Relapsed Pts Research Articles

Impact of Pre-Transplant Molecular and Cytogenetic Remission on Outcomes of Allogeneic Stem Cell Transplant in Patients with Myelodysplastic Syndrome

Background: Allogeneic stem cell transplant (allo-SCT) carries a high relapse rate (~35% within 2 years) in patients (pts) with myelodysplastic syndrome (MDS). Pre-transplant measurable residual disease (MRD) increases the risk of relapse and death in acute myeloid leukemia (Thol et al, Blood 2018). However, the impact of pre-transplant MRD on post-transplant outcomes is less clear in MDS. Prior studies have compared outcomes between myeloablative (MAC) and reduced intensity conditioning (RIC) in pts with pre-transplant MRD persistence based on either cytogenetic remission alone or ultra-deep genomic sequencing with a limited 10-gene panel, suggesting reduced risk of relapse in pts receiving MAC (Festuccia et al, Biol Blood Marrow Transplant 2016; Dillon et al, JCO PO 2021). However, pre-transplant MRD assessment using a commercial next-generation sequencing (NGS) panel in addition to cytogenetic testing to assess post-transplant outcomes has not been evaluated in MDS. Methods: We conducted a multicenter retrospective review of MDS pts who underwent allo-SCT from 2015-2022. Pts with FISH/cytogenetic (FC) and/or molecular abnormalities at diagnosis and MRD assessment by commercial myeloid-panel NGS (with a variant-allele frequency detection limit up to 5%) and FC performed on peripheral blood (PB) or bone marrow (BM) aspirate within 3 months prior to transplant were included for analysis. The Kaplan-Meier method and log-rank tests were used to estimate overall survival (OS). Gray's test/cumulative incidence functions were used to estimate relapse-free survival (RFS) with non-relapse mortality (NRM) as competing risk. Results: Table 1 includes baseline pt characteristics. Of 81 pts, 69 pts (85.2%) had residual FC and/or molecular abnormalities (MRD+) at pre-transplant PB/BM assessment. Twelve (14.8%) pts were in both FC and molecular remission (MRD-) prior to transplant. With a median follow-up of 13.9 months [IQR 6.8 - 38.9], 43 (53%) died and 24 (30%) pts experienced a relapse. Twenty-three of 69 (33%) MRD+ pts had relapsed disease with a 38% cumulative incidence of relapse (CIR) at 2 years. In contrast, only 1/12 (8.3%) MRD- pts experienced a relapse after 7 years, with chromosomal loss of TP53 not present at initial diagnosis. CIR at 2 years was 33% and 41% (p=0.207) for MRD+ pts who received MAC vs RIC, respectively with NRM of 34.5% associated with MAC vs 28.2% for RIC (p=0.61). TP53 mutations were most frequently associated with relapse in 8/24 (33%) pts with a median OS of 9.8 months [8.2 - NR]. Besides the previously defined 10-gene panel (Dillon et al, JCO PO 2021), relapses were also driven by SRSF2, U2AF1, KRAS, SETBP1 and NF1 mutations present in the original clone. Six pts had DNMT3A, TET2 and/or ASXL1 (DTA) mutations only on pre-transplant NGS, with 2/6 pts relapsing without the re-emergence of DTA mutations. Median OS was not reached for MRD- pts and was 14.1 months [11.35-NR] for MRD+ pts, p = 0.061 [Fig.1]. OS probability at 2 years was 35% for MRD+ pts vs 75% for MRD- pts. Type of conditioning regimen, RIC vs MAC, did not impact OS (p= 0.6). An equal number of deaths, 35% each, were attributable to GvHD and relapse, respectively. Thirteen (30%) pts died from other causes, primarily infections and bleeding complications. NRM was 25% and 36% for MRD- and MRD+ cohorts, respectively. Pts received a median of 6 cycles [range, 2-36] of hypomethylating agent (HMA) +/- venetoclax prior to transplant with no association between the number of cycles and MRD status (p=0.80). The incidence of grade 3-4 acute GvHD and chronic GvHD requiring systemic therapy did not significantly differ, at 25% and 18.8% (p= 0.696) and 33.3% and 31.8% (p= 1.00) in MRD+ and MRD- pts, respectively. Conclusions: MRD assessment using commercially available NGS panels and cytogenetic testing that are routinely performed in MDS pts in real-world practice can predict risk of relapse. Pre-transplant MRD is associated with worse OS irrespective of the intensity of conditioning regimen. Although limited in statistical power due to a small sample size of MRD- pts in our cohort, further studies with a larger cohort are underway to better clarify the role of MRD on transplant outcomes in MDS. Our data also highlights that only a small minority of MDS pts (<15%) achieve complete molecular and cytogenetic remission at the time of transplant; strategies to eliminate the pre-transplant MDS clone are urgently needed.

Risk of Central Nervous System Vs. Systemic Relapse in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP: What Should We Focus on?

Background: Clinical outcome of patients (pts) with diffuse large B-cell lymphoma (DLBCL) has improved during the last two decades. However, a significant proportion of DLBCL pts is still at risk of lymphoma relapse (REL)/progression or death due to progression. DLBCL pts with adverse clinical features, i.e., those with high IPI or CNS IPI scores are at the highest risk of lymphoma REL, systemic (S) or central nervous system (CNS) REL. CNS prophylaxis is questionable based on retrospective analyses. Moreover, the risk of S-REL should be discussed in those pts as well. However, the comparison of the risks of CNS vs S-REL within the different CNS IPI risk groups has not been shown. Methods: Using the prospective observational NiHiL project (NCT03199066), we identified pts ≥ 18 years of age with histologically confirmed DLBCL or high-grade B-cell lymphoma (diagnosed 2011-2021), who received R-CHOP as frontline treatment in 2 centres in Czech Republic. Pts with CNS involvement at diagnosis were excluded. Cumulative incidence of CNS (± S) REL was calculated using Kaplan-Meier statistics treating S-REL and death as competing events. Results: A total of 1242 pts were included; according to CNS IPI score (available in 1225 out of 1242 pts), 344 (28.1%), 539 (44.0%) and 342 (27.9%) pts were categorized as being at low (0-1, LR), intermediate (2-3, IR), and high risk (4-6, HiR) resp. Overall, 308 (24.8%) pts received CNS prophylaxis with either high-dose(HD) Methotrexate (MTX), HD-AraC, intrathecal chemotherapy or combination. By CNS IPI, 150 (43.9%) out of 342 pts with HiR CNS IPI received CNS prophylaxis. CNS prophylaxis was given less frequently in the IR (n 111[20.6%] out of 539 pts) or LR (n 45 [13.1%] out of 344 pts) CNS IPI groups. At a median follow up of 5.3 years (range; 0.1 - 13.3), 307 (24.7%) out of 1242 pts developed lymphoma REL, out of which 45 occurred in CNS (35 isolated CNS REL, 10 simultaneous CNS+S-REL) and 262 lymphoma RELs occurred systemically. CNS prophylaxis had no impact on the incidence of CNS REL in pts with HiR CNS IPI. Median time to CNS (± S) and S-REL was 11.5 months (range; 2.7-116.8) and 11.8 months (range; 0.8 - 144.3), resp. Occurrence of RELs within the first 6, 12 and 24 months after lymphoma diagnosis was as follows: 20%, 53.3% and 80% for CNS (± S) RELs and 21%, 50.4% and 67.2% for S-RELs. In the entire cohort, the 7-year cumulative incidence of CNS (± S) and S-REL were 4.4% and 23.7%, resp. Across all CNS IPI risk groups, there was significantly higher risk of S-REL as compared to CNS (± S) REL. The 7-year cumulative incidence of S-REL vs CNS (± S) REL and the respective HRs were 10.5% vs 1.9%, HR 6.2 (95% CI 3.4-11.2) in the LR-, 25.2% vs 2%, HR 11.7 (95% CI 8.3-16.6) in the IR-, and 35.8% vs. 12.4 %, HR 3.6 (95% CI 2.5-4.9) in the HiR CNS IPI ( Fig1), resp. At the time of analysis, 417 (33.6%) out of 1242 pts were dead. CNS (± S) REL was associated with shorter post-REL overall survival (OS) as compared to S-REL (HR 1.8, p=0.001, median OS 0.38 vs 1.04 years, resp). In the entire cohort, the 7-year cumulative incidence of death due to lymphoma was 19.3% (16.7% and 3.1% due to S-REL and CNS (± S) REL, resp). The 7-year cumulative incidence of death due to R-CHOP-related toxicity, unrelated to lymphoma and unknown causes were 2.5%, 4.2% and 9.8%, resp. In HiR CNS IPI, the 7-year cumulative incidence of death due to lymphoma was 34.9% (28.3% and 9.2% due to S-REL and CNS (± S) REL, resp), while the 7-year cumulative incidence of death due to R-CHOP-related toxicity, unrelated to lymphoma and unknown causes were 5.1%, 5.1% and 14.9%, resp ( Fig2). Conclusion: DLBCL pts are at significantly higher risk of S-REL as compared to CNS (± S) REL overall and across all CNS IPI risk groups. In addition, death due to S-REL is the leading cause of death overall and across all CNS IPI risk groups. However, CNS (± S) REL represents remarkable portion of all lymphoma RELs occurring in the HiR CNS IPI group and non-negligible cause of death in DLBCL. Our results support the conclusion that R-CHOP + HD MTX is not sufficient to reduce the risk of S-REL as well as CNS REL especially in pts with HiR CNS IPI. New 1 st line treatment options able to reduce simultaneously the risk of S-REL as well as CNS REL are needed to improve the outcome of DLBCL pts especially in the subgroup with HiR CNS IPI. Grant support: AZV NU23-03-00127, NU21-03-00411, Charles University Hematology-Oncology Cooperatio Program

Outcomes Multiple Myeloma Patients Progressing after BCMA-Directed Chimeric Antigen Receptor T Cell (CART) Therapy

Background: Chimeric Antigen Receptor T Cell Therapy (CART) targeting B-cell Maturation Antigen (BCMA) has gained approval for Relapsed/Refractory Multiple Myeloma (RRMM) following a minimum of four prior lines of therapy (LOT). Despite the significant improvement in outcomes with a remarkable progression-free survival (PFS) reported in pivotal trials, a substantial proportion of patients (pts) eventually experience disease progression. The available treatment options thereafter are currently limited, and the outcomes in this specific cohort of pts have not been extensively characterized. This study aimed to investigate the clinical outcomes of pts with RRMM who failed BCMA CART therapy, either as standard of care (SOC) or as part of a clinical trial. Methods: We conducted a retrospective analysis as of 7/10/2023 of RRMM pts progressing after BCMA CART and receiving the next LOT at the University of Kansas Medical Center in collaboration with US Myeloma Research Innovations Research Collaborative (USMIRC). Those who received therapy on clinical trial as the next LOT were included. Baseline demographic data were described, and outcomes were evaluated for two subgroups: “early” relapse pts (progression ≤ 6 months) and “later relapse”, those progressing after 6 months. Baseline pt characteristics were outlined by descriptive analyses. Responses including overall response rate (ORR), and complete response or better (>CR) were evaluated using the International Myeloma Working Group (IMWG) criteria. Statistical analysis was done with the use of Fisher's exact test and the Kaplan-Meier method for progression-free (PFS) and overall survival (OS) calculations. OS was calculated from relapse after CAR-T till the last office visit/death. Regression models for univariate and multivariate analysis were performed. Results: Thirty pts were included in the analysis. Baseline demographics is summarized in Table 1. The majority (57%) had extramedullary disease (EMD) and 90% had an ECOG performance status of 0-1. The mean age of the pts was 61.3 years (SD=9.6), with 73% male and 80% White. Pts had 5 median prior LOT. All pts were refractory to PI, IMid, Daratumumab, double-refractory and-triple refractory. 63% were penta-refractory. Sixteen (53%) pts relapsed ≤ 6 mo after CART infusion and 14 (47%) relapsed after 6 months, with median follow-up of 21.73 Months (25-75 IQR: 13.87-40.17 mo). Baseline demographics were similar. The presence of 1p genetic mutation was significantly associated with lower incidence of early progression (early: 0% vs later: 36%, p=0.014). Also, pts with 2 autologous stem cell transplants (ASCT) had later relapses (early: 0% vs later: 43%, p=0.009). Outcomes with next LOT: Of these 30 pts, 10 received BCMA-directed therapies (3 got belantamab mefodotin and 7 received bispecifics (BCMA on Harpoon trial and teclistamab, 2 received GPRC5D targeting bispecific, talquetamab. The rest 18 (60%) got chemo immunotherapies including 1 ASCT and 5 VD-PACE/KD-PACE. 70% of pts progressed on the next LOT. Overall response rate (ORR) was 30%. (Figure 2a). There were 14 deaths, all related to myeloma progression. The median OS was 8.53 months (4.9-NR). Figure 2b summarizes the LOT and OS outcomes. In univariate analysis (UVA), EMD was associated with a significantly higher risk of death (HR=4.15, 95% CI=1.12-15.3, p=0.019), but this was not significant after adjusting in the multivariate analysis (MVA) (HR=2.74, 95% CI=0.63-11.8, p=0.2). Male gender was associated with worse survival in UVA. However, no factors were associated with a higher risk of death in a multivariate analysis. Conclusion: This study describes outcomes for post-CART relapse in RRMM. Most pts do not respond to the first LOT post-BCMA CART relapse. The survival was less than a year, suggesting need for further studies with a longer follow-up and larger sample size to establish the best regimen for CART failure and characterize prognostic factors associated with poor outcomes for CART relapses.

Outcomes in Patients with Classical Hodgkin Lymphoma Refractory or Intolerant to Brentuximab Vedotin and Anti-PD-1 Therapy: Real World Analysis from 14 U.S. Academic Centers

Background: Brentuximab vedotin (BV) and anti-PD-1 therapies (nivolumab and pembrolizumab) have changed the therapeutic landscape for patients (pts) with classical Hodgkin lymphoma (cHL) over the past decade. Although first proven to be beneficial in relapsed and refractory cHL, these therapies have moved earlier in the treatment algorithm given superior response rates and survival compared to cytotoxic chemotherapy alone. However, there is limited data regarding outcomes in pts who progress after both BV and anti-PD-1 therapies (double refractory, DR) or become intolerant (INT) of these therapies. Knowledge of outcomes in this subset of pts is important as BV and anti-PD-1 therapies are increasingly used in front-line treatment and early relapsed cHL. Methods: We conducted a retrospective study of adult pts from 14 U.S. academic medical centers who developed DR cHL or became INT of BV and/or anti-PD-1 therapy between January 2011 and December 2021. DR was defined as treatment failure (evidence of progression by imaging or biopsy) during therapy or within 3 months of the last dose of both BV and anti-PD-1 therapy. INT was defined as any toxicity limiting further cycles of BV or anti-PD-1 therapy. Pts with INT were either intolerant to both BV and anti-PD-1 or intolerant and refractory to BV or anti-PD-1. The primary endpoint was assessment of overall survival from time of cHL diagnosis (OS-1) and from DR or INT (OS-2). Secondary endpoints included description of pt characteristics developing DR or INT cHL, estimate of OS comparing DR versus INT, and estimate of OS stratified by prior autologous stem cell transplant (ASCT) at the time of DR/INT. Time-to-event analyses were evaluated by Kaplan-Meier methodology. INT pts were not included in time to progression (TTP) analysis for initial BV or anti-PD-1 therapy. Results: 158 pts were eligible. Clinical characteristics at diagnosis included median age 33 years (range 16-89), 61% male, 77% white race, 66% nodular sclerosing subtype, 47% stage IV, and 56% with B symptoms. Front-line treatment was ABVD/AVD in 122 pts (77%) and BV or anti-PD-1 therapy in 28 pts (18%). 60% had primary refractory cHL (n=94). Table 1 describes pt characteristics in detail. Initial BV treatment was after a median of 2 lines of therapy (LOT) (range 0-7). The majority (60%, n=94) were treated with BV monotherapy and 15% (n=24) were treated with BV combined with anti-PD-1 therapy. Median TTP of BV refractory pts was 168 days (95%CI 138-190). Initial anti-PD-1 therapy was after a median of 3 LOT (range 0-12). Nivolumab was the most commonly used (72%) anti-PD-1 therapy. Median TTP of anti-PD-1 refractory pts was 223 days (95%CI 166-271). DR cHL was observed in 119 pts (75%), while 39 pts (25%) were INT. The median time from cHL diagnosis to DR/INT was 3.3 years (95%CI 0.5-23.1). At the time of DR/INT, 47% (n=75) had prior ASCT. The majority (87%, n=137) received subsequent LOTs after DR/INT (median 2, range 0-14). Table 1 describes DR/INT in detail. The median OS from the time of cHL diagnosis (OS-1) in all pts was 15.0 years (95%CI 9.4-20.9). There was no difference in OS-1 between DR and INT pts (log-rank p=0.83) or primary refractory and front-line relapsed pts (log-rank p=0.94). Pts who developed DR/INT at any time after ASCT had a significantly longer OS-1 compared to DR/INT without prior ASCT with a median OS of 19.1 years (95%CI 19.1-NR) versus 8.6 years (95%CI 5.3-15.0), respectively (log-rank p<0.001, Figure 1). Comparing pts with prior ASCT and no prior ASCT, the median age at DR/INT was 35 (range 20-75) versus 49 (range 18-90) years, Fisher's exact p=0.01. Adjusting for age at DR/INT did not impact the association between prior ASCT and improved OS, Cox proportional hazard ratio 0.48 (95%CI 0.25-0.90, p=0.02). Median OS from time of DR/INT (OS-2) was 7.4 years (95%CI 4.1-NR). OS-2 was not different between DR and INT pts (log-rank p=0.33). Conclusion: To our knowledge, this is the largest cohort of pts refractory to, or intolerant of BV and anti-PD-1 therapy. OS was longer than anticipated both from diagnosis and from time of DR/INT. Pts who were DR/INT after ASCT had a significantly longer OS. Further investigation is needed to determine if OS differences by ASCT may be due to disease biology or sequencing of therapies. Importantly, OS-2 serves as a benchmark for future clinical trials evaluating DR/INT cHL pts.

Mechanisms of Resistance and Relapse with Talquetamab in Patients with Relapsed/Refractory Multiple Myeloma from the Phase 1/2 MonumenTAL-1 Study

Introduction: Talquetamab (tal), a novel GPRC5D×CD3 bispecific antibody (BsAb), has shown deep and durable responses with overall response rates (ORRs) >71%, including in high-risk populations, and a clinically manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (MM) in the MonumenTAL-1 study (NCT03399799/NCT04634552). To better understand mechanisms of resistance and relapse in pts treated with tal, baseline and longitudinal GPRC5D expression and immune profiles were assessed in pts treated with the 0.4 mg/kg weekly (QW) recommended phase 2 dose, including a separate cohort of pts who received prior T-cell redirection therapy (prior TCR; chimeric antigen receptor [CAR]-T cell and BsAb therapies). Methods: MonumenTAL-1 is a first-in-human, phase 1/2, single-arm study of tal monotherapy. Eligible pts had MM and were intolerant to or progressed on established therapies (phase 1) or had ≥3 prior lines of therapy (LOT) including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody (phase 2). Analyses were performed in pts receiving tal 0.4 mg/kg QW who did not receive prior TCR (no prior TCR cohort) and pts receiving tal 0.4 mg/kg QW who received prior TCR (prior TCR cohort). Baseline and on-treatment bone marrow or whole blood were analyzed by flow cytometry for GPRC5D expression and immune cell profiles, respectively. For mechanisms of resistance, samples were analyzed in responders (defined as ≥PR) and nonresponders (defined as stable or progressive disease [PD]); for mechanisms of relapse, samples were analyzed at baseline and at end of treatment (EOT)/PD. Results: Median prior LOT was 6 and 5 in the prior and no prior TCR cohorts, respectively. T-cell counts at baseline were similar between cohorts, whereas pts in the prior TCR cohort had higher expression of single coinhibitory markers (LAG-3, TIM-3, PD-1), dual coinhibitory markers (PD-1/LAG-3 and PD-1/TIM-3), and activation markers (CD38 and CD25) on CD8+ T cells, along with a higher frequency of immunosuppressive regulatory T cells (Tregs) compared with the no prior TCR cohort. GPRC5D was highly expressed on MM cells at baseline; however, expression was variable among pts in both cohorts and was not associated with clinical response. In both cohorts, correlative analyses with response showed that nonresponders vs responders had a more exhausted peripheral immune phenotype at baseline, indicated by lower T-cell counts and higher frequencies of Tregs and expression of coinhibitory markers (LAG-3, TIM-3) on CD8+ T cells. In the first cycle following tal administration, greater and transient activation of T cells was observed in responders vs nonresponders. In addition, greater recovery of CD3+ T cells was observed and sustained in responders within 2 cycles of treatment, whereas persistence of CD38+ expression on CD8+ T cells, higher presence of Tregs, and sustained expression of LAG-3, TIM-3, and PD-1 on CD8+ T cells was observed in nonresponders, consistent with the baseline correlative analysis in the prior and no prior TCR cohorts (Figure). Finally, analysis of progression samples of pts who initially responded and then progressed with tal showed a higher expression of coinhibitory receptors (LAG-3, TIM-3, CD38, PD-1/LAG-3, PD-1/TIM-3) on peripheral CD4+ or CD8+ T cells in both cohorts compared with baseline, indicative of an exhausted T-cell phenotype at relapse. Overall, these correlative data were comparable between prior TCR and no prior TCR cohorts. Conclusions: Baseline immune profiling in heavily pretreated pts from MonumenTAL-1 suggested that compared to pts with prior TCR, pts with no prior TCR had a favorable immune fitness profile (less T-cell dysfunction and immune suppression). In both cohorts, baseline and longitudinal correlative analyses suggest a mechanism of resistance for nonresponders including lower T-cell counts and higher frequency of Tregs and expression of coinhibitory markers on CD8+ T cells, whereas responders show greater T-cell activation and recovery of CD3+ T cells that was sustained longitudinally. Progression data indicated an exhausted T-cell phenotype for pts who relapsed on tal. Approaches to overcome resistance, including combination trials with anti-CD38 monoclonal antibodies (eg, daratumumab) and PD-1 inhibitors as well as alternative dosing regimens, are currently being studied.

Clonal Dynamics of FLT3-ITD Positive Acute Myeloid Leukemia Patients with Relapsed/Refractory Disease Following Intensive Chemotherapy +/- Midostaurin

Introduction: Despite the wider use of midostaurin (MIDO) in combination with intensive chemotherapy (ICT) as the 1st-line treatment for FLT3-mutated acute myeloid leukemia (AML), complete remission (CR) rates are close to 60%, and relapses occur in over 40% of cases, demonstrating the ability of leukemic cells to resist and evade therapy ( Stone et al., NEJM 2017). Conventional fragment-length analyses of paired diagnosis/relapse samples have shown that FLT3-internal tandem duplications (ITDs) are retained in 80% and 50% of cases following ICT alone and MIDO+ICT respectively ( Schmalbrock et al., Blood 2021). Only limited data are available on the dynamics of FLT3-ITDs or other co-mutations in refractory patients (pts). Here, we conducted a retrospective study involving 115 pts with relapsed/refractory AML harboring FLT3-ITD at diagnosis. Materials and methods: Clonal evolution was examined in paired diagnosis/progression blood or bone marrow samples from 115 pts with FLT3-ITD+ AML treated with MIDO+ICT (n=33) or ICT alone (n=82). Among them, 21 pts had primary refractory disease (MIDO+ICT, n=8; ICT, n=13) and 94 pts relapsed after achieving CR (MIDO+ICT, n=25; ICT, n=69). FLT3-ITDs and co-mutations were screened on genomic DNA by high-throughput sequencing at both timepoints using a custom-designed panel. For accurate annotation and quantification of FLT3-ITDs from sequencing data, we used the recentlypublished FiLT3r algorithm ( Boudry et al., BMC Bioinformatics 2022). For each ITD detected, FiLT3r allelic ratio (AR) was assessed by the ratio between the mutated allele and the wild-type allele. Results: A total of 226 FLT3-ITDs were detected in 115 pts at AML diagnosis, among which 120 (53%) ITDs were found with an AR below 0.05 ( Figure 1). Among pts who achieved CR and experienced relapse (n=94), 48 had multiple FLT3-ITDs at diagnosis and 46 had a single FLT3-ITD at diagnosis. Overall, we observed a simplification of the FLT3-ITD repertoire upon relapse with the persistence of at least one initial clone in 8/12 [67%] and 24/36 [67%] pts with multiple ITDs receiving MIDO+ICT and ICT alone respectively. In relapsed pts who initially had a single FLT3-ITD clone at diagnosis, the addition of MIDO to ICT was associated with a higher rate of FLT3-ITD negativity compared to pts receiving ICT alone (6/13 [46%] vs 5/33 [15%]; P = 0.05) ( Figure 2). Interestingly, among 21 pts with primary refractory AML, we observed that FLT3-ITD mutation status became negative in 5/8 pts (62%) and 2/13 pts (15%) after induction with MIDO+ICT and ICT alone respectively. We then compared the initial characteristics between retained and lost FLT3-ITDs at AML relapse. Lost FLT3-ITDs had significantly lower AR than retained clones in both treatment groups. In order to limit the impact of sample dilution on the allele burden, we defined adjusted variant allele frequencies (VAFs) as the VAFs of FLT3-ITDs normalized to the VAFs of NPM1 mutations, whenever applicable. In so doing, we observed that adjusted VAFs of retained FLT3-ITDs increased at relapse, regardless of the treatment group (adjusted VAF, diagnosis vs relapse: 0.28 vs 0.86 and 0.88 vs 1.6 in the MIDO+ICT group and ICT alone group; P = 2.3e-03 and P = 2.4e-04). Importantly, an adjusted VAF higher than 1 was strongly suggestive of a homozygous state of FLT3-ITD. Such situation was found to be more prevalent at relapse in both treatment groups. Besides the selection of a dominant FLT3-ITD clone, other relapse-related changes including the acquisition of additional mutations will be presented. Conclusion: Our study of the clonal dynamics of AML with FLT3-ITD mutations provides insights into the mechanisms underlying therapy escape. Our data suggest that clonal interference characterized by multiple FLT3-ITD clones is associated with a greater ability to select a FLT3-ITD-positive clone at relapse in pts receiving MIDO+ICT. Although the addition of MIDO to ICT increases the probability of eradicating a single FLT3-ITD clone, FLT3-ITD+ relapses remain common following this combination, often with the selection of homozygous FLT3-ITD clones and/or the emergence of new mutations. Finally, our data in refractory situation emphasize the need to reassess mutational status at each stage of progression before implementing targeted therapy.

Patient (pt) Experiences of Receiving Idecabtagene Vicleucel (Ide-Cel, bb2121) Versus Standard (Std) Regimens for the Treatment (Tx) of Relapsed/Refractory Multiple Myeloma (RRMM) in the Randomized, Controlled KarMMa-3 Clinical Trial: Analysis of Longitudinal Qualitative Interviews

Introduction: Ide-cel is a first-in-class B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy approved by the United States (US) Food and Drug Administration; the European Medicines Agency; and Japan's Ministry of Health, Labour, and Welfare for treating adult pts with RRMM who were triple-class exposed (TCE) to an immunomodulatory (IMiD) agent, proteasome inhibitor (PI), and anti-CD38 monoclonal antibody and who experienced disease progression/relapse after last therapy. The phase 3 multicenter, open-label, randomized controlled KarMMa-3 trial (NCT03651128) enrolled pts with RRMM who were TCE (including an IMiD agent, PI, and daratumumab [DARA]) after 2-4 prior lines of therapy. Pts were randomized 2:1 to receive either ide-cel or 1 of 5 std regimens (DARA, pomalidomide [POM], dexamethasone [DEX]; DARA, bortezomib, DEX; ixazomib, lenalidomide, DEX; carfilzomib and DEX; elotuzumab, POM, DEX). At median follow-up (18.6 mo), median progression-free survival (13.3 vs 4.4 mo) and response rate (71% vs 42%) were significantly higher in the ide-cel versus std regimen arm (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014). In addition to the standard pt-reported outcomes instruments, trial-embedded interviews provide further insights into the patient Tx experience (Delforge M, et al. J Clin Oncol 2023;41[suppl 16]. Abstract 8032). This study assessed Tx experience, changes in health-related quality of life, and advantages and disadvantages of assigned Tx for pts enrolled in the KarMMa-3 trial. Methods: To obtain pts' experiences and perspectives in their own words while on the assigned Tx arms during the study, qualitative interviews were embedded into the KarMMa-3 trial. Pts were randomized (1:4) to participate in a series of optional qualitative interviews conducted at baseline (BL), and 3 and 6 mo post Tx. Interviews were audio-recorded and transcribed. Non-English interviews were transcribed directly into English. Transcripts were analyzed in MAXQDA qualitative analysis software; inter-coder agreement exercises were completed to ensure reliability. Analytic approaches included thematic analysis and longitudinal analysis across aspects of health and well-being. Results: In total, 64 pts (n = 43 ide-cel, n = 21 std regimen) across 9 countries in Europe and in the USA participated in ≥ 1 interview. Across both arms, 60, 48, and 38 pts completed interviews at BL, and 3 and 6 mo post Tx, respectively. The mean (median) age of interviewed pts at time of consent in the trial was 60.5 (60) years, and 33% were female. When describing their overall well-being during the previous 4 weeks at 3 mo, 53% of ide-cel pts described their well-being as mostly improved versus 19% in the std regimen arm. In the ide-cel arm, 59% and 56% of pts reported improvements in physical health versus 19% and 10% of pts in the std arm at 3 and 6 mo from BL, respectively; 25% and 28% of pts in the ide-cel arm reported worsening physical health at 3 and 6 mo from BL versus 63% and 80% of pts in the std arm (Table 1). In the ide-cel arm, 47% and 48% of ide-cel pts described improvements in physical functioning at 3 and 6 mo from BL versus 19% and 20% of std regimen pts, respectively; 22% and 16% of pts in the ide-cel arm versus 50% and 60% of pts in the std arm reported worse physical functioning at 3 and 6 mo from BL. Regarding Tx advantages, ide-cel pts reported efficacy (n = 25, 58%), minimal side effects (n = 21, 49%), avoidance of other therapies (n= 16, 37%), and having a 1-time Tx (n = 12, 28%). Std regimen pts also described efficacy (n = 10, 48%) and minimal side effects (n = 8, 38%) as Tx advantages. Disadvantages discussed by pts treated with ide-cel included lack of efficacy (n = 10, 23%), side effects after infusion (n = 9, 21%), or none (n = 9, 21%). Greater proportions of std regimen pts described side effects (n = 9, 43%) and lack of efficacy (n = 7, 33%). Additional well-being results for both arms are presented in Table 1. Conclusions: This study provides unique insight into key pt perceptions of ide-cel Tx compared to std regimens. Overall, pts receiving ide-cel reported more positive changes 6 mo post Tx than pts receiving std regimens, specifically in physical health and functioning. Fewer pts treated with ide-cel described side effects than pts receiving std regimens. These data show that ide-cel as a 1-time infusion can alleviate the burden of managing complex medication regimens in TCE early-line relapse pts.

EXPLORING DIFFERENTIAL MUTATIONAL DISTRIBUTION BY TARGETED SEQUENCING IN A R‐CHOP TREATED COHORT OF DIFFUSE LARGE B‐CELL LYMPHOMA PATIENTS

Background: Diffuse large B-cell lymphoma (DLBCL) harbors striking clinical and molecular heterogeneity, which continues to encumber risk stratification with a consequently high rate of refractory/relapsed patients (pts). Though the genomic landscape of DLBCL has been comprehensively uncovered, the search for eligible molecular biomarkers continues. Exploratively, we set out to retrospectively evaluate differential mutational distributions in a DLBCL cohort using targeted sequencing. Patients and method: A cohort of 105 de novo DLBCL pts, uniformly treated with first-line R-CHOP, were studied. Thirty pts relapsed, of which 70% had early relapses (<2 years after completing therapy), while 30% had late relapses (≥2 years). Targeted next-generation sequencing (90 gene panel) was applied on archival paraffin-embedded diagnostic samples and, if available, first relapse samples. Results: In total, 118 samples were sequenced, each displaying a median of 12 (range 1–46) putative somatic protein-coding mutations. Germinal center B-cell (GCB) DLBCL (n = 60) displayed a differential somatic signature with enrichment of EZH2, TNFRSF14, BCL2, ACTB, SOCS1, and FAS mutations (Fisher's Exact, p < 10-4), whereas mutations in CDKN2A, PRDM1, MYD88, and CD79B were significantly enriched in non-GCB pts (p < 10-4, n = 44). Survival analysis confirmed inferior overall survival (OS) in non-GCB DLBCL (5-year OS, log-rank (Mantel-Cox), p = 0.01, hazard ratio (HR) 1.7). Pts with double-hit biology (DHB), defined as either MYC and BCL2 and/or BCL6 fluorescent in situ hybridized positive and/or with MYC and BCL2 immunohistochemical double expression (n = 32), did not display a significant mutational signature or differential OS. However, a subgroup of DHB pts characterized by mutations in MYC, PRDM1, or IRF4 (n = 15) had markedly inferior OS (5-year OS, log-rank, p = 0.0003, HR 3.34) compared to negative non-DHB pts (n = 55) or negative non-DHB/DHB pts (p = 0.0017, HR 2.7, n = 72). Noticeably, ACTB mutations were only present in non-DHB pts. The mutational distribution at diagnosis did not differ between pts with relapse and in sustained remission. However, in the relapse group, GNA13 mutation at diagnosis was more frequent in early relapses than late relapses (43% vs. 0%, Fisher’s Exact without correction, p = 0.03). The presence of GNA13 in the entire cohort showed a trend towards inferior survival. Conclusion: Differential distribution with significant mutational signatures were expectedly found in GCB versus non-GCB, but not in subgroups with DHB or relapse. Interestingly, mutations in MYC, PRDM1 or IRF4 identified a distinct subset of DHB pts with inferior survival. Furthermore, GNA13 mutations were significantly enriched in early relapse pts. These preliminary findings call for validation of GNA13 as a potential marker of early relapse as well as the prognostic value of MYC, PRDM1 and IRF4 mutations in DHB DLBCL. The research was funded by: The Danish Cancer Society and The Vissing Foundation Keywords: aggressive B-cell non-Hodgkin lymphoma, genomics, epigenomics, and other -omics, tumor biology and heterogeneity Conflicts of interests pertinent to the abstract T. S. Larsen Consultant or advisory role Roche, Gilead, Novartis, Celgene/BMS Research funding: Genentech

Evaluation of the GELTAMO guidelines for surveillance in follicular lymphomas after first‐line immunochemotherapy: a real‐world prospective study

Introduction: CT scans have been traditionally recommended in the surveillance of patients (pts) with follicular lymphoma (FL) by international societies. In asymptomatic FL pts responding to first line (1L) immunochemotherapy, the Spanish GELTAMO FL guidelines recommends CT scan every 6 months for 2 years (during rituximab maintenance). The real value of surveillance with CT scans remains an open question, even more after the incorporation of PET in the response evaluation of FL. Our aim was to evaluate the detection rate of relapses by CT surveillance according to GELTAMO guidelines in FL pts with complete metabolic response (CMR) or partial metabolic response (PMR). Methods: observational prospective study in a single center between 2008 and 2020. Newly diagnosed FL who had CMR or PMR to 1L therapy were identified. Evaluation for both relapse and method of relapse detection, having special interest in the CT surveillance according to GELTAMO guidelines. Results: From 108 FL treated pts, 81 were included in the final analysis. Median age and female proportion were 59 years (range 24–83) and 49.4%. Treatment: R-CHOP/R-CHOP-like 63%, R-CVP 15% and rituximab 22%. Response: CMR 82%, PMR 18%. Median follow-up was 79.7 months (IQR 57.8–117.3). A total of 29 pts relapsed or progressed (35.8%) during the whole study period: 24 from CMR and 5 from PMR. Of these pts, 9 relapsed in the first 2-y (31.0% of all relapses and 11.1% of all patients) and were more common in pts in PMR versus CMR (60% vs. 25%, p = 0.1238). Relapse detection method in the first 2-y was: 5 (55.5%) by CT scan, 2 by physical examination and 2 by other methods. Beyond 2-y, 12 (60%) were detected by physical examination, 5 (25%) by CT scan, 2 (10%) by blood tests and 1 (5%) by ultrasound echography. Protocol adherence was 75.3%. A total of 262 CTs were performed in first 2-y with only 5 positive CT scans in this time-lapse (diagnostic yield 2%). Globally, 17.2% of all relapses were diagnosed by GELTAMO recommended surveillance CT scans. Time from first relapse to second line treatment was 4.02 months in those with relapse detected by CT in schedule versus 2.03 months in those detected by other methods (p = 0.81) (Figure 1A). In relapsed pts, OS at 3-y from relapse was 30.0 months in those with relapse detected by CT in schedule versus 66.2 months in the other patients (p = 0.077) (Figure 1B), probably because of the enrichment of POD24 cases in the first group. However, OS at 3-y from relapse in those patients in which relapse was detected by CT at any time (in or out schedule) was 43.8 months versus 66.9 months in those detecting relapse by other methods (p = 0.19). Keywords: Imaging and Early Detection, Indolent non-Hodgkin lymphoma, PET-CT No conflicts of interests pertinent to the abstract.

P752 Predictors of time to relapse upon ozanimod withdrawal in patients with moderately to severely active ulcerative colitis

Abstract Background Ozanimod (OZA) is approved in the EU, US, and other countries for the treatment of moderately to severely active ulcerative colitis (UC) in adults based on the phase 3 True North (TN) trial. Data on time to disease relapse in patients (pts) who withdrew OZA treatment in TN were previously reported (Sands BE et al. Am J Gastroenterol. 2022;17(suppl):S506-7). The objective of this post hoc analysis was to identify predictive and prognostic variables of time to disease relapse in the TN maintenance period (MP). Methods Pts in TN were randomised to once-daily oral OZA 0.92 mg or placebo (PBO) in a double-blind manner or to open-label OZA for a 10-week induction period. Those with clinical response to OZA at Week 10 were then rerandomised to continue OZA (OZA/OZA) or switch to PBO (OZA/PBO) in the MP. Disease relapse was defined as an increase in partial Mayo score of ≥2 points from Week 10, absolute partial Mayo score ≥4, Mayo endoscopy subscore (MES) ≥2, and exclusion of other causes of increased disease activity unrelated to UC. Time to disease relapse was estimated using the Kaplan-Meier method in both MP groups. The saturated Cox proportional-hazards model for assessing predictors of time to disease relapse included demographics, disease characteristics, prior medications, and laboratory and efficacy variables at the end of the induction period. Insignificant terms at α=0.05 were removed via backward elimination. Results The OZA/OZA arm (n=230) had a slightly higher proportion of pts with baseline severe endoscopic disease than the OZA/PBO arm (n=227). Otherwise, baseline and Week 10 characteristics were balanced across MP arms (Tables 1 and 2). In multivariable analyses, corticosteroid use at Week 10 was prognostic for time to relapse (P&amp;lt;0.0001; no interaction with individual treatment arms). MES &amp;gt;1 and clinical response but not remission at Week 10 were also assessed as prognostic variables, but these did not achieve statistical significance at α=0.05 (P=0.071 and P=0.171, respectively). Relapse rates were low and similar regardless of prior biologic exposure in the OZA/OZA arm. Prior biologic exposure was an independent predictor of time to relapse after withdrawal of OZA in the OZA/PBO arm (P=0.027) (Figure 1). For OZA/PBO pts, Week 16 Kaplan-Meier estimates and 95% CI of no relapse were 83.8% (76.7–88.8%), 72.1% (54.4–83.9%), and 48.5% (30.8–64.1%) for the biologic-naive, 1 failed biologic, and ≥2 failed biologics groups, respectively. Conclusion Increasing numbers of prior biologics were predictive of increased rates of disease relapse in pts who discontinued OZA. Pts with UC, especially those with prior biologic failures, should minimise OZA discontinuation to mitigate the risk of disease relapse.

The First Report of Third-Generation TKI Olverembatinib in Adult Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia with T315I Mutation and Relapsed Disease

Background Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients(pts) with Ph/BCR-ABL1-positive (Ph/BCR-ABL1+) acute lymphoblastic leukemia (ALL). However, mutations in the ABL1 kinase domain, especially T315I, are the main mechanism of resistance to the first- or second-generation TKIs. Olverembatinib is a novel third-generation TKI developed in China and approved in Dec. 2021, which has been demonstrated great efficacy and safety in clinical trials of CML with T315I mutation. Our study is the first application of Olverembatinib in adult Ph/BCR-ABL1+ ALL with T315I mutation. Herein, we report the preliminary results. Methods In this exploratory study, adult Ph/BCR-ABL1+ ALL pts with T315I mutation or disease progression were treated with olverembatinib monotherapy (40 mg, every 2 days) or in combination with VP based low intensive chemotherapy (Vincristine/Prednisone) in our institution. Efficacy was assessed by complete remission (CR) rate, MRDneg (<0.01%) rate by multiparameter flow cytometry (MFC) and CMR (BCR-ABL1 transcript<10-5) rate by real-time quantitative polymerase chain reaction (RT-qPCR). Safety profiles were also monitored in this study. Results From December 2021 to June 2022, 10 Ph/BCR-ABL1+ ALL pts were treated with olverembatinib due to T315I mutation or disease recurrence, after prior TKIs combined with chemotherapy. Median age was 60.5 years (range, 37-65), and 6/10 were males. 5 pts had received 2 types of TKIs previously, of which 2 pts relapsed after ponatinib (Table 1). Among 10 pts, 6 were still in CR1 (pt 1-6), their T315I mutations were detected during regular follow-up. 4/6 pts were persistently molecular positive, while the other 2 had molecular relapse. Median time from diagnosis to the administration of olverembatinib was 5 months (range, 3-17). Among the 4 pts with hematologic relapse (pt 7-10), 2 (pt 7, 8) had T315I mutation. Because of the successive occurrence of G250E, Y253H, L248V mutations and L248 K274del, the 3rd one (pt 9) relapsed twice and failed to response to two kinds of TKIs and chemotherapy. As for the last pt (pt 10), although no ABL1 mutations were found, she was in 3rd relapse with CNS and BM involvement. Median time from diagnosis to the start of olverembatinib for these 4 relapsed pts was 28 months (range, 5-41). Among 6 pts with T315I mutation and persistent molecular diseases or molecular relapse, the CMR rate was 66.7%, with a median time of 3 months (range, 1-4) to achieve CMR. Then 2 pts underwent allo-HSCT (pt3, 4), who were still in CR. Among 4 hematological relapsed pts, the CR rate was 75%. 1 pt (pt8) with T315I was unresponsive, while another T315I positive patient achieved MRDneg by MFC after 1 month of treatment, with a complete disappearance of T315I mutation (pt7), though the BCR-ABL1 transcript was still positive. The remaining 2 relapsed pts without T315I mutation achieved hematologic CR after 1 month of olverembatinib monotherapy (pt9,10). Totally, overall response rate (ORR) was 70% and MRDneg rate by MFC was 71.4% (5/7), while the CMR rate by PCR was 57.1% (4/7). Notably, olverembatinib was ineffective in neither of the 2 pts who have been previously treated by ponatinib. Meanwhile, the olverembatinib-based therapy was well-tolerated, and the main adverse events of the third-generation TKIs, such as cytopenia, elevated transaminases, hypertension, and cardiovascular events, were less frequent than those reported relating to ponatinib. In addition, 4 patients developed grade 1 skin pigmentation (pt2,3,6,9). There were no drug-related death or permanent discontinuation due to toxicity. Conclusion This work suggests that Olverembatinib is a very promising 3rd-generation TKI. It is effective and safe in Chinese adult Ph/BCR-ABL1+ ALL with extremely poor prognosis, especially in T315I mutated or relapsed pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of Emergent FLT3 Mutations (FLT3m) at Relapse in Patients (Pts) with Wild-Type FLT3 Acute Myeloid Leukemia (AML)

Background:FLT3 mutations (FLT3m) are detected in approximately 30% of newly diagnosed (ND) pts with AML and are associated with poor prognosis. FLT3m can also emerge in relapse in pts with previously wild-type FLT3 AML; however, their frequency and clinical implications are not well studied. Our objective was to identify pts who relapsed with emergent FLT3m and compare their clinical and pathological characteristics to those who relapse without FLT3m. Methods: We identified 686 pts with ND AML treated at our institution between 12/2005 and 01/2020, who achieved complete remission (CR) / CR with incomplete count recovery (CRi) and subsequent relapse of AML. Pts with available FLT3 status (ITD and TKD) at diagnosis and within 4 weeks of first relapse were included (N=300). A multiplex fluorescent-based PCR analysis followed by capillary electrophoresis for detection of FLT3 ITD and/or TKD was performed on DNA isolated from BM aspirate samples. Next-generation sequencing (NGS) at baseline was performed using the Illumina MiSeq platform with multigene panels (either 28-gene, 53-gene, or 81-gene) interrogating genes recurrently mutated in myeloid neoplasms. Results: Among 300 pts who achieved CR/CRi after induction and eventually relapsed, 216 (72%) had FLT3 wild-type (WT) AML and 84 (28%) had FLT3m AML at diagnosis. Baseline clinical features are shown in Table 1. 43 (14%) pts had a change of FLT3 status between baseline and relapse: 30 pts had FLT3m at baseline that wasn't detected at relapse, and 13 pts with FLT3 WT AML at baseline experienced relapse with FLT3m AML. The median remission duration (until 1st relapse) for the entire study cohort pts withFLT3 WT and pts with FLT3m AML was 7.8 months (range, 0.2-147.2), 9 months (0.2-147.2), and 6.1 months (range, 0.5-79.6), respectively. FLT3 wild-type at Diagnosis Among 216 pts with FLT3 WT AML at baseline, 203 (94%) and 13 (6%) experienced relapse with FLT3 wild-type and FLT3m AML, respectively. Comparison of baseline molecular features of FLT3 WT and FLT3m cohorts showed that pts who had relapsed AML with a positive FLT3m had more frequent concomitant NRAS mutations compared with pts who had FLT3 WT AML at relapse (60% vs 5%; p=0.003). No significant difference was seen in the frequency of TP53 (49% vs. 20%; p=0.36), NPM1 (15% vs. 40%; p=0.19), DNMT3A (16% vs. 40%; p=0.21), KRAS (5% vs. 0%; p=1), or PTPN11 (3% v. 0%; p=1) mutations between the two cohorts, respectively. Among 13 pts with AML with emergent FLT3m, 12 had diploid cytogenetics at diagnosis, but only 6 maintained the diploid status at relapse. The remaining 6 pts developed karyotypic clonal evolution at relapse (complex, n=1; KMT2A rearrangement, n=1; trisomy 8, n=1; other alterations, n=3). We had paired baseline and relapse NGS performed in 5 of 13 pts with relapsed AML, among these AMLs acquired new mutations. Nine newly acquired mutations were detected in the following genes: NPM1 (n=1), KRAS (n=1), RUNX1 (n=1), IDH2 (n=1), DNMT3A (n=1), ZRSR2 (n=1), WT1 (n=2), and STAG2 (n=1). Two of 5 pts had AML with no mutations at baseline, and 1 pt had AML with the same mutation profile at baseline and relapse. The median OS after relapse was 5.3 months and 5.5 months in pts with WT vs. FLT3m AML, respectively (P=0.29) (Figure 1). FLT3 mutant at diagnosis Among 84 pts with FLT3m AML at diagnosis, 52 (62%) and 32 (38%) pts experienced relapse with FLT3m and WT AML, respectively. Comparison of baseline molecular features of FLT3 WT and FLT3m AML showed a trend towards a higher frequency of NPM1 (77% vs. 47%; p=0.09) and DNMT3A mutations (55% vs. 21%; p=0.08) in patients who experienced relapse with FLT3m AML compared with FLT3 WT AML. No difference in the frequency TP53 (0% vs. 23%; p=0.13), KRAS (0% vs. 14%; p=0.27), NRAS (14% vs. 9%; p=0.63) and PTPN11 (7% vs. 14%; p=1) mutations was observed among both cohorts, respectively. The median OS after relapse was 8.1 months vs. 3.9 months in pts with FLT3 WT vs. FLT3m AML, respectively (p=0.005) (Figure 2). Conclusion: Our data suggest that FLT3m are more likely to emerge at AML relapse with concomitant NRAS mutations and indicate that FLT3m testing should be performed at relapse, irrespective of FLT3status at diagnosis. It is common for the FLT3 status to change, either from mutant to WT or vice versa. FLT3 status has immediate and clinically important implications for selection of appropriate therapeutic agents in the setting of salvage therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Molecular Characterization of Clinical Response and Relapse in Patients with IDH1m ND-AML Treated with Ivo+AZA in the AGILE Study

Background: Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in approximately 6-10% of patients (pts) with AML. Ivosidenib (IVO), a potent, oral, targeted inhibitor of mIDH1, is FDA approved as monotherapy for the treatment of relapsed/refractory AML and newly-diagnosed AML (ND-AML) in adults >75 years of age or with comorbidities that preclude the use of intensive chemotherapy. In addition, the combination of IVO with azacitidine (AZA) was recently FDA approved in older or unfit AML pts with mIDH1 as a result of the global Phase 3 AGILE trial (NCT03173248). Compared to placebo (PBO) + AZA, the combination of IVO + AZA extended event-free survival (EFS; hazard ratio 0.33, 95% CI [0.16 - 0.69]; P = 0.002), overall survival (OS; median 24.0 months vs. 7.9 months; hazard ratio 0.44; 95% CI [0.27 - 0.73]; P = 0.001), and increased the rates of complete remission or complete remission with partial hematologic recovery (CR/CRh; 52.8% vs. 17.6%). To date, biomarker analysis has shown that IVO+AZA is associated with deep and durable clearance of IDH1m clones with improved clinical responses and EFS/OS in several pt subgroups, including those with mutations in receptor tyrosine kinase (RTK) pathway genes, a subgroup refractory to IVO monotherapy. Aim: To characterize clonal evolution and relapse mechanisms in pts with mIDH1 ND-AML treated with IVO+AZA. Methods: Patients received oral IVO + AZA per study protocol. Next-generation DNA sequencing (DNA-seq) on baseline and longitudinal samples was performed on bone marrow aspirates (BMA), bone marrow mononuclear cells (BMMCs), or peripheral blood mononuclear cells (PBMCs) depending on sample availability using the ACE Extended Cancer Panel (Personalis, Inc); limit of detection (LOD) 2% variant allele frequency (VAF). This analysis was focused on variants in 95 AML-associated genes with known or likely oncogenic potential. Results: Among 72 pts enrolled on the IVO+AZA arm, 46 had both baseline and longitudinal DNA-seq data available, with a median follow-up of 366 days on study (range 16 - 1210). The median number of baseline mutations was 3 (range 1 - 10). Suppression of all baseline non-DTA (DNMT3A / TET2 / ASXL1) mutations to below the LOD ("mutation clearance") was observed in 28 patients, including 22/34 (65%) pts who achieved CR/CRh [Table 1]. To identify potential mechanisms of acquired resistance, on-treatment samples were analyzed for the emergence of mutations not detected at baseline. Overall, emerging mutations were identified in 22/46 (48%) pts (median 2 emerging mutations; range 1-6). 2/46 (4%) pts had emerging mutations in IDH2, but discontinued treatment due to adverse events and stable disease, respectively. No second-site IDH1 mutations were observed across any response category. Longitudinal samples were available for 8/10 (80%) pts who discontinued treatment due to relapse (RL) following an objective response (4 CR, 2 CRh, 1 CRi, 1 MLFS). Emerging mutations were detected in 6/8 (75%) of RL pts [Table 2]. Genes with emerging mutations recurrently associated with RL included ASXL1, FLT3, RUNX1, and TET2 (2 pts each). The IDH1 mutation was not detected at RL in 6/8 (75%) pts. Among the two RLs that occurred in the absence of emerging mutations, one was associated with expansion of a baseline FLT3-ITD subclone, and one was not associated with any new emerging or expanding mutations. To further evaluate clonal evolution and disease progression of these pts, scDNA-seq is being performed and will be presented. Conclusion: IVO+AZA combination therapy leads to deep and durable remissions associated with clearance of mIDH1 and baseline co-mutations. To date, no second-site IDH1 mutations have been observed, but mutations in other genes, including IDH2, can emerge and may provide an opportunity for relapse. Relapses were observed in a subset of responders and were generally associated with expansion or emergence of high-risk mutations occurring independently of mIDH1. Further study is needed to better characterize mechanisms of RL to IVO+AZA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Adjuvant palbociclib for ER+ breast cancer (PALLAS Trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13): A preplanned analysis of the stage IIA cohort

390216 Background: CDK4/6 inhibitors have become standard of care for advanced hormone receptor positive, HER2-negative (HR+/HER2-) breast cancer in combination with endocrine therapy (ET), with one approved for high-risk patients (pts) in the adjuvant setting. The PALLAS Trial investigated the addition of palbociclib to adjuvant ET in pts with stage II-III breast cancer. Stage IIA patients were specifically enrolled to evaluate the potential benefit of using palbociclib with adjuvant ET pts diagnosed at lower risk who may have more indolent disease. Methods: In the prospective, randomized, phase III PALLAS trial, pts with HR+/HER2- early breast cancer were randomly assigned to receive adjuvant ET for at least 5 years with or without 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle). ET was of provider’s choice. Stage IIA enrollment was capped at 1,000 patients. While the primary end point of the overall study was invasive disease-free survival (iDFS) for the entire cohort, there was a preplanned analysis of recurrence and survival endpoints in the stage IIA cohort. Outcomes were compared between arms using stratified log-rank tests and Cox models (stratification factors: chemotherapy and age ≤ 50). Results: Among 5,796 pts enrolled at 406 centers in 21 countries worldwide between 9/1/2015 and 11/30/2018, a total of 1,010 stage IIA pts were enrolled. The protocol-defined number of events occurred at a median follow-up of 50 months for this subgroup (43.1 months for the overall study). Median age within this subgroup was 54 (range 29-85 yrs), and 410 (40.6%) were pre/perimenopausal, 506 (50.1%) T2/N0 (vs T0-1/N1), 272 (26.9%) grade 3 (vs. grade1/2), and 561 (55.5%) received chemotherapy. iDFS events occurred in 31 of 503 (6.2%) pts who received palbociclib plus ET and in 45 of 507 (8.9%) pts who received ET alone, resulting in a statistically nonsignificant difference in iDFS at 4 years (92.9% vs. 92.1%; hazard ratio, 0.75; CI, 0.48 to 1.19; P = .23). Nonsignificant differences were also observed for invasive breast cancer-free, distant recurrence-free, and locoregional cancer-free survival. No significant differences in iDFS were observed in subgroups including age group, receipt of chemotherapy, tumor grade, and clinical risk (T1/N1 vs. T2/N0).Conclusions: In this preplanned analysis of the stage IIA cohort of the PALLAS trial, the addition of adjuvant palbociclib to standard ET did not improve outcomes over ET alone, suggesting no benefit from the agent in reducing the incidence of early relapse in pts with lower-stage HR+/HER2- breast cancer. Future analyses will incorporate genomic risk and other molecular patterns from the extensive transPALLAS correlative program. Additional follow-up (10-year minimum) is also underway to assess the impact of palbociclib exposure on late recurrence in HR+ disease. Clinical trial information: NCT02513394.

P548: BEMCENTINIB COMBINED WITH LOW-DOSE CYTARABINE IS EFFICACIOUS AND WELL TOLERATED IN RELAPSED AML PATIENTS UNFIT FOR INTENSIVE CHEMOTHERAPY. UPDATES FROM THE ONGOING PHASE II TRIAL (NCT02488408)

Background: The new standard of care (SOC) in newly-diagnosed AML patients (pts) unfit for intensive chemotherapy (IC) due to age or co-morbidities yields favourable efficacy. However, beyond 1st line, these pts have limited treatment options, with a dismal mOS of 2.4 months at relapse, highlighting a significant unmet need for new treatments in this pt population. Bemcentinib (BEM) is a first-in-class, orally bioavailable, highly selective AXL-inhibitor. AXL (a receptor tyrosine kinase) represents an important target in AML, as its expression on AML cells and stem cell compartment is associated with poor prognosis, resistance to chemotherapy and decreased antitumor immune response. Aims: The ongoing BGBC003 PhII trial studied the safety and efficacy of the BEM+LDAC combination in relapsed (REL) AML pts unfit for IC; in addition, a comprehensive translational biomarker analysis was pursued. Here, we present preliminary efficacy and safety data and include initial translational multiomics data from bone marrow mononuclear cells (BMMNC). Methods: Pts received BEM at 200 mg/OD with 3 loading doses at 400 mg/OD and LDAC at SOC schedule. Study endpoints included overall survival (OS), objective response (OR), clinical benefit rate (CBR) (OR+unchanged [UC]) and exploratory biomarker analyses. Longitudinal BMMNC samples (n=32) from 13 pts underwent scRNA-seq and CITEseq (Chromium 10x genomics; TotalSeq, Biolegend). Pts were stratified by best response: CR, CRi, PR for Responders; UC, PD for Non-Responders. Cell type annotations were inferred from expression of known markers at RNA and protein level and for identification of malignant cells copy number variation was included. Results: As of 13 Dec 2021, 22 REL AML pts (10/22 in 1st relapse) were treated with BEM+LDAC. Median age was 75.5yrs [66-86], median prior lines of therapy 1 [1-8] and adverse cytogenetic risk in 7/22 (32%). Only 19/22 pts were evaluable for efficacy. The overall REL population (n=19) demonstrated a composite CR (CRc=CR+CRi) of 26% (5/19) and CBR of 79% (14/19); AML pts in 1st relapse (10/19) showed a CRc of 30% (3/10) and CBR of 70% (7/10) whereas REL pts with time on treatment (ToT) > 3 months (11/19) achieved CRc of 45% (5/11) and CBR 91% (9/11); median ToT of 12.9 months for CR/CRi pts; 1 pt remains on treatment. Median OS was 6.2 months in the overall REL pts (n=19), 7.4 months in the AML pts in 1st relapse (10/19) and 11.3 months in REL pts with ToT >3 months. Late onset responses suggest an immunological mechanism of action (iMOA) and may contribute to a longer ToT and survival. CITEseq analysis identified differences in the immune compartment, underscoring an iMOA associated with response to BEM+LDAC. Furthermore, increased gene set enrichment of TNFα signalling via NfkB at screening in malignant blasts of responders emphasizes the influence of the TNFα signalling pathway as an interesting field of further research. The safety profile of BEM+LDAC in the REL AML pts (n=19) is comparable with the known safety profile of LDAC. TRAEs of ≥G3 observed in ≥10% of pts were anaemia (33% BEM+LDAC; 22% BEM), and ECG QT prolonged (11% BEM+LDAC; 11% Bem). No G5 TRAEs reported. Summary/Conclusion: BEM+LDAC is efficacious and well tolerated in REL AML pts unfit for IC, with promising survival benefit compared to historical data. Translational research showed activation of CD8+T cells and B/Plasma cells in response to treatment, indicating that BEM elicits activation of two major adaptive immune cell populations responsible for anti-AML immune responses. BEM+LDAC warrants further evaluation in this population.

P1217: INTRATHECAL METHOTREXATE PROPHYLAXIS AND CENTRAL NERVOUS SYSTEM RELAPSE IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH INTENSIFIED R-ACVBP STRATEGY

Background: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma is relatively uncommon (2-5%) and remains catastrophic with a median survival of 2 to 5 months. Intrathecal (IT) or intravenous high-dose methotrexate (HD MTX) have limited if any prophylactic impact on CNS relapse. We recently demonstrated in a cohort of 2203 patients included in multicenter clinical trials conducted by LYSA and GLA/ DSHNHL, that only 4 (1.6%) CNS relapses were seen with the R-ACVBP strategy in pts with aaIPI 2, 3 (and intermediate/high CNS-IPI), while 15 (3.9%) relapses did occur after R-(Mega)CHO(E)P. Aims: To address the role of IT in this intensified strategy R-ACVBP, we took the advantage of real world data of patients treated in four centers, and compared CNS relapses occurring in patients treated with R-ACVBP strategy with or without IT. Methods: The LYSA R-ACVBP strategy include four cycles of R-ACVBP (75 mg/m2 doxorubicin, and 1200 mg/m2 cyclophosphamide; 2 mg/m2 vindesine and 10 mg bleomycin on days 1 and 5) with four IT, two cycles of high dose methotrexate (3g/m2), four cycles of R-etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) and 2 cycles of cytarabine(100 mg/m2) given sub cutaneously for 4 days. 233 patients with previously untreated diffuse large B-cell lymphoma (DLBCL) aged 18 to 59 years old received this intensified strategy between 2010 and 2020. We excluded 30 patients who received ASCT in first line and 10 others who received less than four cycles of R-ACVBP. We assessed the risk for of relapse and CNS-relapse. We also assesed the impact of the 2 courses of subcutaneous aracytine on overall survival (OS) and progression free survival (PFS). Results: A total of 193 pts were included. Median age was 44.4 years (IQR, 30.8-53, range: 17-62). Distribution of CNS IPI was not significantly different comparing IT (n=132) vs non-IT (n=61) groups within aaIPI categories (Table 1). 92 patients did not receive the two courses of subcutaneous Aracytine (no AraC group) for consolidation and 101 patients received the two courses (AraC group). With a median follow-up at 57.2 months, the 3 year OS and 3 year PFS of the whole cohort was 93.6% and 86.2%, respectively, without significant difference between IT and non IT groups in terms of OS (3yr-OS, = 92.3% versus 95.1%, HR= 1.29 (95%CI, 0.41 to 4.04, p=0.67) and PFS (3yr-PFS, 84.4% versus 90.1%, HR= 1.26 (95%CI, 0.59 to 2.72, p=0.55). The 3y-cumulative incidence of CNS relapse for pts treated IT group was 3.2% (95%CI, 1.0 to 7.4), and 3.3% (95%CI, 0.6 to 10.2) in the non-IT group (p= 0.93). In pts with aaIPI 1, two patients experienced a CNS relapse, one in the IT group and one in the non-IT group. In pts with aaIPI 2,3 and intermediate/high CNS IPI, 4 patients experienced a CNS relapse, three out of four in the IT group. 92 patients did not receive the two courses of subcutaneous Aracytine (no AraC group) for consolidation and 101 patients received the two courses (AraC group). Receiving or not AraC did not have any impact on the CNS relapse with a risk of CNS relapse at 4.1% (95%CI, 1.3 to 9.5) for patients receiving AraC and 2.2% (95%CI, 0.4 to 6.9) for patients not receiving AraC (p= 0.48). Image:Summary/Conclusion: CNS relapse was rare in younger DLBCL treated with this intensified strategy. Only 6 CNS relapses were observed without difference between IT and non-IT groups. The results presented at the EHA will included the total cohort of more than 600 patients.

Long-term results of a phase 2 trial of crenolanib combined with 7+3 chemotherapy in adults with newly diagnosed FLT3 mutant AML.

7007 Background: Crenolanib is a potent type I FLT3 inhibitor active against FLT3- ITD, TKD and variant mutations. We report the long-term outcomes of a phase II trial evaluating crenolanib combination therapy in patients (pts) with newly diagnosed FLT3 mutant AML. Methods: Pts (≥ 18 yrs) with newly diagnosed FLT3-AML received 7+3 induction with cytarabine 100 mg/m2/d for 7 days and daunorubicin (DNR) (&lt;60 yrs: 90 mg/m2; ≥60 yrs: 60 mg/m2) or idarubicin (IDA 12 mg/m2) for 3 days. Crenolanib 100 mg TID was administered starting on day 9 until 72 hrs prior to next chemotherapy. Re-induction was allowed. Up to 4 cycles of HiDAC consolidation (&lt;60 yrs: 3 g/m2; ≥60 yrs: 1g/m2) was allowed. Eligible pts could proceed to transplant. Crenolanib maintenance therapy was offered for 1 yr after HiDAC or transplant. Results: 44 pts (22 male) with a median age of 57 yrs (range 19-75) were treated; 15 (34%) pts were &gt;60 yrs. 7 pts had initial WBC &gt;100,000/μL (2 had WBC &gt;200,000). 4 pts had AML following MDS/MPN. 39 (89%) pts had intermediate risk cytogenetics, 3 (7%) had adverse risk, and 2 were unavailable. 33 (75%) pts had FLT3-ITD, 8 (18%) had TKD, and 3 (7%) had ITD and TKD mutations. 11 pts had concomitant NPM1/ DNMT3A mutations, 11 pts had secondary AML-type mutations, and 2 pts had TP53. 28 pts received DNR/crenolanib; 16 pts received IDA/crenolanib. Overall CRc (CR + CRi) was 73% (32/44) after one induction cycle; 86% (38/44) after two cycles. CRc rates &gt; 80% were noted in pts ≤ 60 yo, FLT3-ITD mutations, concomitant FLT3/DMT3A/NPM1 mutations, intermediate risk cytogenetics, and WBC ≥ 100,000/µL. Median time to count recovery was 30 days. MRD-negative CRc was achieved in 94% of evaluable pts (17); 22 pts underwent HSCT. The most common treatment related adverse events (AE) were diarrhea (66%), nausea (57%) and febrile neutropenia (52%). Grade ≥3 AE included febrile neutropenia (50% pts), diarrhea (18%), nausea (6%), and rash (6%). No QTC prolongation was observed. 6 pts required crenolanib dose reduction during induction. High levels of serum crenolanib were achieved and maintained throughout therapy. With a median follow-up of 45 mos (4.4-54.9), the median OS for all pts has not been reached with 57% of pts alive. Median EFS for all pts was 45 mos. In younger pts (≤ 60 yo) OS was 69% and EFS 62%. Cumulative incidence of relapse was 15%. In older pts (61-75), 80% achieved CR/CRi, and median OS was 20 mos. Mutational analysis demonstrated clearance of multiple variant FLT3 mutations and no new FLT3 clones at relapse in pts completing protocol therapy. Conclusions: Long-term outcomes of a phase 2 trial of crenolanib combined with 7+3 induction and consolidation in adults with newly diagnosed FLT3 mutant AML demonstrate high response rates (CRc 86%). With a median follow-up of 45 mos, median OS has not been reached. A phase 3 trial (NCT03258931) randomizing pts with newly diagnosed FLT3 mutant AML to crenolanib vs midostaurin with 7+3 is ongoing. Clinical trial information: NCT02283177.

Bemcentinib (Oral AXL Inhibitor) in Combination with Low-Dose Cytarabine Is Well Tolerated and Efficacious in Older Relapsed AML Patients.Updates from the Ongoing Phase II Trial (NCT02488408) and Preliminary Translational Results Indicating Bemcentinib Elicits Anti-AML Immune Responses

Bemcentinib (Oral AXL Inhibitor) in Combination with Low-Dose Cytarabine Is Well Tolerated and Efficacious in Older Relapsed AML Patients.Updates from the Ongoing Phase II Trial (NCT02488408) and Preliminary Translational Results Indicating Bemcentinib Elicits Anti-AML Immune Responses

Exploring the Impact of Diffuse Large B-Cell Lymphoma (International Prognostic Index [IPI] 2-5) on Clinical and Patient-Relevant Outcomes in the Context of a Clinical Trial

Background: Most patients (pts) with diffuse large B-cell lymphoma (DLBCL) receiving first-line (1L) rituximab plus CHOP (R-CHOP) have similar mortality to the general population (gen popn) if they are progression-free at 24 months (PFS24; Maurer et al. Ann Oncol 2018). Characterization of quality of life (QoL) and clinical outcomes may enable more patient-relevant treatment decisions. Using GOYA trial data (NCT01287741) comparing obinutuzumab (G) + CHOP (G-CHOP) with R-CHOP, we present an exploratory analysis of 1L DLBCL pts with IPI 2-5 and assess overall survival (OS) and QoL relative to the gen popn. GOYA was not included in the previous PFS24 analysis by Maurer et al.Methods: We used data from both GOYA treatment arms to identify pts with IPI 2-5 DLBCL (n=1132 pts, intent-to-treat popn). Post-progression survival (PPS) in DLBCL is independent of prior treatment (Coiffier et al. Blood 2010) and as PFS was similar between treatment arms in GOYA, we assumed similar mortality after PFS24. Clinical outcomes were PFS24 (progression-free ≥24 months [m] from treatment start); early relapse (disease progression [PD]<24m from treatment start); late relapse (PD after PFS24). Outcomes for study pts vs gen popn were evaluated using standardized mortality ratios (SMR; deaths in study pts relative to expected deaths in gen popn matched by age, sex, country, and calendar time-at-risk). Expected deaths were derived using the Human Mortality Database, which provides detailed mortality and population data by country and can be used to estimate the background mortality during the observation period.Post-relapse survival in pts with early vs late relapse was assessed using Kaplan-Meier (KM) estimates and Cox regression. QoL was assessed using EQ-5D-3L and UK-based tariffs (Dolan. Med Care 1997); association between QoL and clinical outcomes used a linear mixed-effects model. The proportion of pts with PFS24 reporting QoL problems at baseline and after 24m was compared with age- and country-matched values in the gen popn (Janssen et al. Springer 2014). Data cut-off was Jan 2018 (GOYA final data cut); overall median follow-up was 48m.Results: In the overall IPI 2-5 population, mean age at treatment initiation was 61 yrs. 711 pts reached PFS24, of whom 64 experienced a late relapse (Table 1). Early relapse was experienced by 261 pts, of whom 164 were <6 months from end of treatment (EOT). OS following PFS24 was 98.6% at 2 years (including patients who later relapsed). 2-year PPS was 35.7% for pts with early relapse vs 74.8% for patients with late relapse (Figure 1.)Mortality following PFS24 was 72% of the matched gen popn (SMR 0.72; not significant: 95% CI 0.44-1.11). Mortality following relapse in pts who experienced early relapse was over 33 times higher than expected in the matched gen popn (SMR 33.57, 95% CI 27.69-40.33). However, risk of death following late relapse was reduced by 78% compared with risk following early relapse (HR 0.22 95 CI% 0.12-0.40), and mortality following late relapse was significantly higher than in the matched gen popn (SMR 6.7, 95% CI 3.05-12.67). Mean QoL utility score at baseline was 0.69 for all pts. After pts reached PFS24, estimated mean utility score was 0.86 (95% CI 0.84-0.87) and worsened by -0.07 (95% CI -0.14 to -0.01) at time of subsequent relapse. For early-relapsing pts, the worsening in utility was -0.15 (95% CI -0.20 to -0.10) compared with those still progression-free (Table 2).Among all PFS24 pts at baseline, problems were reported with mobility (28.1%), self-care (12.6%), usual activities (41.8%), pain/discomfort (62.7%), and anxiety/depression (48.8%); these rates were 2.2-4.7 times higher than the gen popn based on age- and country-standardized values. Compared with the gen popn, after pts reached PFS24, pain/discomfort was 10% lower, whereas anxiety/depression was 34% higher and other QoL items were approximately 20% higher.Conclusions: Most of the clinical course of 1L DLBCL occurred ≤2 years after start of treatment. In DLBCL pts with IPI 2-5 achieving PFS24, mortality was similar to the gen popn, and with the exception of mental health metrics, QoL scores were also similar to the gen popn. Late relapse (≥2 yrs) was associated with better post-relapse survival than early relapse (<2 yrs); however, this was inferior to the gen popn. Health state utilities improved whilst patients were relapse-free but the decline in QoL after early relapse was worse than after late relapse. [Display omitted] DisclosuresLaunonen: F. Hoffmann-La Roche Ltd: Current Employment. Ho: F. Hoffmann-La Roche Ltd: Current Employment. Knapp: F. Hoffmann-La Roche Ltd: Current Employment. Canales Ruiz: Clinical Project Manager in Clinica Universidad de Navarra: Current Employment. Simonella: F. Hoffmann-La Roche Ltd: Current Employment. Thuresson: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company.

Diffuse Large B-Cell Lymphoma (DLBCL) Patients with Late Relapses Who Are Transplant-Eligible Have Excellent Outcomes and May Represent Unique Biology

Diffuse Large B-Cell Lymphoma (DLBCL) Patients with Late Relapses Who Are Transplant-Eligible Have Excellent Outcomes and May Represent Unique Biology