretreatment and interim time point revealed a CMR or PMR in early PET-CT scans, only 62% of patients with a smaller ctDNA decline responded to treatment according to PET-CT. Conclusions Our data suggests, together with previously published studies (Sworder BJ et al., Cancer Cell, 2023; Frank MJ et al. J Clin Oncol, 2021), that ctDNA profiling may allow robust noninvasive genotyping, accurate risk-stratification, and early prediction of clinical outcomes in r/r DLBCL patients undergoing CAR T-cell therapy. Although limited by small sample size, this pilot study highlights a potential future role of ctDNA measurements for personalized treatment selection and guidance in clinical trials.

Efficacy of CD19-Directed CAR T Cell Therapy in Patients with Primary or Secondary CNS Lymphoma - an Analysis of the EBMT Lymphoma WP and the Gocart Coalition

Introduction: The prognosis of patients (pts) with relapsed or refractory (r/r) large B cell lymphoma (LBCL) and central nervous system (CNS) involvement is dismal. Standard treatment for pts with r/r LBCL are anti-CD19 chimeric antigen receptor T-cells (CART). Several reports with limited numbers of patients suggest that CART might also be an effective treatment for pts with CNS lymphoma. This EBMT registry study aimed at compiling data to investigate the potential of CART in pts with primary (PCNSL) or secondary CNS lymphoma (SCNCL). Methods: Centers contributing to the EBMT database were asked for cases of PCNSL and SCNSL, treated with CART between 01/ 2018 and 07/ 2022. Reported pts were identified in the database, patient characteristics and pre-treatment retrieved, and major clinical endpoints analyzed. To calculate overall survival (OS) and progression-free survival (PFS) from date of CART infusion Kaplan Meier estimates were used, whereas cumulative incidence was used for relapse incidence (RI) and non-relapse mortality (NRM). Results: 88 pts with PCNSL (n=10) or SCNSL (n=78) with complete information on major endpoints were analyzed. Median follow-up was 20.3 months [95% CI: 16-27]. Median age was 63 years (range 31-80), 52 pts (59%) were male. ECOG was ≥ 2 in 19 of 86 pts (22%). 41 of 65 pts (63%) had undergone ≥3 prior treatment lines, 56 of 82 pts (68%) were refractory to at least one previous line of chemotherapy. 29 of 86 pts (34%) had received autologous stem-cell transplantation (ASCT). Of 84 patients 68% were not in remission at time of CART, 8% were in complete remission (CR) and 24% in partial remission (PR). Information on disease status was missing for four patients. 49 pts were treated with axicabtagene ciloleucel, 39 pts received tisagenlecleucel. OS- and PFS-rates at 24 months were 47% [95% CI: 37-61] and 32% [CI: 23-45] for the whole cohort (figure 1). RI at 24 months was 58% [CI: 47-68], NRM 10% [CI: 4-19]. OS and PFS for pts in CR/PR were 58% [CI 40-85] and 51% [CI: 33-77]. For 57 pts not in remission at CART infusion OS and PFS were 42% [CI: 30-59] and 24% [CI: 14-39], respectively. Conclusion: With a 47% OS rate at 24 months CART seem to be a very effective therapeutic option in heavily pre-treated r/r LBCL with CNS manifestation. These results compare favorably with those reported for conventional treatment including pts treated with ASCT. Indeed, these results are similar to those reported by real-world analyses of CART in LBCL without CNS manifestation (Bethge et al., 2021, Le Gouill et al., 2021). Based on these promising early results, we consider treatment with CART for pts with CNS involvement and r/r LBCL as the preferred treatment option.

Predicting the Clinical Course of Treatment with Midostaurin in Patients with Advanced Systemic Mastocytosis

Introduction: Advanced systemic mastocytosis (AdvSM) is characterized by presence of the KIT D816V mutation and variably other somatic mutations in the mast cell but also non-mast cell lineages, e.g. monocytes or eosinophils, in ≥80-90% of patients. Midostaurin is an approved multikinase/KIT inhibitor for treatment of AdvSM. The intricate landscape in assessment of response, resistance or progression, the occurrence of adverse events with its impact on dose modification and the recent approval of the specific KIT D816V inhibitor avapritinib contribute to complex decision-making. We here sought to characterize the most valuable baseline and on-treatment parameters for prediction of response and survival in midostaurin-treated patients with AdvSM. Methods: On basis of the ´German Registry on Disorders of Eosinophils and Mast Cells' (GREM), this retrospective-prospective analysis included 79 patients with AdvSM. Treatment was initiated between 2009 and 2022 accumulating into a 239 patient-years overall follow-up period. In addition to common serological, morphological, and molecular response parameters, we specifically examined the recurrent observation of an early flare-up in alkaline phosphatase (AP) levels, which was defined as a ≥25% AP increase within three months after treatment initiation, followed by a subsequent decline below baseline within six months. Results: Midostaurin was used in first-line (1L) or second and further lines (2L+; median 1 prior treatment line, range 0-4) in 63 (80%) and 16 (20%) patients, respectively. In 1L/2L+, median overall survival (OS) was 2.6/2.4 years. At baseline, the presence of additional somatic mutations in SRSF2 (n=36, 46%, HR 2.0 [1.2-3.6], P=0.014), ASXL1 (n=15, 19%, HR 2.0 [1.0-3.9], P=0.043), and EZH2 (n=6, 8%, HR 4.3 [1.7-11.3], P=0.003) significantly stratified patients according to their hazard ratio-weighted risk (median OS, 5.8 vs. 2.9 vs. 1.0 years; P<0.001). In 25 evaluable patients, the variant allele frequency in 72 additional somatic mutations remained stable (mean change 8%, absolute change >5% in 16/72 (22%) mutations). New mutations were identified in 9/25 (36%) patients during follow-up (Figure). Durable responses (complete, partial, clinical improvement) according to modified Valent criteria, IWG-MRT-ECNM criteria or Pure Pathological Response (PPR) criteria over a median duration between 12 and 24 months were achieved in 60%, 29% and 13% of patients, respectively. Within the first 12 months, duration of response was associated with an OS benefit ( P<0.001). An AP flare-up was observed in 22/79 (28%) patients, was paralleled by contemporaneous decrease of serum tryptase (median -35%, range -82 - 191%) and resulted into improved OS (median 5.8 vs. 2.2 years, P=0.007). Multivariable analysis identified the AP flare-up ( P=0.029), a ≥25% reduction of bone marrow (BM) mast cell (MC) infiltration ( P=0.046) and a ≥25% reduction of the KIT D816V expressed allele burden (EAB; P=0.034) at any time within the first 6 months as independent markers for improved OS (Table). Dynamic risk assessment of the independent parameters during follow-up allowed to abrogate a negative baseline risk-categorization. The initial dose was 200 mg/d (100 mg BID, including patients with a prespecified rapid dose escalation), 150 mg/d or 100 mg/d in 63/79 (80%), 2/79 (3%) and 14/79 (18%) patients, respectively. In the combined 150 mg and 100 mg cohorts, a dose increase to 200 mg/day was achieved in 9/16 (56%) patients. The 200 mg could be maintained at month 3, 6, 12, 24, and 36 in 50/63 (79%), 30/48 (63%), 23/34 (68%), 15/22 (68%) and 9/9 (100%) patients, respectively. Overall, 96 adverse events (AE) led to dose-adjustment (including temporary or permanent discontinuation). Hematologic and nonhematologic toxicities accounted for 24 (25%) and 36 (38%) of AEs with neutropenia (n=8, 8%) and nausea/emesis (n=22, 22%) being the most common AEs leading to dose-adjustment. Of note, the various dose levels had no impact on response or survival. Conclusions: Baseline mutations in SRSF2, ASXL1 and EZH2 conferred resistance to midostaurin. The various dose levels had no impact on response or survival. The on-treatment parameters AP flare-up, and a ≥25% reduction of BM MC infiltration and of KIT D816V EAB abrogated a negative baseline risk-categorization. No new safety signals occurred.

A First-in-Human, Phase 1, Dose Escalation Study of Sgr-2921 As Monotherapy in Subjects with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Background Cell division cycle 7-related protein kinase (CDC7), or DBF4-dependent CDC7 kinase (DDK), is a cell cycle kinase that maintains DNA replication by phosphorylation and activation of the minichromosome maintenance protein 2 and 4 (MCMs), components of the replicative DNA helicase. Due to the central role of CDC7 in maintenance of the replication fork integrity, chemical inhibition of CDC7 kinase can ultimately lead to cancer cell death. SGR-2921 is an oral, small molecule inhibitor of CDC7. Preclinical studies demonstrate that, among all cell lines tested, SGR-2921 has the most potent anti-proliferative activity in AML. Potent antitumor activity has also been demonstrated in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) AML models. This antitumor response is observed in animal models representative of difficult to treat patient populations and appears to be agnostic of serious mutations (including those with p53 mutations and FLT3 mutations), BTK resistance, and multiple prior lines of treatment. Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or high-risk (HR) or very high-risk (VHR) myelodysplastic syndrome (MDS) have low response rates and poor overall survival. Considering the potent preclinical activity of SGR-2921 in AML and MDS models, coupled with the high unmet medical need in this population, SGR-2921 is being evaluated in patients with R/R AML and HR/VHR MDS. Study Design and Methods This is a phase 1, FIH, open-label, single-agent, two-arm, dose escalation study (NCT#05961839) designed to evaluate safety and tolerability and identify the recommended phase 2 dose (RP2D) of SGR-2921 as monotherapy in subjects with R/R AML, HR MDS, or VHR MDS. The study utilizes a hybrid accelerated titration design with single patient cohorts that transitions to a 3+3 design once a single Grade 2 event or DLT is observed. This is a multicenter global study (US, Spain and France) with an estimated study recruitment start date in October, 2023. SGR-2921 will be administered orally, once daily, utilizing a 5-day on and 9-day off dosing schedule over a 28-day cycle. Up to a maximum of 144 patients will be enrolled in the dose escalation and exploratory cohort phase of the study. To evaluate the effect of CYP3A4 inhibition on SGR-2921 exposure, subjects will be enrolled into one of two staggered, parallel study treatment arms, according to concomitant administration with (Arm B) or without (Arm A) azole antifungals that are strong CYP3A4 inhibitors at time of first dose. Safety and tolerability must be demonstrated in treatment Arm A, at the first two dose levels before initiating treatment Arm B. A single dose PK run-in will be required for subjects enrolled into the first 3 cohorts of each treatment arm. Subjects will be treated at increasing doses of study drug until all dose levels have been investigated or any dose level is found to exceed the maximum tolerated dose (MTD). A RP2D will be selected from one of the tolerable dose levels which will not exceed the MTD (see Figure 1 for study design). Key study inclusion criteria include: Age ≥ 18 years of age; Life expectancy ≥ 8 weeks; Confirmed diagnosis of R/R AML or HR and VHR MDS; Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Key study exclusion criteria include: Active malignancies not related to AML or MDS within two years prior to the first dose or requiring ongoing treatment; Clinical evidence of central nervous system (CNS) or pulmonary leukostasis; ≥ Grade 3 disseminated intravascular coagulation, or active CNS leukemia; QT interval corrected for heart rate per Fridericia's formula ≥470 msec during screening ECG. The study primary objectives are to evaluate the safety and tolerability of SGR-2921 as monotherapy and identify RP2D including MTD. Secondary objectives include evaluating the pharmacokinetics (PK) of SGR-2921 and investigating preliminary antitumor activity (composite complete remission rate, objective response rate, duration of response, etc.).

Long Term Durable Responses in Relapsed/Refractory (r/r) ALL, DLBCL, and FL Patients Treated with Tisagenlecleucel and Its Association with Persistence of CAR T-Cells

Introduction: Monitoring of chimeric antigen receptor (CAR) transgene levels in peripheral blood post tisagenlecleucel (tisa-cel) infusion provides information on expansion and persistence of CAR T-cells. In adult diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) patients (pts), the expansion of CAR T-cells was similar between responding and non-responding pts, while in pediatric and young adult acute lymphoblastic leukemia (ALL) pts, higher expansion in responding pts was observed. Based on long term follow up data from tisa-cel treated pts, analyses were performed to delineate the impact of CAR persistence and B cell aplasia on duration of remission (DOR). Methods: Transgene levels in blood measured by quantitative polymerase chain reaction were available from pivotal phase II studies in pts with r/r ALL (ELIANA [N=79], ENSIGN [N=64], NCT03123939 [N=69], NCT01626495 [N=60]), r/r DLBCL (JULIET [N=115]), and r/r FL (ELARA [N=97]), along with the long term follow up study (NCT02445222). The time related to loss of persistence of CAR T-cells (T loss) was defined as the time at which transgene levels first dropped below 50 transgene copies/µg DNA (approximates to lower limit of quantification (LLOQ) of the assay) after maximal expansion. Kaplan Meier analysis was performed to investigate the impact of duration of T loss and time corresponding to last quantifiable level (T last) on DOR/relapse. The impact of time to B cell recovery (>1% CD19+ B cells/WBCs or >3% CD19+ B cells/lymphocytes for ALL, and 80-616 cells/µL for DLBCL and FL), on DOR/relapse was also investigated. Results: Long term CAR persistence in tisa-cel treated pts has been observed for up to 9, 6, and 2.5 years for ALL, DLBCL, and FL pts, respectively, reflecting differing length of follow up based on initiation of trials in respective indications. Across indications, pts who lost transgene within 6 months or between 6-12 months had shorter DOR relative to pts with persistent transgene (Fig 1, ALL pts). In ALL, the median T loss was 27.4, 18.2, 9.7, and 18.0 months for ongoing complete response (CR) > 12 months, CR pts between 6-12 months, relapsed pts < 12 months, and relapsed pts > 12 months, respectively. However, of the pts who lost transgene within first 6 months, some pts maintained durable responses for ≥12 months (29%, 15%, and 50% in ALL, DLBCL, and FL, respectively). Among ALL relapsed pts, majority (17/26, 65%) of the pts with T loss < 6 months showed B cell recovery, however 6 pts had T loss at < 6 months as well as B-cell recovery but maintained response for ≥ 12 months. In ALL, Pulsipher et al.,(Blood Cancer Discov. 2022)have shown that NGS MRD within the first 6 months to 1 year post infusion may be a more reliable predictor of potential relapse than B cell recovery. The median time to B-cell recovery was 266 days in pts who relapsed/censored within 12 months but was not reached for pts with ongoing response at 12 months. On the contrary, B cell recovery seems to have no association with relapse in DLBCL or FL pts. Of the ALL pts with CAR persistence, pts with <50% morphologic blasts at any time prior to infusion of tisa-cel had longer DOR compared to pts with ≥50% blasts. This may also reflect a more resistant high risk ALL at the time of study entry or greater potential for stochastic loss of CD19 in pts with the higher disease burden. Conclusions: Long term sustained remission/response was observed in tisa-cel treated pts in the pivotal trials. The analyses demonstrate a positive association between CAR persistence and durable clinical responses across indications, however, some pts maintained durable responses despite early loss of transgene and/or early B cell recovery (< 6 months post infusion; Myers et al., J Clin Oncol. 2021). To note, in DLBCL and FL, the transgene levels in blood may not represent the levels at target sites including lymph nodes, moreover, T last and T loss are dependent on the duration of follow up, LLOQ etc. Of note, these analyses represent data from pivotal tisa-cel clinical studies with a heavily treated pt population post multiple lines of therapy including prior HSCT, and may not represent pts treated with commercial product, at earlier times post diagnosis in current studies with fewer lines of prior treatment, lower pre-infusion disease burden, and/or other CAR product. In pts with early loss of transgene, further research is needed to identify potential factors or patient characteristics resulting in durable responses.