CR Pts Research Articles

Comprehensive genomic profiling (CGP) of clinical T2-4N0M0 muscle-invasive bladder cancer (MIBC) treated with neoadjuvant pembrolizumab or cisplatin-based chemotherapy before radical cystectomy (RC).

653 Background: The identification of tumor biomarkers associated with pathological complete response (CR: ypT0N0) to neoadjuvant therapies is a primary goal of the ongoing clinical research in MIBC. Furthermore, evaluating the shifting spectrum of genomic alterations (GA) in matched pre-post therapy samples could orient novel therapeutic sequences. Methods: We retrospectively evaluated the clinical and genomic findings of patients (pts) with cT2-4N0M0 MIBC who received neoadjuvant pembrolizumab in the PURE-01 study, or standard cisplatin-based neoadjuvant chemotherapy (NACT), preceding RC at our center. We focused the analyses on the DNA GA via CGP assays, performed on tumor samples, to identify GA in 324 cancer-associated genes and genomic signatures, including TMB, using a hybrid capture-based comprehensive genomic profiling assay. TMB was categorized as low (<10 mutations [mut]/Mb), high (10-19), or very high (≥20). Germline status of GA was predicted using a validated somatic-germline computational method. Genomic signatures were analyzed via the principal Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways distribution according to the pathological response. The primary endpoint was to compare differences between ypT0N0 responders and nonresponders (NR: ypT≥2 and/or ypN1-3). All p-values were two-sided, and multiple hypothesis testing correction was performed using the Benjamini–Hochberg procedure to calculate the false discovery rate (FDR). Results: We identified TURBT samples from 129 pts included in PURE-01 and 27 patients treated with NAC, from 2017 to 2022. Mean GA/tumor of CR from PURE-01 was 28.8 vs 17.3 from NAC. No germline GA were found. In PURE-01, higher mean GA/tumor and higher mean TMB were the only GA associated with CR vs NR (p<0.001), whereas no differences were found at single gene and gene pathways level. In NAC cohort, no GA nor signatures were found to be significantly associated with CR. Despite the mean TMB of CR pts were similar between PURE-01 and NAC cohorts (16.4 vs 19.6 mut/Mb), mean TMB of NR in PURE-01 cohort was lower than that of NR from NAC cohort (9.3 vs 18.6 mut/Mb). In PURE-01 we analyzed 37 matched TURBT-RC samples: there were no significant differences in GA or pathways, with a nonsignificant decrease in mean TMB values in RC vs TURBT samples (6.73 vs 8.86 mut/Mb, p=0.16). Conclusions: In our study, no genomic biomarkers linked to NAC activity emerged at the CGP. Conversely, in PURE-01 TMB confirmed to be to most reliable DNA biomarker to separate CR vs NR. Interestingly, TMB values could also help predicting the lack of benefit from neoadjuvant pembrolizumab use, confirming the reliability of the 10 mut/Mb cutoff to allow the exclusion of predicted nonresponders from neoadjuvant pembrolizumab trials.

Circulating Tumor DNA Dynamics as Early Outcome Predictors for Lisocabtagene Maraleucel as Second-Line Therapy for Large B-Cell Lymphoma from the Phase 3 TRANSFORM Study

Background: While the prognostic value of MRD using ultrasensitive circulating tumor DNA (ctDNA) assays after first-line immunochemotherapy for DLBCL has been shown (Roschewski M, et al. Blood 2022;140[suppl 1]:785), its relevance to outcomes after second-line (2L) treatment with CD19-directed CAR T cell therapy remains unclear. The phase 3 TRANSFORM study (NCT03575351) showed statistically significant and clinically meaningful improvements in event-free survival (EFS), CR rate, and PFS for lisocabtagene maraleucel (liso-cel) compared with standard of care (SOC) for patients (pts) with primary refractory or early relapsed large B-cell lymphoma (LBCL) eligible for autologous HSCT (Kamdar M, et al. Lancet 2022; Abramson JS, et al. Blood 2023). Here, we report longitudinally measured ctDNA levels from TRANSFORM as a prospective measure of disease burden and describe the predictive value of ctDNA after 2L liso-cel therapy for LBCL. Methods: From the original randomized population (n = 184), 551 plasma samples from 160 pts (liso-cel, n = 79; SOC, n = 81) were used for ctDNA assessment in a blinded manner by Phased Variant (PV) Enrichment and Detection Sequencing (PhasED-Seq) at Foresight Diagnostics. Tumor-derived PVs were identified directly from baseline plasma samples taken at screening without use of tumor tissue; matched DNA from peripheral blood mononuclear cells was used to censor germline variants and clonal hematopoiesis. PVs were used to longitudinally assess ctDNA on the day of liso-cel infusion; at Day 15; and Months 1, 2, 3, and 12 after infusion. For the SOC arm, only pretreatment samples were evaluated. ctDNA levels were compared with baseline characteristics, responses by Lugano 2014 criteria, and EFS. Pts/samples were reported as having detectable MRD when ctDNA levels exceeded a detection threshold (≈1:10 6 cell-free DNA molecules) corresponding to 98% specificity. Results: PVs were identified from 136 of 160 pts (85%) with evaluable pretreatment samples from the liso-cel and SOC treatment arms. The remaining samples had lower disease burden (sum of product of diameters[SPD]; 13%) or failed quality check (2%). Pretreatment ctDNA levels varied widely (median [IQR]: 136 [35‒696] haploid genome equivalents/mL) and were correlated with disease indices portraying higher-risk disease, including stage ( P = 0.02), age-adjusted International Prognostic Index ( P < 0.0001), disease burden (SPD; P < 0.0001), and LDH ( P < 0.0001). Serial ctDNA levels were evaluated after liso-cel infusion in 63 pts. Achieving undetectable ctDNA was associated with achieving CR and longer EFS at all time points after liso-cel infusion. ctDNA levels decreased rapidly in pts who achieved CR at Month 3, with 50% (17/34) having undetectable ctDNA by Day 15 after liso-cel infusion. Conversely, 89% of pts (16/18) with PD at Month 3 still had detectable ctDNA at Day 15 with lower levels of ctDNA clearance. These results highlight significant enrichment of undetectable ctDNA observed as early as Day 15 after infusion between pts with Month 3 CR versus PD ( P = 0.006). ctDNA clearance in pts who achieved CR at Month 3 continued to deepen further over time, with undetectable ctDNA rates of 63%, 74%, and 86% at 1, 3, and 12 months after liso-cel infusion, respectively. Furthermore, most pts in CR by PET/CT had undetectable ctDNA at paired time points (71%), confirming that pts achieving CR also achieved durable molecular remission. In the cases with discordant CR and ctDNA results, detection of residual ctDNA was significantly prognostic for shorter EFS at all respective response assessments (fraction of CR cases with residual ctDNA at 1 month and Log-rank test P value for EFS: 47% [15/32], P = 0.011; 3 months: 26% [9/34], P = 0.025; 12 months: 13% [4/31], P = 0.003). Conclusions: Achieving undetectable ctDNA in the first 3 months and as early as 15 days after liso-cel infusion was significantly associated with durable clinical benefit. Conversely, detectable ctDNA captured relapse risk unmeasured by imaging. These results demonstrate the potential clinical value of ctDNA monitoring as a biomarker for disease surveillance and as an early predictor of clinical benefit of liso-cel treatment for LBCL, which could guide and accelerate future clinical trials.

A Phase II Study of Flumatinib with Chemotherapy for Newly Diagnosed BCR::ABL1-Positive Acute Lymphoblastic Leukemia in Adults: Updated Results from RJ-ALL2020.2A Trial

Background The introduction of the second-generation TKIs further improved outcomes in BCR::ABL1-positive acute lymphoblastic leukemia (BCR::ABL1+ ALL). Flumatinib is a novel second-generation TKI approved in China in 2019. It has shown better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL. Herein, we report the updated results of the RJ-ALL2020.2A trial, which is the first reported registered clinical trial of flumatinib in adult BCR::ABL1+ ALL last year. The enrollment will be completed at the end of Aug. 2023. Methods In this prospective phase II study, patient (pt) eligibility mainly includes: 18≤age＜65 years; newly diagnosed BCR::ABL+ ALL; with adequate organ function. Once the diagnosis is confirmed, the combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is given promptly. Allo-HSCT is recommended for all eligible pts. Blinatumomab is allowed to administer for MRD clearance before allo-HSCT. All pts receive central nervous system (CNS) prophylaxis once achieving remission. The choice of subsequent salvage treatments is based on the discretion of physicians. Multiparameter flow cytometry (minimal residual disease[MRD]<10 -4) and RT-qPCR (BCR-ABL1 transcript<10 -5) are used to monitor MRD. The primary endpoints are MRD clearance, PFS, and OS. (Clinical Trial Registration Number: ChiCTR2100042248) Results From Dec. 2020 to Jun. 2023, 81 adult pts with de novo BCR::ABL1+ ALL were enrolled. Seventy-eight pts were included in the efficacy and safety assessment (3 were excluded due to the short duration of treatment), and 76 were available for survival analysis (2 withdrew). Median age was 42 years (range, 18-63). Median WBC count at diagnosis was 38.7×10 9/L (0.6-675.3). Four pts had primary CNS leukemia (Table 1). Among 78 pts, 75 (96.2%) achieved CR/CRi at the end of induction, and 78 (100%) achieved CR/CRi at any time. No early death occurred during the induction course. MRD flow negative rates were 67.1% (51/76) and 79.7% (55/69), while the CMR rates were 31.1% (23/74) and 52.2% (36/69) at the end of induction and 3 months, respectively. With a median follow-up time of 16.2 months (range, 1.8-29.2), the estimated 2-year PFS and OS rates were 64.8% and 81.3% (Figure 1). Among the 69 survived pts, 61 were in continuous remission, and 8 were relapsed (4 had CNS involvement). Among 7 deaths, 6 died of disease progression (4 had CNS involvement), and 1 of pulmonary infection post-HSCT. There was a survival superiority in pts who achieved MRD flow negativity (PFS: p=0.091, OS: p=0.005) or CMR (PFS: p=0.055; OS: p=0.033) at 3 months. With a median time of 6.4 months (range, 1.6-10.3) from diagnosis, 46 pts (median age of 39 years [range, 20-60]) received allo-HSCT with 45 pts in CR1. The MRD flow negativity and CMR rates were 82.2% (37/45) and 70.5% (31/44) before HSCT, respectively. PFS and OS significantly improved in patients who underwent HSCT (PFS: p<0.001, OS: p=0.012). In multivariate analysis for PFS and OS, MRD flow negativity at 3 months (PFS: HR: 0.129, p=0.016; OS: HR: 0.151, p=0.029) and allo-HSCT (PFS: HR: 0.247, p=0.036; OS: HR: 0.176, p=0.042) still had a significant effect on PFS and OS as protective factors. When including CMR as a variable, CMR at 3 months (PFS: HR: 0.221, p=0.02; OS: HR: 0.115, p=0.054) and allo-HSCT (PFS: HR: 0.169, p=0.01; OS: HR: 0.139, p=0.021) had the similar impact on survival. Among 75 pts evaluable for ABL1 mutations, 24 (32%) pts were mutated, and T315I was the most frequently identified (75%). Pts with T315I mutation showed a poorer outcome than non-T315I mutation (PFS: p<0.001, OS: p=0.01). Meanwhile, the safety profiles of the flumatinib-based therapy were acceptable. Non-hematological AEs were mostly G1-2, which were reversible rapidly after symptomatic management. Most of the G3-4 AEs were hematological, possibly related to chemotherapy. No permanent discontinuation or death related to flumatinib was observed. Conclusion This prospective study further confirmed the efficacy and safety of the promising second-generation TKI flumatinib combined with chemotherapy in newly-diagnosed Chinese adult pts with BCR::ABL1+ ALL. Achieving MRD flow negativity or CMR at 3 months and bridging allo-HSCT could further improve survival. The long-term follow-up data will be disclosed soon.

Disease Control Affects Outcomes of Patients with Relapsed Diffuse Large B Cell Lymphoma Treated with CD19 Directed CAR T-Cell Therapy

Introduction: CAR T-cell therapy against CD19 (CART-19) has become the standard of care for pts with primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL) in the second and third line settings. The use of CART-19 therapy improves clinical outcomes compared to standard chemotherapy-based salvage regimens. However, DLBCL pts with disease progression following CART-19 therapy have poor overall survival (OS). Identifying biomarkers associated with improved outcomes can inform the optimal timing for CART-19 implementation. We report the impact of disease control at the time of CART-19 therapy on clinical outcomes. Methods: We conducted a retrospective study of relapsed/refractory (r/r) DLBCL treated at our institution with commercial CART-19 products between 4/2018 and 2/2023. Clinical, pathologic, and pharmacologic (type of bridging, lymphodepletion) characteristics were collected. PET/CT imaging prior to CART-19 therapy was used to determine pretreatment disease status (CR, PR or chemo-resistant disease). Treatment outcomes included best response to CART-19 therapy, frequency and severity of adverse events (CRS or ICANS), PFS and OS. Associations with clinical outcomes were evaluated using logistic regression models by Firth's method. Odds ratios [OR] and 95% CI were obtained. OS and PFS were summarized via Kaplan-Meier method; estimates of median 6- and 12-m rates were obtained with 95% CI. Associations with OS and PFS were evaluated using Cox regression models. Analyses were conducted in SAS v9.4; significance level 0.05. Results: 94 pts were included in this study. Median age was 64 yrs [range 22-81]; 66% were male; 90% Caucasian. Comorbidity index [assessed by HCT-CI] was 2+ in 51.7% pts. Median time from CART-19 discussion to re-infusion was 3.1 m [range 0.2-80 m]. Based on PET/CT scan assessment prior to CART-19 therapy, 9.6% pts achieved CR to bridging, 19% had PR, 64% were resistant (SD or PD). High risk IPI score was present in 23.4%. 14.9% pts had prior ASCT. FluCy lymphodepletion was given in 83% pts. Best response to CART-19 therapy: CR 45.7%, PR 12.8%. PD and SD observed in 28.7% and 3.2% of pts respectively. At median follow up of 36.5 m, median PFS was 6.7 m [95% CI 3.8-18.4]; median OS was 16.0 m [95% CI 9.8-30.6]. Any grade CRS occurred in 61.7%; Grade 3+ CRS 8.5%. Any grade ICANS occurred in 45.7%; Grade 3+ ICANS 16%. Second cancers occurred in 9.6%; 4 pts developed MDS. Adequate disease control at the time of CART-19 therapy was associated with improved ORR (P=0.028). Lack of disease control determined by PET/CT at the time of CART-19 infusion correlated unfavorably with OS and PFS. Pts with chemoresistant disease at the time of CART-19 therapy had a median survival of 7.2 m [HR 2.07 (0.74-5.79)] compared to pts in CR or PR at the time of CART-19 (median survival 27.9 m and 26.8 m respectively, p=0.023). Any grade ICANS [HR 2.46 (1.43-4.23) p=0.001], and ICANS grade 3+ [HR 3.38 (1.82-6.26) p=<0.001] were associated with an increased risk of death. On analysis of associations with PFS, lack of response to CART-19 therapy [SD/NR HR 15.05 (3.92-57.74) p=<0.001], any grade ICANS [HR 1.74 (1.06-2.87) p=0.029], and ICANS grade 3+ [HR 2.52 (1.38-4.59) p=0.003] were associated with increased risk for progression. Grade 3+ ICANS was adversely correlated with PFS in CR pts [HR 3.81 (1.22-11.90) p=0.021] and CR + PR pts. Several factors were associated with increased risk for toxicities. Lack of disease control at the time of CART-19 therapy, [OR 3.30 (0.79-13.79) p=0.003], development of ICANS, any grade [OR 4.08 (1.64-10.14) P=0.003] or grade 3+ ICANS [OR 7.71 (1.28-46.27) p=0.025] correlated with the development of any grade CRS. ICANS of any grade [OR 6.92 (1.12-42.79) p=0.037] and ICANS grade 3+ [OR 6.57 (1.50-28.77) p=0.013] correlated with Grade 3+ CRS. Lack of disease control status [OR 4.18 (0.85-20.55) p=0.011], any grade CRS [OR 4.08 (1.64-10.15) p=0.003], and grade 3+ CRS [OR 6.92 (1.03-46.64) p=0.047] were associated with an increased incidence and severity of ICANS. Conclusions: Disease control assessed by functional imaging at the time of CART-19 therapy for r/r DLBCL may be an independent predictor of CART-19 therapy outcomes. In this cohort, adequate disease control prior to CART-19 therapy was associated with improved ORR, PFS and OS. Optimizing disease control prior to cellular therapy may ultimately improve clinical outcomes while mitigating cellular therapy related toxicity.

Outcome of Children with B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) with Hypodiploidy or BCR-ABL1 Fusion Given Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Results from the Prospective Forum Study

Introduction: Hypodiploid karyotype (HYPO) and bcr-abl1 fusion (BCRABL) define high-risk BCP-ALL subtypes, with historically worse outcomes. Many front-line treatment protocols recommend allogeneic HSCT for these patients (pts), either in first complete remission (CR1) irrespective of response (adolescents/young adults with HYPO), if minimal residual disease (MRD) signals persist at specific time points (younger pts with HYPO and all pts with BCRABL), or following leukemic relapse. We have assessed the outcomes of BCP-ALL pts aged 4 to 18 years (y) with either HYPO or BCRABL who participated in the phase III ALL SCT PED FORUM study (EudraCT: 2012-003032-22) and underwent HSCT from either a matched sibling (MSD) or matched unrelated donor (MUD). Patients and Methods: Between 2014 and January 2023, 741 evaluable BCP-ALL pts were enrolled in FORUM (Table 1). HYPO was present in 61 pts, BCRABL in 82 pts, and neither lesion in 598 pts (NEITHER). 43/61 (70%), 40/82 (49%) and 215/598 (36%) pts with HYPO, BCRABL and NEITHER were in CR1, respectively (p= n.s.). Prior to HSCT, 82 of 101 HYPO/BCRABL pts with available MRD data were MRD negative by PCR and/or flowcytometry (<10-4). Total body irradiation (TBI) + VP16 was administered to 42 and 50 pts in the HYPO and BCRABL groups, respectively, while 18 HYPO and 30 BCRABL pts received non-TBI conditioning (busulfan or treosulfan + fludarabine and thiotepa, as per study protocol). Randomization determined allocation to TBI/non-TBI treatment arms until randomization closure in 03/2019, while treatment in some pts was dictated by lack of access to TBI, or contraindication to TBI in individual pts. An MSD was available in 14 (23%) and 24 (29%) HYPO and BCRABL pts, respectively. Notably, 24 out of 143 pts (17%) with HYPO/BCRABL received immunotherapy before HSCT (blinatumomab, inotuzumab ozogamicin, and/or CAR-T cells). Post-HSCT, 14 out of 82 BCRABL pts (17%) received a tyrosine kinase inhibitor (TKI), either prophylactically or pre-emptively. Results: With a median follow-up of three years post-HSCT, the 5-y probabilities of overall survival (OS) for pts with HYPO, BCRABL and NEITHER were 0.79±0.06, 0.83±0.05, and 0.74±0.02 (p=n.s.), while those of event-free survival (EFS) were 0.73±0.06, 0.65±0.07, and 0.61±0.02, respectively (p=n.s.). The 5-y cumulative incidence of relapse (CIR) for HYPO/BCRABL and NEITHER pts was 0.21±0.04 and 0.29±0.02 (p=0.036), and 5-y non-relapse mortality (NRM) was nearly identical for these groups (0.07±0.2 and 0.08±0.1). Among pts who received TBI, 5-y OS and EFS for HYPO, BCRABL, and NEITHER groups were 0.76±0.08 and 0.70±0.08, 0.89±0.05 and 0.70±0.10, and 0.80±0.03 and 0.71±0.03, respectively (p=n.s., Figure 1), while 5-y CIR and NRM post TBI were 0.15±0.06 and 0.11±0.05, 0.15±0.06 and 0.11±0.05, and 0.20±0.02 and 0.07±0.02, for the three groups, respectively (p=n.s.). The 3-y GvHD-free/relapse-free survival (GRFS) was similar between HYPO/BCRABL and NEITHER (0.60±0.06 and 0.58±0.03, respectively) and reached a plateau at 5-years (0.60±0.06 and 0.57±0.03, respectively). In subgroup analyses of pts in CR1 and >CR1, comparable outcomes were observed for HYPO, BCRABL, and NEITHER, hence results were not affected by the remission status. BCRABL and NEITHER pts receiving non-TBI conditioning had inferior outcomes (5-y EFS of 0.56±0.10 and 0.47±0.04, respectively) with a high 5-y CIR (0.36±0.09 and 0.43±0.04, respectively) as compared to those who received TBI. Similar 5-y OS and EFS were seen in HYPO pts whether receiving TBI (0.76±0.8 and 0.70±0.08) or chemo conditioning (83±0.09 and 83±0.09). Rates of NRM and acute/chronic graft-versus-host disease were similar in pts receiving TBI/ non-TBI conditioning and in BCRABL/HYPO vs. NEITHER pts. In multivariate analysis adjusted for CR status, conditioning and MRD, EFS did not differ between HYPO/BCRABL and NEITHER pts. Conclusions: Children receiving HSCT for treatment of BCP-ALL with either hypodiploidy or bcr-abl1 fusion showed outcomes comparable to BCP-ALL pts without these genetic lesions. CIR and EFS reached plateaus beyond 3 y post-HSCT, indicating that approximately two-thirds of these pts can be cured by HSCT with low rates of treatment-related mortality. Pts with BCRABL achieved favorable outcomes without the need for long-term or lifelong TKI therapy.

CNS Irradiation in Adult De Novo B-Precursor ALL / Lbl: Results of the Randomized GMALL T rial 08/2013 Indicate Potential Antileukemic Efficacy

In the past decade outcome of adult ALL was improved significantly using pediatric-based chemotherapy. The GMALL Trial 08/2013 (NCT02881086) for patients (pts) aged 18-55 years (yrs) with newly diagnosed ALL/LBL is a pediatric based regimen with MRD based treatment stratification and risk adapted stem cell transplantation (SCT) (Gökbuget et al, ASH 2021). CNS prophylaxis consisted of three doses i.th. MTX during induction II, 11 doses of triple i.th. for standard risk (SR) in consolidation (C)/maintenance and 1 dose before SCT in high risk (HR); 7 vs 1 cycle of HDMTX (1.5 g/m 2 as 24h infusion) were scheduled in SR and HR resp. Prophylactic fractionated CNS irradiation (RAD) with 24 Gy during induction II (IP2) was part of all previous GMALL trials. The trial incorporated a randomization for Ph/BCR::ABL1 negative (Ph-) B-precursor ALL/LBL without initial CNS involvement and treated until C1 in order to compare standard IP2 with i.th. MTX with vs without CNS RAD. The key endpoint was the time from start of induction to start of C1 in CR pts, reasoning that less toxicities and treatment delays would occur without CNS RAD. Further endpoints were remission duration (RD), event-free survival (EFS) and cognitive disturbances (DemTect Test). The statistical assumption was that it is possible to detect a shortening of time to C1 from 74 to 69 days with a power of more than 90% with 215 pts per arm with a two-sided α-niveau of 5%. Between 8/2016-8/2022 1023 pts from 78 centers were included. 512 pts had Ph- B-precursor ALL/LBL (497/15). 31 pts had initial CNS involvement (N=20) or were not randomized due to other reasons (N=11). 241 pts were randomized in arm A (RAD) and 241 in arm B (NoRAD). The median age was 33.5 (18-55) yrs; c/pre B-ALL versus pro B-ALL was present in 83% vs 17%. 191 were HR vs 291 SR. No significant differences were observed between both arms. 477 pts were randomized (ITT population) and 422 were eligible (analysis population) since they achieved CR and were treated until C1. Reasons for non-eligibility were protocol violation (N=5), early death (ED) (N=15), withdrawal (N=12), no CR before C1 (N=18) and late withdrawals in CR before C1 (N=10). 207 pts in the RAD-arm (86%) vs 215 pts in the NoRAD-arm (89%) were eligible. In the analysis population treatment per randomization was 97% in NoRAD and 95% in RAD arm. CR rates before C1 (95% RAD vs 96% NoRAD), ED rates (5% vs 4%), rates of grade III/IV leukopenia in IP2 (14% vs 16%) and infections (29% vs 29%) were similar. The median time to C1 was similar too (75 vs 76 days; p=0.34). Relapse rates (RR) were lower in RAD (13%) vs NoRAD (18%) (p=0.14). Whereas CNS relapses were infrequent in both arms (N=1 vs N=3 i.e. 1% vs 1%; p=0.62), the rate of BM±other relapses (11% vs 15%; p=0.15) was lower in the RAD arm. The cumulative incidence of CNS relapse at 3 yrs was 1% vs 1% and of all relapses 14% vs 20% (p=0.13). The EFS at 3 yrs was higher for the RAD (79% [95%-CI: 72% - 85%]) vs NoRAD (72% [95%-CI: 65% - 78%])(p=0.10) in the analysis population and 74% vs 67% (p=0.13) in the ITT population. In the ITT population the impact was statistically significant (p=0.05) in SR pts whereas no difference was detected in HR (i.e. pts with indication for SCT) (figure 1); differences did not reach significance in the analysis population. We further analyzed the impact of randomization arm on cognitive function (analysis population). After C1 results were available in 264 pts. In the RAD vs NoRAD arm 2% vs 2% resp. had low scores (0-8) and 10% vs 8% intermediate scores (9-12) indicating a relevant or limited cognitive disturbance. At the end of therapy (week 130), results are available in 53 pts treated in SR arm. 0% vs 4% had low and 4% vs 4% intermediate scores. Thus, relevant cognitive limitations were present in both arms. The primary endpoint (time to C1) was not met. Pts with RAD did have a trend towards better EFS and RD. The CNS RR was overall low but CNS RAD might have an impact on the systemic relapse rate in SR pts. We recorded no significant negative impact of CNS RAD on DemTect results, but this requires further observation. Results must be interpreted in the context of adult pts with potentially lower risks for cognitive disturbances compared to children and - on the other hand - a relatively low dose of systemic HDMTX. Overall, no clear negative effects of CNS RAD were detected whereas a trend towards positive impact on EFS was observed. GMALL 08/2013 is an independent academic trial funded by the Deutsche Krebshilfe.

High Progression-Free Survival with Low Relapse Rates after Double-Unit Cord Blood Transplantation in Patients with High-Risk AML

Background : Double-unit cord blood transplantation (dCBT) is standard therapy for patients with acute myelogenous leukemia (AML) who do not have suitable adult donors. We & others have reported low relapse rates & high progression free survival (PFS) in dCBT recipients suggesting robust CB-derived graft-versus-leukemia effects. However, the efficacy of dCBT in high-risk AML as determined by ELN genetic risk & pre-transplant minimal residual disease (MRD) status has not been performed to date. Methods : All consecutive adult patients with AML who received first dCBT with intermediate intensity conditioning (Cy50/ Flu150/ Thio10/ TBI400) between 2014-2022 were analyzed. GVHD prophylaxis was with either Cyclosporine-A (CSA)/ Mycophenolate Mofetil (MMF) or CSA/MMF/Tocilizumab on an institutional protocol. Results : 63 patients (pts) (median age 49 years, range 23-63) were eligible for analysis (Table); 42 (67%) were CMV seropositive, 31 (49%) had non-European ancestry, & median HCT-CI was 2 (range 0-6). Most (n = 55, 87%) were in CR1, 5 (8%) in CR2, & 3 were relapsed or primary refractory at transplant (5-9% blasts). By ELN2022 genetic risk criteria, 8 pts had favorable, 29 intermediate, & 20 adverse risk AML (6 were missing ELN status). Of the 60 pts in CR, 36 were MRD- & 18 MRD+ by multicolor flow cytometry (6 had unknown/ indeterminate MRD status). Sixty-one of 63 pts engrafted for a 60-day cumulative incidence of 98% (95%CI:81-100). The median follow-up of survivors was 58 months (range 8-104 months). The 1- & 3-yr incidences of transplant-related mortality (TRM) were 13% (95%CI: 5.9-22) & 18% (95%CI: 9.6-29), respectively. The 1- & 3-year relapse incidences were 3.2% (95%CI: 0.6-9.9) & 8.6% (95%CI: 3.1-18), respectively. The 1- & 3-year OS were 87% (95%CI: 79-96) & 82% (95%CI:72-92) respectively, whereas the 1- & 3-year PFS were 84% (95%CI: 76-94) & 73% (95%CI: 63-85), respectively. When stratified by ELN2022 genetic risk, the 3-year relapse incidence was 0% in favorable, 10% (95%CI: 2.5-25) in intermediate & 13% (95%CI: 2-36%) in adverse risk AML patients. Pts with favorable risk AML had a 3-year PFS of 88% (95%CI: 67-100); the 3-year PFS was similar in patients with intermediate [68% (95%CI: 53-88)] or adverse [67% (95%CI: 48-93)] risk AML (Figure 1A). When stratified by MRD status, the 3-year relapse incidence was 8.4% (95%CI:2.1-20) in MRD- & 13% (95%CI: 1.9-34) in MRD+ patients. The 3-year PFS was similar in patients with AML in CR who were MRD- 80% (95%CI: 68-94) or MRD+ 76% (95%CI: 57-100), whereas all 3 relapsed/ refractory patients died of TRM (Figure 1B). Of 4 TP53-mutated AML patients, one relapsed, one died of TRM, & two are alive in remission. Conclusions: While retrospective, our findings highlight the low relapse rates & promising PFS in adult AML patients, including those with high risk features such as adverse-risk ELN genetic risk &/ or MRD positivity supporting robust CB-derived graft-versus-leukemia (GVL) effects. This observation, together with the mitigation of TRM in recent years due to the optimized transplant practices in adult dCBT (see Politikos et al, ASH 2023), makes intermediate intensity dCBT an attractive strategy for AML patients with a suitable dCB graft & high-risk disease. Our findings warrant prospective multi-center investigation with correlative studies to elucidate the biology of CB-derived GVL.

Phase Ib/II Study of Multi-Targeted Therapy with Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR) in Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Background: Foundational studies have revealed essential oncogenic pathways in DLBCL, triggering the development of drugs targeting distinct survival pathways in this malignancy. While many of these agents are active in DLBCL as monotherapy, they rarely induce deep responses or cure. Based on our identification of drug synergy in DLBCL models, we hypothesized that targeting multiple survival pathways concurrently could be curative in DLBCL. We developed a 5-drug combination regimen (ViPOR) that targets DLBCL survival sustained by constitutive B-cell receptor (BCR) signaling (ibrutinib, lenalidomide, prednisone) and by BCL2 (venetoclax), and also enlists the innate immune system using obinutuzumab. To maximize drug exposure and minimize toxicity, we administered all agents in non-continuous cycles for fixed duration in R/R DLBCL. Methods: R/R DLBCL pts with adequate organ function were eligible. In Ph I, pts were treated at 4 doses of venetoclax (200-800 mg) PO D2-14 to identify the MTD. An initial 12d venetoclax ramp-up was given in combination with fixed-dose ibrutinib 560 mg PO D1-14, prednisone 100 mg PO D1-7, obinutuzumab 1000 mg IV D1-2, and lenalidomide 15 mg PO D1-14. Ph II expansion cohorts of R/R GCB and non-GCB DLBCL were included at the MTD. Max 6C of ViPOR q21d were given without maintenance. TLS, G-CSF, and PCP prophylaxis were given to all pts. Baseline CT, PET, BM, and tumor biopsies were performed with CT after C1, 2, 4, and 6 and PET after C6. CT was then performed q3m x 1y, q4m x 1y, q6m x 1y, then q12m x 2y. Tumor genomics and ctDNA (clonoSEQ) were studied. Results: 50 DLBCL pts were enrolled (25 DLBCL NOS, 17 HGBCL-DH-BCL2, 3 HGBCL-DH-BCL6, and 5 THRLBCL). 52% and 48% were GCB and non-GCB subtype by IHC, respectively, with transformed lymphoma in 34%. Median age was 61y (range 29-77), with stage 3-4 disease in 92%, elevated LDH in 86%, >2 extranodal sites in 56%, and IPI >3 in 68% of pts. Median prior txs were 3 (range 1-9), with 40% post-CAR-T pts and 58% refractory. A single DLT of G3 intracranial hemorrhage occurred, and venetoclax 800 mg was identified as the MTD. Heme AEs were most common, with G3-4 neutropenia in 24%, thrombocytopenia in 23%, and anemia in 7% of cycles. Febrile neutropenia occurred in 3 (1%) cycles. The only G3-4 non-heme AE in >10% pts was hypokalemia (28%). G3 A.fib occurred in 3 pts, and G4 TLS occurred in 1 pt, which resolved. Other common any grade non-heme AEs (% pts) included diarrhea (68%), hypokalemia (67%), nausea (45%), rash (35%), and fatigue (33%). Dose reductions occurred in 17% of pts, and 8% discontinued tx due to AE. Of 48 evaluable pts (2 came off tx prior to restaging), ORR was 54% (26/48), and CR was 38% (18/48). Responses were observed across all molecular DLBCL subtypes, including a CR rate of 62% (8/13) in non-GCB DLBCL, 53% (8/15) in HGBCL-DH-BCL2, 25% (2/8) in other DLBCL, and a PR rate of 33% (4/12) in GCB DLBCL (non-DH) (Fig. 1A). CR rate was 20% (4/20) and 19% (5/27) in post-CAR-T and refractory pts, respectively. With a median FU of 40m, 72% of CRs are ongoing, with a 2-year PFS and OS of 34% and 36%, respectively. By histology, 2-year PFS was 47%, 38%, 38%, and 8% in HGBCL-DH-BCL2, non-GCB DLBCL, other DLBCL, and GCB DLBCL (non-DH), respectively (Fig. 1B). 2-year PFS was 30% and 21% in post-CAR-T and refractory pts, respectively. MRD was undetectable in 38% (16/42) of pts at end of therapy (EoT), and in 93% (14/15) of pts in PET CR at EoT. Elevated baseline ctDNA or detectable ctDNA during or at EoT were associated with significantly inferior PFS and OS, as were quantitative PET parameters (elevated baseline TMTV and TLG). Two genetic subtypes known to rely on BCR-dependent NF-kB signaling - MCD and N1 - had a significantly higher CR rate (5/6, 83%) than all other genetic subtypes (4/22, 18%; p=0.0066). Conclusions: This is the first study to show the feasibility and curative potential of multi-targeted therapy in R/R DLBCL. ViPOR was well tolerated across all ages in R/R DLBCL with rare febrile neutropenia. ViPOR was most effective in non-GCB DLBCL, as expected from its reliance on BCR signaling and BCL2. ViPOR was also highly active in HGBCL-DH-BCL2, possibly due to inhibition of MYC-driven apoptosis by BCL2 in this subtype. Durable remissions and likely cure were observed in non-GCB DLBCL (38%) and HGBCL-DH-BCL2 (47%), including pts relapsed after or refractory to CAR-T (30%). Multicenter Ph II testing is in development to confirm the activity of ViPOR in R/R non-GCB DLBCL and HGBCL-DH-BCL2.

Comparing PD-L1 scores for predicting pembrolizumab efficacy in first-line treatment of unresectable cutaneous squamous cell carcinomas.

e21593 Background: In the CARSKIN study (NCT02883556), 1L pembrolizumab demonstrated promising activity with durable responses and manageable safety in patients (pts) with unresectable locally advanced or metastatic CSCC. Here we report best ORR and survival endpoints of the entire cohort by PD-L1 status. Methods: The imaging assessment per RECIST v1.1 was blinded with independent central review. Best ORR, PFS, DOR OS, in the overall sample and by PD-L1 status was centrally assessed by 2 blinded independent pathologists, one using the anti–PD-L1 E1L3N clone (TPSE1L3N), the other using the 22C3 antibody (TPS22C3 and CPS22C3). Among 57 pts, 6 were excluded from the analysis: 2 untreated pts, 1 early unrelated death and 3 pts tested only with 1 assay). ROC curve analysis was used to compare assays. Results: With a median follow-up of 26 mo, best ORR was 51% with 14 PR (27%) and 12 CR (24%). Relapse occurred in 3 PR and 1 PD-L1 – CR pts. Respective median PFS, DOR, and OS were 13.7, NR, and 25.3 mo; respective 1-year PFS, DOR and OS were 50% [38-66], 80% [65-97] and 73% [61-86]. With a cutoff of 1%, best ORR was higher either for TPSE1L3N + pts vs TPSE1L3N – pts (60% vs 18%, p = 0.02) and for CPS22C3 + pts (59% vs 20%, p = 0.038), but not TPS22C3 + pts (p = 0.76). The optimal cutoff of CPS22C3 for ORR using a ROC curve was estimated to be ≥ 7% with a sensitivity of 0.70 and a specificity of 0.75. For best ORR, area under the ROC curve was higher for CPS22C3 (0.72) than TPSE1L3N (0.62) but the difference was not significant (P = 0.21). Pts with TPSE1L3N ≥ 1% had a higher 1-y PFS (57% vs 27%, p = 0.004) and OS (82% vs 42%, P = 0.01). Pts with CPS22C3 ≥ 1%, had a better 1-y OS (79% vs 50%, p = 0.03), but not 1y-PFS. Conclusions: CPS22C3 ≥ 7% appeared equivalent to TPSE1L3N ≥ 1% for predicting ORR and OS in pts receiving pembrolizumab in 1L treatment of advanced or metastatic CSCCs. Replications are warranted for validation. Pts with low scores might beneficiate from combined treatments. Clinical trial information: NCT02883556 .

Clinical and molecular characteristics of patients with AML with an exceptional response to ivosidenib.

7036 Background: Ivosidenib (IVO) twas approved based on a CR/CRh rate of 31.8% in IDH1 mutant (IDH1m) R/R AML; median duration of CR/CRh (DOR) was 8.2 months (mo). The purpose of this study is to elucidate the clinical and molecular characteristics of exceptional responders to single agent IVO. Methods: We analyzed all patients (pts) with IDH1m R/R AML who received IVO 500mg QD on the phase 1 dose escalation/expansion study and had a DOR of >12 mo. Results: Of 179 pts who received IVO 500 mg QD, 57 (31.8%) achieved a CR/CRh. Of these, 20 (35.1%) had a DOR >12 mo. After excluding 7 pts who went to HSCT, 13 (22.8% of responders, 7.3% of cohort) had DOR >12 mo (exceptional response) and 8 (14% of responders, 4.5% of cohort) had DOR >24 mo. The 13 exceptional responders all achieved CR as best response, and median DOR was 42.6 mo. Median OS was not reached; estimated OS at 48 mo was 67.1%. Median EFS was 44.4 mo. Reasons for discontinuing treatment included relapse (n=4), adverse event unrelated to IVO (n=3), and patient (pt) decision (n=3). Three pts remain on treatment. All pts who relapsed had DOR between 1-2 years; none of the 8 pts with DOR >2 years relapsed. Baseline characteristics are in the table. The most common co-mutations were DNMT3A, ASXL1, SRSF2, and JAK2 (3 each, 23%). Five pts (39%) had a splicing factor mutation. No pts had FLT3 or RTK pathway mutations other than JAK2. Only 1 pt with NPM1 had an exceptional response, and 1 pt had TP53 (VAF 3.6%). Six pts (46%) had an abnormal karyotype, 6 normal (46%), and 1 missing (8%). Most pts had intermediate-risk cytogenetics (10 pts, 77%), 2 poor-risk, and 1 missing. The median IDH1 VAF was 25% (range 10-50%). The median number of co-mutations was 1 (range 0-6). Having 0-1 co-mutations was associated with a longer response. Eleven pts (85%) had an IDH1 R132C mutation; 1 each (7.7%) had R132H and R132L mutations. Mutation clearance of IDH1 was noted in 8 pts (61.5%). Conclusions: A subset of pts with IDH1m R/R AML have prolonged CR on single agent IVO without HSCT (22.8% of CR/CRh responders) and no pts in CR for >2 years (14% of CR/CRh responders) relapsed. A low mutational burden, lack of RTK pathway mutations and canonical AML drivers, and co-occurrence of mutations associated with clonal hematopoiesis appear to be associated with exceptional response. Clinical trial information: NCT02074839 . [Table: see text]

Brigatinib in patients with ALK‐positive anaplastic large cell lymphoma who have failed brentuximab vedotin

ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) patients (pts) who have failed brentuximab vedotin (BV) have a poor prognosis with a median OS after BV failure of 2.9 months and 2-year OS of 27.1% (Chihara D, 2019). ALK-inhibitors have shown interesting results in relapsed ALK+ ALCL, but in these studies, most pts had not received prior BV, which does not correspond to current standards of treatment in adults. Furthermore, there are currently several ALK-inhibitors, but too few pts available to test them in this rare and difficult-to-treat population. It is therefore important to evaluate these ALK-inhibitors in preclinical studies, before selecting one for a clinical study. We carried out a preclinical study and then a real-life clinical study. We generated a patient-derived xenograft (PDX) model from a fresh lymph node biopsy of a 41-year-old man newly diagnosed with ALK+ ALCL. Our PDX closely mimicked the patient’s primary tumor, as assessed by pathology, FISH, TCR gene rearrangement, WES and RNA-seq. We used this model to assess 8 ALK-inhibitors (alectinib, brigatinib, ceritinib, crizotinib, ensartinib, entrectinib, lorlatinib, gilteritinib). We selected and recommended brigatinib for clinical off-label use based on our preclinical results and the safety profile in pts with ALK-positive non-small cell lung cancer (NSCLC). Between Jan 2020 and Oct 2022, 15 French adults who have failed BV started brigatinib. At brigatinib initiation, the median age was 35 y (19–73; 2 pts > 60 y), 8/15 were male, the median number of prior treatment lines was 2 (1–8), 4/15 (27%) had received prior crizotinib, including 3 crizotinib-resistant (crizo-R) and 1 crizotinib-sensitive (crizo-S) who relapsed after discontinuation of the drug. 4 pts had previously undergone stem cell transplantation (3 autoSCT, 1 alloSCT). ALCL was refractory to the last treatment in 10/15 pts. 10/11 pts had detectable ALK transcript in blood by RT-PCR. Pts received brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg), as recommended in ALK-positive NSCLC. The best ORR was 93% (14/15) with 73% (11/15) CR according to Lugano response criteria. 2 crizo-R and the crizo-S pts achieved CR, and 1 crizo-R pt reached PR. Time to achieve CR ranged from 8 to 325 days. 9 pts were monitored for ALK transcript in blood over time and kinetics correlated with response. 5 CR pts were bridged to alloSCT. There were 4 progressions/relapses after brigatinib initiation, all occurring within the first 6 months. After a median follow-up of 1.3 years, 1-year PFS and OS were 72% and 85%, respectively. There was no permanent discontinuation of brigatinib related to adverse event (AE), and 3 pts had dose reduction for moderate AE (1 dyspnea and 2 cramps), with complete resolution. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. D. Sibon Consultant or advisory role: Takeda, AbbVie, Janssen, Roche

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: The Nordic Lymphoma Group (NLG) performed a dose-finding/expansion trial evaluating pixantrone, etoposide, bendamustine and, in CD20+ lymphomas, rituximab (P[R]EBEN) in patients (pts) with relapsed diffuse large B-cell (DLBCL) or peripheral T-cell (PTCL) lymphomas. The regimen was out-patient based, and applicable in frail, heavily pre-treated pts. Here we present a long-term follow-up of the trial and a per-protocol correlative biological analysis of pre-therapeutic tumour biopsies looking for gene expression profiles associated with long-term response. Methods: We enrolled 60 pts (37 DLBCL and 23 PTCL; age range: 39–84 yrs, median: 71 yrs). Time to event parameters were analyzed by Kaplan-Meier estimates, log-rank test and Cox regression models. Pre-therapeutic biopsies from 42 pts (25 DLBCL, 17 PTCL) were analyzed for gene expression by NanoString PanCancer Pathways and Immune profiling panels (altogether 1348 genes). Results: Of the original 60 patients, 22 were alive at the time of the present analysis. The median follow-up of surviving pts was 41 mo (range 26–76 mo). The 38 deaths were due to: lymphoma (24; 63%), infections (3; 8%) and other causes (11; 29%: 1 lung carcinoma, 5 acute myeloid leukemia-AML, 1 myelodysplasia-MDS, 1 lung embolism, 1 allotransplant related and 2 unknown). Of the 6 pts with AML/MDS, 5 were PTCL and 1 DLBCL. Of 58 evaluable pts, 38 (65%) had a complete (CR) and 1 (3%) a partial response (B: 51%; T: 70%). The median duration of response (DoR) of the 38 CR pts was 17 mo (range 0.5–55 mo; B: 18 mo; T: 17 mo). Four pts were bridged to allogeneic transplant. The overall 5-yr OS and PFS were 33% and 19%, respectively. The median OS for DLBCL was 16.0 mo [IQR 7.0>] and for PTCL 18.0 mo [IQR 8.0>]. The median PFS for DLBCL was 10.0 mo [IQR 4.0–32.0] and for PTCL 10.0 mo [IQR 5.0–26.0]. To better understand molecular alterations underlying the delay of relapse in this heavily pre-treated elderly population, we determined differentially expressed genes between short (<12 mo) and long term (>12 mo) responders. In DLBCL, 31 genes showed significant differential expression between short- and long-term responders (P < 0.05). The latter had higher expression of genes related to transcription factor activity. The gene most significantly associated with long-term response was Neutrophil Cytosolic Factor 4 (NCF4). In PTCL, 23 genes were differentially expressed between short- and long-term responders, the latter showing enrichment in Ras signaling pathway genes (e.g., Rac Family Small GTPase 3, RAC3, and phospholipase A2 group IIA, PLA2G2A). The research was funded by: Servier Laboratoires Keywords: Aggressive B-cell non-Hodgkin lymphoma, Aggressive T-cell non-Hodgkin lymphoma, Combination Therapies No conflicts of interests pertinent to the abstract.

Safety and efficacy of HB0025, an anti-PD-1/VEGF bispecific antibody fusion protein, in patients with advanced solid tumors: Preliminary results from an FIH trial.

2589 Background: HB0025 is a recombinant humanized anti-PD-L1 monoclonal antibody-VEGFR1 fusion Protein. Nonclinical data both in vitro and vivo have shown high-affinity binding to both targets as well as the inhibition of tumor growth in animal models. Here, we present preliminary safety and efficacy data from a dose escalation phase I study of HB0025. Methods: Eligible patients(pts) were ≥18 years old (ECOG PS 0–1) who had advanced solid tumors (NSCLC, gynecological tumors, digestive system tumors, etc.) and failed standard treatment. This phase 1 dose escalation includes accelerated titration (0.01, 0.03, 0.1 and 0.3mg/kg) and conventional 3+3 dose escalation (1.0, 3.0, 6.0, 10, 12, 20, and 30.0 mg/kg). HB0025 is administered intravenously every 14 days (Q2W). Objectives include evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and antitumor activity. Adverse events (AEs) were reported with CTCAE v5.0 and DLTs were evaluated within a 28-day window. Results: As of Aug 30th 2022, 30 pts including 8 male and 22 female from Caucasian and Mongoloid have received HB0025 at doses of 0.01 mg/kg (n=1), 0.03 mg/kg (n=2), 0.1 mg/kg (n=1), 0.3 mg/kg (n=1),1.0 mg/kg (n=3), 3.0 mg/kg (n=7), 6.0mg/kg (n=7), 10.0 mg/kg (n=5), and 12.0mg/kg (n=3) Q2W. Overall, the median age was 55 years and the median lines of previous treatment was four. Of the 22 evaluable pts dosed at ≥ 3 mg/kg Q2W, the ORR was 9.1% (2/22) and the disease control rate (DCR) was 50% [11/22]. Among the 2 responders, a CR (colorectal ca) pt whose prior therapy was no immune checkpoint inhibitor (ICI) or bevacizumab have continued more than 36 weeks; and a PR (NSCLC) pt with duration more than 18 weeks whose tumor was 60.2% regression and prior ICI failure. Till the date of submission, the therapy was continuing for the CR and PR pts. Treatment-related adverse events (TRAEs) occurred in 83.3% of pts. The grade 3 TRAEs occurred in 20% [6/30] and treatment-related SAEs occurred in 13.3% [4/30]. One DLT occurred in the 12.0mg/kg cohort. No death occurred related to HB0025. TRAEs leading to treatment discontinuation occurred in 13.3% of pts [4/30]. The most frequent TRAEs were hypertriglyceridemia (23.3%), hypercholesterolemia (23.3%), anemia (16.7%), alanine aminotransferase increase (16.7%), and proteinuria (13.3%). Conclusions: HB0025 shows manageable safety and promising anti-tumor activity in pts with various solid tumors. To better characterize the risk-benefit profile, HB0025 is currently enrolled at 20.0 mg/kg Q2W and is being explored at doses 10 mg/kg in expansion cohorts. The future data, including PK, PD and ADA will be presented. Clinical trial information: NCT04678908 .

Fast-Track Measurable Residual Disease Detection By Multiparametric Flow Cytometry in Acute Myeloid Leukemia before Allogeneic Hematopoietic Cell Transplantation

Introduction In acute myeloid leukemia (AML), measurable residual disease (MRD) becomes more and more important for individualized treatment decisions. The MRD status at the time of allogeneic hematopoietic cell transplantation (alloHCT) provides prognostic information beyond baseline risk features. Peri-transplant treatment strategies and conditioning intensity can be stratified according MRD-levels. However, therapeutic interventions (e.g. conditioning intensity) usually require the prompt availability of reliable information on the MRD status. We assessed the prognostic value of a standardized, reproducible, and fast turnover multiparametric flow cytometry (MFC) approach that has been validated at the end of intensive induction therapy to monitor MRD before alloHCT (Röhnert, Leukemia 2022). This approach allows for the simultaneous detection of MRD by the leukemia-associated immunophenotype (LAIP) and the different from normal (DfN) method. Methods Between October 2016 and March 2020, bone marrow (BM) aspirates of patients (pts) with AML were analyzed for the presence of MRD immediately before the start of conditioning. therapy with the aim of analyzing to predictive value of this fast-track parameter. Pts receiving sequential regimens (re-induction chemotherapy followed by reduced-intensity conditioning) were excluded. Briefly, the LAIP-based DfN analysis is based on a hierarchical gating strategy with fixed gates and encompasses the antigens CD34, CD117, HLA-DR (backbone markers), CD13, CD33 (myeloid markers), CD7 and CD56 (lymphoid markers). Within less than 5 minutes, the analysis checks for the presence of the aberrant categories i) deficiency of myeloid markers and ii) cross-lineage expression of lymphoid markers. Reference values for 32 immunophenotypically defined populations were established on BM aspirates of 90 leukemia free controls. An aberrant category already detectable at diagnosis on ≥10% of myeloid progenitors/ monocytes was termed aberrant LAIP (aLAIP) and a de-novo appearance (after chemotherapy) post-treatment DfN (ptDfN). In conclusion this approach is very fast and provides high reproducibility. Results We identified 58 pts with a median follow-up of 33.3 months after alloHCT (Table 1 with pts characteristics). Response assessment was performed in median 8 days before alloHCT. Most of the patients were in morphologic complete remission (CR n=37). A subset of 21 patients had refractory disease with a median BM blast count of 6.5%. Samples at AML diagnosis were available for 48/58 (83%) pts, of whom 34/48 (71%) showed at least one aLAIP at initial diagnosis. Before start of conditioning, 44/58 (76%) patients were MRDpos. The proportion of MRDpos in responders was lower compared to non-responders: 24/37 (65%) vs. 20/21 (95%) (p=0.0106). MRDpos was designated by aLAIPonly, ptDfNonly and aLAIP+ptDfN in 18%, 48% and 34% of cases, respectively. Noteworthy, 8 of 21 pts classified MRDpos by ptDfNonly had no sample available at diagnosis and therefore could not be assessed for aLAIP persistence. Amongst 37 pts in CR before alloHCT, 12/24 (50%) of MRDpos pts relapsed compared to 3/13 (23%) of MRDneg pts. TRM in these patients did not differ (13% vs. 8%). In a univariable Cox regression analysis, the 1-year Overall survival (OS) rate of MRDpos cohort was significantly shorter compared to MRDneg pts (64% vs. 93%, Hazard ratio (HR) 10.5, p=0.004). MRD was detected by ptDfNonly in 23/44 (52%) of MRDpos pts. The OS of these pts was comparable to MRDpos by aLAIP with or without ptDfN (Figure 1). As expected, the MRDpos cohort was enriched for non-responders. However, when the analysis was restricted to pts in CR (n=37), MRD status preserved its prognostic significance (HR 7.9, p=0.019). And even in the subpopulation of pts in first CR, MRDpos was associated with a significantly reduced OS compared to MRDneg (HR 6.3, p=0.043). Interestingly, a single non-responder was classified as MRDneg and showed a long-term OS. Conclusions Our fast-track LAIP-based DfN approach provides relevant prognostic information prior to conditioning for allo HCT. On top of the classical LAIP approach, the ptDfN analysis gives additional prognostic information. The LAIP-based DfN approach might be a suitable tool for fast-track and reliable MRD assessment before starting the preparative regimen for alloHCT and might help to guide potential treatment modifications. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CREST-UK: CPX-351 Real-World Effectiveness and Safety Study for the Treatment of Newly Diagnosed Therapy-Related AML and AML with Myelodysplasia-Related Changes in the UK

Background: In the UK, CPX-351 (Vyxeos® liposomal) has been licensed since August 2018 for adults with newly diagnosed, therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), primarily based on favorable outcomes for CPX-351 versus 7+3 chemotherapy in a phase 3 trial in adults aged 60 to 75 y with newly diagnosed, high-risk/secondary AML. However, the phase 3 trial population did not reflect the full CPX-351 licensed population. As a complement to the phase 3 trial and to address important data gaps, CREST-UK was performed to assess the effectiveness and safety of CPX-351 in routine clinical practice in the UK and observe the impact of COVID-19 infection in these patients (pts). Methods: CREST-UK is a retrospective, noninterventional, multicenter, single-arm, observational study (NCT05169307) that collected pseudonymized pt data abstracted from the medical records of adults aged ≥18 y with newly diagnosed t-AML or AML-MRC (per WHO 2016 criteria) who received ≥1 infusion of CPX-351 in routine practice; pts who received CPX-351 in a clinical trial were excluded. The primary objective was to describe complete remission (CR or CRi) and overall survival (OS). Key secondary objectives described pt and disease characteristics, frequency of hematopoietic cell transplantation (HCT), OS landmarked from the HCT date, and the CPX-351 safety profile. Median follow-up for OS was 10.6 mo (interquartile range [IQR]: 4.5, 18.4). Results: A total of 147 pts who received their first CPX-351 induction from November 2018 to March 2022 were included from 15 centers. Median age was 64 y (range: 18, 83), with 17 (12%) pts aged <45 y, 39 (27%) aged 45-59 y, 64 (44%) aged 60-69 y, and 27 (18%) aged ≥70 y. Overall, 35 (24%) pts had t-AML and 112 (76%) had AML-MRC (n=43 with prior MDS, n=9 with prior CMML, n=41 with MDS-related cytogenetics, and n=19 with multilineage dysplasia alone); 13 (9%) had received prior azacitidine. The majority (90%) of pts had an ECOG performance status ≤1. Disease risk by European LeukemiaNet 2017 criteria was favorable for 13 (9%) pts, intermediate for 39 (27%), adverse for 66 (45%), and unknown for 29 (20%) due to limited mutational data. Complex karyotype, monosomal karyotype, and/or abn(17p) were reported for 37 (25%) pts. TP53 mutations were reported for 15/66 (23%) pts with evaluable data. A best response of CR+CRi was achieved by 73/138 (53%) evaluable pts, and overall response (CR+CRi+MLFS+PR) was achieved by 88/138 (64%) pts. Post induction, 19/37 (51%) pts in CR or CRi with a known measurable residual disease (MRD) status achieved MRD negativity; 3 additional pts achieved MRD negativity at a later time point. Kaplan-Meier median OS was 12.85 mo (95% CI: 9.2, 15.4; Fig 1), with 2- and 3-y OS estimates of 36% and 34%, respectively. Fifty (34%) pts proceeded to HCT; median OS landmarked from the HCT date was not reached (Fig 2), with a 2-y OS estimate of 71%. Among pts in CR or CRi, median recovery (IQR) to neutrophils ≥500/μL was 33 d (28, 43) and to platelets ≥50,000/μL was 34 d (27, 48) during the first induction. Grade ≥3 treatment-related adverse events (TRAEs) of interest included febrile neutropenia (36%; n=1 grade 5), infections (29%; n=6 grade 5), bleeding (4%; n=1 grade 5), and gastrointestinal events (3%). Cardiac TRAEs of any grade were reported for 5% of pts, with grade ≥3 events in 3% (n=1 grade 5). No extravasation was reported. Estimated all-cause mortality was 7% at 30 d and 14% at 60 d. This study included pts who were diagnosed and treated for AML during the COVID-19 pandemic. A total of 26 COVID-19 infections happened at variable time intervals pre- or post-AML treatment. In this cohort, 2 deaths were directly linked to COVID-19; both were assessed by the site investigator as unrelated to CPX-351 treatment. Conclusion: CREST-UK, a real-world study in the context of the COVID-19 pandemic, confirmed the efficacy and safety of CPX-351 in a broad population that included substantial proportions who were aged <60 y or ≥70 y and/or had adverse-risk disease. CR or CRi with MRD negativity and/or proceeding to HCT was achieved in proportions consistent with clinical trials and other real-world studies. Survival outcomes were also consistent with other real-world studies. No new safety concerns with CPX-351 were identified. These data provide new insights into the use of CPX-351 in routine clinical practice in the UK and support its continued use in adults with newly diagnosed t-AML and AML-MRC. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR) in Relapsed and Refractory Follicular Lymphoma: Analysis of Safety, Efficacy, and Minimal Residual Disease

Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR) in Relapsed and Refractory Follicular Lymphoma: Analysis of Safety, Efficacy, and Minimal Residual Disease

Polatuzumab Vedotin Combined with R-ICE (PolaR-ICE) As Second-Line Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Introduction: Currently, the standard of care for patients (pts) with relapsed/refractory (RR) diffuse large B-cell lymphoma (DLBCL) who relapse > 1 year after frontline treatment is salvage chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) in appropriately selected, chemosensitive pts. Following first-line therapy (tx) with a rituximab-containing anthracycline-based regimen in the modern era, response rates to platinum-based chemoimmunotherapy are suboptimal. More effective salvage regimens for RR DLBCL remain an unmet need. Polatuzumab vedotin (Pola) is an antibody-drug conjugate directed against CD79b that is safe and effective when combined with chemotherapy in frontline and relapsed, transplant-ineligible DLBCL pts [Tilly NEJM 2022, Sehn, JCO 2020]. We evaluated the safety and efficacy of Pola combined with rituximab, ifosfamide, carboplatin, and etoposide (RICE) as second-line tx in RR DLBCL in a multicenter phase 2 study. Methods: Adult transplant-eligible pts with ECOG ≤ 2 who had biopsy-proven RR DLBCL following frontline CD20-directed anthracycline-based chemoimmunotherapy were eligible. Pts with DLBCL not otherwise specified (NOS), transformed indolent lymphoma, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma (HGBCL) NOS, and HGBCL with MYC and BCL2 rearrangements were eligible. Pts with central nervous system lymphoma, peripheral neuropathy (PN) ≥ grade (gr) 2 or prior tx of RR DLBCL were excluded. Participants received PolaR-ICE: 1.8mg/kg Pola day (d) 1, rituximab 375mg/m2 d1, etoposide 100 mg/m2 IV d1-3, carboplatin AUC 5 (750 mg max) IV d2, ifosfamide IV 5000 mg/m2 d2 (inpatient) or divided between d1-3 (outpatient) every 21d for 2 cycles followed by PET-CT. G-CSF prophylaxis was mandatory. Pts in CR were eligible to proceed directly to ASCT or could receive a 3rd cycle of PolaR-ICE at investigator's discretion. Pts with partial response (PR) [or stable disease, MD discretion] received a 3rd cycle of PolaR-ICE. After ASCT, pts in ongoing response who had recovered from ASCT toxicities were eligible to receive Pola consolidation (1.8mg/kg) in 21d cycles starting d+30-60 to complete a cumulative 6 doses of Pola. A safety lead-in of up to 8 pts were enrolled according to the IQ rolling 6 design, with a de-escalation dose available (Pola 1.4mg/kg). Following the lead-in, a 2-stage design was employed with 20 pts enrolled (including lead-in) and since 8+ CRs were observed, the study proceeded to enroll a total of 40 pts. The co-primary endpoints were safety and CR rate according to 2014 Lugano classification. ORR, PFS and overall survival were secondary endpoints. Results: 41 pts were enrolled; baseline characteristics are shown in Table 1. 37 pts were evaluable for response: 1 pt died prior to response assessment, 1 pt was inevaluable for response and replaced, 1 pt had clinical progressive disease (PD) and counted in ORR evaluation as PD, and 1 pt is pending response evaluation. 40 pts have toxicity data available, including 22 pts who received 3 cycles of PolaR-ICE, 16 treated with 2 cycles to date, and 2 pts who received 1 cycle to date. Of 38 pts (37 evaluable + 1 clinical PD), 35 had an objective response after 2 cycles of PolaR-ICE for an ORR of 92%, 21 (55%) had a CR, 14 (37%) had a PR, 1 had stable disease and 2 had PD. The end of salvage (PolaR-ICE x 2 or 3) ORR was 89% and CR rate 61% (1 PR became PD and 2 PR converted to CR with a 3rd cycle). To date, 21 pts proceeded to ASCT and 13 pts received consolidation Pola. The most common treatment-emergent adverse events (TEAE, all gr) related to PolaR-ICE were anemia (78%), nausea (70%), thrombocytopenia (70%), leukopenia (50%), fatigue (48%), neutropenia (48%), lymphopenia (38%), constipation (35%), hypertension (30%), and hypophosphatemia (28%). The most common gr ≥ 3 TEAEs were anemia (43%), thrombocytopenia (43%), neutropenia (43%), and no other non-hematologic TEAE occurred in more than 2 (5%) pts. 1 pt underwent Pola dose reduction due to gr 4 cytopenias, gr 2 nausea. Gr ≥ 3 infection/febrile neutropenia/sepsis occurred in 3 (8%) pts. 1 pt had a study treatment-related gr 5 AE due to sepsis. PN occurred in 10 (25%) pts, all gr 1 except one gr 2 event. Conclusion: PolaR-ICE produced a high ORR with CR in a majority of pts and the safety profile was similar to RICE, without added toxicity due to Pola. Longer follow-up is needed to assess the durability of responses and outcomes following ASCT/Pola consolidation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase II Study of Inotuzumab Ozogamicin for the Treatment of Measurable Residual Disease-Positive B-Cell Acute Lymphoblastic Leukemia

Background: Persistence or re-emergence of measurable residual disease (MRD) after remission induction therapy in B-cell acute lymphoblastic leukemia (B-ALL) is strongly associated with shorter relapse-free survival (RFS) and overall survival (OS). Inotuzumab ozogamicin (INO) is an anti-CD22 antibody-drug conjugate with the potential to eradicate MRD in patients (pts) with B-ALL, including in pts with prior exposure to blinatumomab. Methods: This is a single-arm phase II trial of pts with B-ALL in complete remission (CR) who did not achieve MRD negativity (MRD-ve) or had MRD-positive (MRD+ve) relapse after at least 3 months (mos) from the start of frontline therapy or 1 month from the start of any salvage therapy. Eligibility was defined by MRD+ve at ≥ 0.01% by multiparametric flow cytometry (MFC) for Philadelphia chromosome (Ph) negative (Ph-) B-ALL and ≥ 0.01% by MFC and/or BCR::ABL1 transcripts for Ph positive (Ph+) B-ALL. MRD-ve was defined as undetectable MRD by MFC at a minimum sensitivity of 10-4 for Ph- B-ALL and undetectable MRD by both MFC and BCR::ABL1 transcripts at 10-4 for Ph+ B-ALL. For pts with p210 BCR::ABL1 transcript, the international scale (IS) was used for reporting. INO was administered at a dose of 0.6 mg/m2 on D1 and 0.3 mg/m2 on D8 of cycle 1 and 0.3 mg/m2 on D1 and D8 of cycles 2-6 (cycles given every 21-28 days). Pts received ursodiol prophylaxis while on INO. Pts with Ph+ ALL could receive a concomitant BCR::ABL1 tyrosine kinase inhibitor (TKI). Results: Between 11/2018 and 6/2022, 27 pts with MRD+ve B-ALL were treated. The median age was 44 years (range, 19-70). Seventeen pts (63%) had Ph+ ALL (12 pts with p190 transcript and 5 pts with p210 transcript), 15 of whom received concurrent ponatinib and 2 dasatinib. Ten pts were Ph- (including 3 with Ph-like ALL). Twenty pts (74%) were in CR1, and 7 pts (26%) were in ≥ CR2 (4 in CR2, 2 in CR3 and 1 in CR4). Fourteen pts (52%) had received prior blinatumomab and 5 pts (18%) had prior stem cell transplantation (SCT). The median level of BCR::ABL1 by PCR in pts with Ph+ ALL was 0.21% (range, 0-18.9%) and median level by MFC in pts with Ph- ALL was 0.21% (range, 0.05-1.24%). Seven pts with Ph+ ALL were MRD+ve by MFC at a median of 0.04%, and 1 pt with Ph+ B-ALL was MRD+ve by MFC (1.15%%) but negative by PCR. Eighteen pts (67%) responded and became MRD-ve, 16 after cycle 1 and 2 after cycle 2. In the Ph+ group, 10 pts (59%) responded; another 3 of 5 pts who had >0.1% BCR::ABL1 transcripts at enrollment attained major molecular response as best response. Eight of 10 (80%) pts with Ph- ALL responded. The median number of cycles was 3 (range, 1-6). Eleven of 13 pts (85%) without prior blinatumomab exposure became MRD-ve compared with 7/14 (50%) pts with prior blinatumomab exposure (p=0.1). At a median follow up of 18 months (mos) (range, 1.1- 35 mos), 14 of the 18-responding pts (78%) are in ongoing MRD-ve CR. The median RFS and OS of the pts were not reached. The estimated 18-mos RFS and OS were 56% and 65%, respectively, for the whole group. 18-mos OS was 73% and 60% for responders and non-responders, respectively (p=0.7). Amongst the 18 responders, 5 pts were consolidated with SCT after a median of 3 cycles (range, 1-3) of INO, all in MRD-ve CR prior to SCT. Four (22%) responders had morphological relapse (including one relapse after SCT and one isolated CNS relapse). One pt died in MRD-ve CR due to SCT-related complications. Survival was similar between pts with Ph+ ALL vs. Ph- ALL (p=0.41), pts in CR1 vs. ≥ CR2 (p=0.23) and those with prior blinatumomab exposure vs. no prior exposure (p=40). INO was overall well-tolerated with no grade 4 non-hematological toxicities. Two pts (7%) developed veno-occlusive disease (VOD); both had Ph+ ALL and were on concurrent ponatinib. One pt developed VOD (diagnosed radiologically) 1 month after ponatinib dose of 15mg/day) and another pt developed VOD (diagnosed by liver biopsy) during cycle 5 (cumulative INO dose of 3.3 mg/m2, ponatinib dose of 15mg/day). The overall 60-day mortality was 0%. Conclusion: Lower doses of fractionated INO is a well-tolerated option for MRD eradication in pts with Ph+ or Ph- B-ALL, including in those with prior blinatumomab exposure or SCT. This approach can also facilitate consolidative SCT in these pts. The therapy is well tolerated, but pts should be monitored for development of VOD of the liver, though the absolute risks remain low. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interim Results of a Phase 1/2 Study of Pembrolizumab Combined with Blinatumomab in Patients with Relapsed/Refractory (r/r) ALL

Background: Blinatumomab, a bispecific anti-CD19/CD3 antibody has resulted in significantly improved outcomes in patients (pts) with r/r B-ALL compared to conventional chemotherapy. However, over half of treated pts fail to respond (CR/CRh/PR 44%), and majority of responders eventually relapse without consolidation therapy. There is an unmet need to design novel strategies to improve efficacy. Upregulation of PD-L1 on leukemic blasts and PD-1 on T cells has been shown to associate with resistance to blinatumomab in preclinical and clinical studies. Therefore, blockade of the PD-1 pathway represents a reasonable strategy to augment blinatumomab efficacy. Here we set out to test the combination of pembrolizumab and blinatumomab in a single arm, phase 1/2 trial (NCT03512405). Methods: Pts [≥18 years old (yo); ECOG <1] with CD19+ R/R B-ALL, received standard blinatumomab 9 mcg/day on days 1-7, 28 mcg/day on days 8-28 in cycle 1, and on days 1-28 in subsequent cycles. Pembrolizumab 200mg was given on day 15 (schedule A) or day 22(schedule B) in cycle 1, and on days 1 and 22 in subsequent cycles. Cycle length was 42 days except 35 days for cycle 1 in schedule A. The study completed the schedule A phase 1 portion with primary objectives of safety, tolerability and proceeded with recommended phase 2 dose (RP2D) using the "3+3” design. Results: As of June 15, 2022, 7 pts were enrolled to phase 1 with one unevaluable, and 8 patients to phase 2. All received schedule A dosing. Fourteen evaluable pts received a median of 2 (1-6) cycles of treatment. At baseline, the median age was 53 yr (24-76) with median 2 (1-3) prior lines of regimens, and median 62% (10-95) BM blasts. All except one patient accrued were poor risk. In cycle 1, 64% experienced cytokine release syndrome (CRS) with 1 gr 3 CRS and no gr 4. All CRS except 1 started prior to the day 15 dose of pembrolizumab. Neurologic toxicities were all reversible with only 1 pt with ≥ gr3 AE. All-non-hematologic gr3 toxicities were reversible. No dose limiting toxicity, ≥ gr4 non-hematologic toxicity, or treatment related deaths were seen. The complete remission (CR/CRi) rate is 79% (11/14). Ten of 14 evaluable pts (71%) achieved flow cytometry MRD negative CR/CRi after a median of 1(1-2) cycle. 6/8 patients with ≥50% blast achieved CR/CRi. One patient had >83% blasts after cycle 1 and achieved CR after cycle 2, supporting the positive impact of pembrolizumab. Seven pts in CR received allogeneic transplant (alloHCT) with post-transplant cyclophosphamide (PTCy) as graft versus host disease (GVHD) prophylaxis. Only 1 patient had ≥gr3 acute GVHD which resolved with treatment. With a median follow-up of 9.6 (1.8- 34) months, 6 CRs are ongoing (5 post-transplant) and 10 of 14 evaluable pts are still alive at the data cut-off. PD-1 detection decreased among both responders and non-responders after pembrolizumab administration. Responders after cycle 1 had higher CD8+ T cells which increased further following pembrolizumab administration. Correlative studies are ongoing. Conclusions: The combination of pembrolizumab and blinatumomab in phase 1/2 of this study in pts with r/r B-ALL was deemed safe with a manageable side effect profile. Encouraging anti-leukemic activity has been seen in the majority of treated patients (CR+CRi rate of 79%) and most CR are MRD negative, supporting the rational combination of these 2 agents. The phase 2 portion of the trial is continuing to recruit patients.

Inotuzumab Ozogamicin Induction Followed By Standard Chemotherapy Yields High Remission Rates and Promising Survival in Older (>55 Years) Patients with De Novo B-Lymphoblastic Leukemia (GMALL-Initial1 Trial)

Introduction: Acute lymphoblastic leukemia (ALL) represents approx. 5% of all newly diagnosed leukemias in patients (pts) between 55 and 70 years of age. Incorporation of novel antibody-based therapies in the first line induction therapy bears the potential of a significantly increased response rates and survival together with a reduction of treatment toxicity. Methods: This open label phase II study (ClinicalTrials.gov, identifier: NCT03460522) of the German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia was conducted at 13 centers. Pts aged >55 years with newly diagnosed Ph/BCR-ABL negative B-precursor ALL (at least CD20 positivity of leukemic blasts) were eligible. The 1st induction cycle consisted of InO 0.8mg/m2 on day1 and 0.5mg/m2 on d8 and d15 together with dexamethasone 10 mg/m2 (day7-8, day14-17) and one intrathecal injection (i.th.) of methotrexate (MTX), cytarabine (AraC) and dexamethasone (Dex). The 2nd and 3rd induction cycle consisted of InO 0.5mg/m2 on day 1, 8 and 15 plus i.th. MTX/AraC/Dex. Pts achieving a complete remission (CR) were offered to receive 5 conventional consolidation therapies (3 x ID-MTX/asparaginase; 2 x ID-AraC) and one reinduction therapy (idarubicine/ AraC/ cyclophosphamide / Dex.) in combination with rituximab (for CD20+ ALL), followed by a maintenance therapy with 6-MP/MTX. The primary endpoint was event free survival (EFS) at 12-months follow-up. An event was defined as any of the following: persisting bone marrow blasts after 2 cycles of InO, relapse or death. An event rate of ≤40% at 12 months follow-up was considered to qualify the experimental treatment as very promising for additional testing. Results: 43 out of the 45 pts included were analyzed regarding the primary end point. Two pts were excluded per protocol from further analysis, as they received only one cycle of induction or withdraw consent. At diagnosis, median age was 64 years (range 56-80 years, 20 pts ≥65 years and 12 pts ≥70 years), median bone marrow blast count was 80% and median CD22 expression on leukemic blasts was 69% (range 21-99). 38 pts were diagnosed with a common- and 5 with a pro-B ALL. 42/43 pts completed all 3 cycles of induction therapy. All 43 pts achieved a complete remission (CR/CRi), mainly after the 1st induction. Median time between start of 1st induction to start 2nd induction, from 2nd to 3rd induction and from 3rd induction to 1st consolidation therapy was 21 days, 28 days and 30 days, respectively. Results of minimal residual disease (MRD), measured by real-time quantitative PCR, are available for all 43 pts, with 23/43 (53%) and 31/42 (74%) pts being MRD negative after 2nd and 3rd induction therapy, respectively. With a median follow-up of 697 days, the probability of OS at 1 and 2 years is 91% (95% C.I. 82-99%) and 81% (95% C.I. 69-94%), respectively. No patient died within the first 6 months after start of induction therapy. 5 events occurred within the first year after study inclusion, 3 deaths in CR and 2 relapsed ALL, resulting in event rate of 12% and a probability of EFS at 1 year (primary endpoint of the study) of 88% (95% CI 79-98). EFS at 2 years was 73% (95% CI 59-88). So far, 7 pts with persisting/reappearance of MRD (2 pts) or relapse (5 pts) were treated with blinatumomab. 9 pts received an aSCT (4 pts in CR1 and 5 pts >CR1), 6 of these pts are alive in CR. Regarding adverse events (AEs) during induction cycles 1, 2 and 3, most common AEs ≥CTC grade 3 reported were leukocytopenia (in 74%, 19% and 2% of all cases, respectively), anemia (37%, 5%, 0%), thrombocytopenia (49%, 7%, 2%) and elevation of liver enzymes (14%, 5%, 0%). One patient was reported with suspected veno occlusive disease (after 2nd induction therapy). Classical factors which may be associated with inferior survival outcomes like age, diagnosis of pro-B ALL, disease burden at diagnosis, co-morbidity or no MRD negative CR after induction had no significant impact on OS or EFS. Conclusion: Three cycles of InO as induction therapy for the treatment of older pts with de novo acute B-lymphoblastic leukemia resulted in a very high remission rate. Given that our study met the primary end point (predefined event rate at 1 year ≤40%, observed event rate 12%), these promising study results could be a rationale for integrating InO induction therapy in future treatment recommendations. Ideally, this novel induction therapy should be evaluated in prospective randomized trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal