We report correlative circulating tumor DNA (ctDNA) analyses from TRANSFORM (ClinicalTrials.gov identifier: NCT03575351) evaluating lisocabtagene maraleucel (liso-cel) versus standard of care (salvage immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation [ASCT]) in second-line large B-cell lymphoma (LBCL). ctDNA association with efficacy was investigated at predefined time points (random assignment, day 43, day 64, and day 126 [3 months after liso-cel, approximately 2 months after ASCT]) for 136 patients using ultrasensitive PhasED-Seq. ctDNA clearance (measurable residual disease [MRD]neg) predicted longer event-free survival (EFS) at all time points in both arms, with significantly more liso-cel-treated patients achieving MRDneg. Liso-cel demonstrated superior outcomes versus ASCT, including longer EFS, progression-free survival (PFS), and duration of response among patients in complete response (CR) and MRDneg. ctDNA re-emergence in patients with CR after ASCT confirmed its potential in predicting relapse. MRDneg remained significantly associated with EFS after adjusting for positron emission tomography (PET) response, while interaction testing revealed a significant interaction between PET status and treatment arm for EFS. Liso-cel achieved deeper, more durable molecular clearance by ctDNA, consistent with superior EFS and PFS versus ASCT for second-line LBCL treatment. ctDNA-MRD provided prognostic value beyond PET, supporting its role as a complementary biomarker for treatment response and relapse prediction.

The InflaMix (INFLAmmation MIXture) model classifies the disease of patients with R/R LBCL as inflamed or noninflamed using routine pre-infusion laboratory tests. In the published cohorts (Raj S, et al. Nat Med 2025) comprised primarily of patients with third-line or later (3L+) LBCL, this classification predicts response to CAR T cell therapy. As liso-cel is a robust treatment option in second-line (2L) LBCL, we sought to understand the value of InflaMix stratification for this population. Here, we retrospectively compared efficacy outcomes by treatment arm in inflamed versus noninflamed groups in patients with 2L LBCL who received liso-cel or historical standard of care (SOC) in TRANSFORM. For patients with available data, albumin, hemoglobin, AST, alkaline phosphatase, C-reactive protein, and LDH values were collected before leukapheresis and at the time of infusion from patients with 3L+ LBCL (n = 256; TRANSCEND NHL 001, NCT02631044) and before leukapheresis from patients with 2L LBCL (n = 127; TRANSFORM, NCT03575351). InflaMix, which was trained on the published derivation cohort with laboratory values taken at infusion (n = 149; 98% had 3L+ LBCL; Raj S, et al. Nat Med 2025), classified all patients as either inflamed or noninflamed. Endpoints were CR rate, ORR, PFS, and rates of cytokine release syndrome (CRS) or neurological events (NEs). PFS was analyzed using KM estimates with log-rank tests. Categorical outcomes were compared with chi-square tests of association. Efficacy outcomes in patients with 3L+ LBCL were compared stratifying based on inflamed (72%) versus noninflamed (28%) status at the time of infusion or before leukapheresis and were consistent with published results on the InflaMix model. The 2L LBCL analysis was based on laboratory features before leukapheresis to enable comparison between treatment arms. In patients with 2L LBCL, InflaMix classified 109/127 patients (86%) as noninflamed and 18/127 patients (14%) as inflamed. A significantly greater proportion of patients were classified as noninflamed in the 2L setting compared with the 3L+ setting (P = 0.004). Among patients in the liso-cel arm, median PFS was similar between inflamed and noninflamed groups (33.2 versus 30.9 months; P = 0.29). In contrast, InflaMix was predictive in the SOC arm, with a median PFS of 2.1 months for the inflamed group versus 5.7 months for the noninflamed group (P = 0.022). Across both InflaMix groups, liso-cel outperformed SOC, resulting in longer median PFS, consistent with clinical results from TRANSFORM. In the noninflamed group, median PFS was 30.9 months with liso-cel treatment versus 5.7 months with SOC (P = 0.003). Inflamed patients treated with liso-cel had a median PFS of 33.2 months versus 2.1 months for those treated with SOC (P = 0.146); the lack of statistical significance was likely due to limited patient numbers in the inflamed group for both arms. Differences in CR rate and ORR mirrored PFS results favoring liso-cel in both groups. Notably, liso-cel treatment in the inflamed group resulted in longer median PFS than SOC in the noninflamed group (33.2 versus 5.7 months). InflaMix groups were not associated with incidence of any grade or grade ≥ 3 CRS or NE. InflaMix is consistently prognostic in patients with LBCL treated with CAR T cell therapy in later-line settings. However, in 2L LBCL, InflaMix stratified outcomes in patients treated with SOC, but not in those treated with liso-cel. The results from this study support prior data showing InflaMix stratification of patients treated with bispecific antibodies (Magno G, et al. Blood 2024), further suggesting that the stratification may be broadly prognostic for patients with LBCL. Importantly, liso-cel outperformed SOC in 2L regardless of inflammatory status, reinforcing liso-cel as a robust treatment option delivering deep and durable efficacy for a broad population of patients with 2L LBCL.

This study assessed the comparative efficacy of lisocabtagene maraleucel (liso-cel) in the open-label, phase II PILOT study (clinicaltrials.gov NCT03483103) versus conventional second-line (2L) chemotherapy regimens in the real world administered to patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) who were not intended for hematopoietic stem cell transplantation (HSCT). The liso-cel-treated cohort (N=61) was based on patients who received liso-cel in the PILOT study. The conventional chemotherapy cohort included patients who met PILOT eligibility criteria and received conventional 2L chemotherapy in the real-world clinical setting (N=273). After using the trimmed stabilized inverse probability of treatment weighting method to balance cohorts according to baseline characteristics, there were statistically significant differences in all tested measures of efficacy. Compared with real-world conventional chemotherapy regimens, liso-cel demonstrated higher overall response rates (79.6% with liso-cel vs. 50.5% with conventional chemotherapy; relative risk [RR]: 1.6; P<0.0001) and complete response rates (53.1% vs. 24.0%; RR: 2.2; P<0.0001), longer median duration of response (12.1 vs. 4.3 months; hazard ratio [HR: 0.40; P=0.0001), longer median event-free survival (7.0 vs. 2.8 months; HR: 0.43; P<0.0001), longer median progression-free survival (7.0 vs. 2.9 months; HR: 0.46; P<0.0001), and longer median overall survival (not reached vs. 12.6 months; HR: 0.58; P=0.0256). Results from analyses applying various additional statistical approaches consistently favored outcomes with liso-cel over real-world conventional chemotherapy regimens. These results reinforce the efficacy of liso-cel as 2L therapy for patients with R/R LBCL who are not intended for HSCT.

Improved understanding of the timing of cytokine release syndrome (CRS) and immune effector cell-mediated neurotoxicity syndrome (ICANS)/neurological events (NE) after chimeric antigen receptor (CAR) T-cell therapy infusion can inform patient safety monitoring. To report CRS and ICANS/NE outcomes, including incidence, onset, and resolution, in patients treated with lisocabtagene maraleucel (liso-cel) in clinical trials and the real-world setting. This analysis included patients treated with liso-cel in 5 clinical trials across different B-cell non-Hodgkin lymphoma indications (n = 702) and in the real-world setting for large B-cell lymphoma, as captured in the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry (n = 877). All outcomes are reported descriptively. Among 702 patients in clinical trials, 54% had any-grade CRS (grade ≥3 at onset, 1%), with 98% of events occurring ≤day 15 after infusion; median time to resolution was 5 days. Any-grade NEs occurred in 31% of patients (grade ≥3 at onset, 5%), with 88% of events occurring ≤day 15 after infusion; median time to resolution was 7 days. Among 877 patients in the real-world setting, 49% had any-grade CRS (maximum grade ≥3, 3%), with 97% of events occurring ≤day 15 after infusion; median time to resolution was 4 days. Any-grade ICANS occurred in 27% of patients (maximum grade ≥3, 10%). Of 150 patients with reported onset date, 95% had onset ≤day 15 after infusion; median time to resolution was 5.5 days. The vast majority of CRS or ICANS/NEs occurred ≤day 15 after liso-cel infusion. These results support the recently updated United States Food and Drug Administration monitoring requirements aimed to improve treatment access while maintaining patient safety.

7026 Background: CAR T cell therapies have shown remarkable efficacy in B-cell NHL. Here, we report CRS and ICANS timing in 1579 patients (pt) treated with liso-cel in clinical trials across indications or in the standard of care (SOC) setting to inform safety monitoring requirements. Methods: Data from pivotal trials (TRANSCEND NHL 001, TRANSCEND CLL 004, TRANSFORM, PILOT, TRANSCEND FL) included pts treated with liso-cel for R/R LBCL, CLL/SLL, MCL, and FL; data from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry included pts who received commercial liso-cel for R/R LBCL and had ≥ 1 assessment after infusion. Outcomes were incidence, onset, grade (gr), and duration of CRS and ICANS from pivotal trials and the CIBMTR Registry. Results: Of 702 pts treated with liso-cel in 5 clinical trials, 46% had no CRS, 54% had any-gr CRS (gr ≥ 3 at onset, 1%); 98% of events had onset ≤ 2 wk after infusion and median duration was 5 d (Table). Of 7 pts with CRS onset > Day 15 (gr 1, n = 5; gr 2, n = 2), all resolved. Most (69%) pts had no ICANS, 31% had any-gr ICANS (gr ≥ 3 at onset, 5%); 88% of events had onset ≤ 2 wk after infusion and median duration was 7 d (Table). Of 27 pts with ICANS onset > Day 15 (gr 1, n = 20; gr 2, n = 6; gr 3, n = 1), all resolved except 1 pt with gr 2 leukoencephalopathy. Of 877 liso-cel–treated pts from the CIBMTR Registry, 51% had no CRS, 49% had any-gr CRS (gr ≥ 3, 3%); 97% of events had onset ≤ 2 wk after infusion and median duration was 4 d (Table). Of 15 pts with CRS onset > Day 15 (gr 1, n = 9; gr 2, n = 2; gr 3, n = 1; unknown, n = 3), 13 resolved (missing, n = 2). Most (73%) pts had no ICANS, 27% had any-gr ICANS (gr ≥ 3, 7%). Of 150 pts with reported onset date, 95% had onset ≤ 2 wk after infusion and median duration was 5.5 d. Of 8 pts with ICANS onset > Day 15 (gr 1, n = 5; gr 2, n = 1; gr 4, n = 2), 5 resolved (missing, n = 3). Further characterization/management of CRS/ICANS events will be presented. Conclusions: Data from the liso-cel pivotal clinical trials and SOC setting from the CIBMTR Registry demonstrated that most CRS/ICANS events occurred ≤ 2 wk after infusion and were not severe. For the few pts who experienced onset of CRS/ICANS after Day 15, most events were low grade and resolved. Clinical trial information: NCT02631044 , NCT03331198 , NCT03483103 , NCT03575351 , NCT04245839 . CRS and ICANS in liso-cel–treated pts. Pivotal clinical trials (N = 702) CIBMTR Registry (N = 877) CRS ICANS CRS ICANS Any gr, n (%) 381 (54) 220 (31) 430 (49) a 234 a,b (27) Gr 3/4/5, c n (%) 4 (0.6)/3 (0.4)/0 29 (4)/3 (0.4)/0 4 (0.5)/13 (1)/7 d (0.8) 43 (5)/17 (2)/5 (0.6) Median (range) time to onset, d 5 (1–63) 8 (1–63) 4 (IQR, 3–6) 6 (IQR, 4–9) Median (range) duration from onset, d 5 (1–37) 7 (1–119) 4 (IQR, 2–6) 5.5 (IQR, 2–11) Onset > Day 15, n/N (%) 7/381 (2) 27/220 (12) 15/430 (3) 8/150 (5) a Gr was to be determined for 3 pts; b A total of 150/234 had a reported onset date; c Gr at onset for clinical trials; maximum gr during reporting period for CIBMTR; d Three pts had PD and 1 had ICANS reported as primary cause of death.

What is this summary about? People diagnosed with a disease called large B-cell lymphoma (LBCL) may experience return, or early relapse, of their disease within the first year after receiving and responding to their first (first-line) treatment regimen. Others may have primary refractory disease, meaning that the disease either did not respond to first-line treatment at all or only responded for a very brief period. Second (second-line) treatment includes immunotherapy followed by high-dose chemotherapy and ASCT, which has the potential to cure LBCL. However, if the disease does not respond to immunotherapy, people cannot receive ASCT, and less than 30% of people are cured. Therefore, new second-line treatment options are required, such as CAR T cell therapy, which uses a person's own genetically engineered lymphocytes, also called T cells, to fight their lymphoma. In this article, we summarize the key results of the phase 3 TRANSFORM clinical study that tested if liso-cel, a CAR T cell treatment, can safely and effectively be used as a second-line treatment for people with early relapsed or primary refractory (relapsed/refractory) LBCL. A total of 184 adults with relapsed/refractory LBCL who were able to receive ASCT were randomly treated with either liso-cel or standard of care (SOC) as second-line treatment. SOC included immunochemotherapy followed by high-dose chemotherapy and ASCT. What were the key takeaways? Almost all (97%) people in the liso-cel group completed treatment, whereas 53% of people in the SOC group did not complete treatment, mostly due to their disease not responding or relapsing, and therefore they were not able to receive ASCT. People who received liso-cel as a second-line treatment lived longer without the occurrence of an unfavorable medical event or worsening of the disease and had a better response to treatment than those who received SOC as second-line treatment. People who received liso-cel reported side effects that researchers considered to be manageable, and that were known to occur with CAR T cell treatment. What were the main conclusions reported by the researchers? Results from the TRANSFORM study support the use of liso-cel as a more effective second-line treatment compared with SOC that is safe for people with relapsed/refractory LBCL. Clinical Trial Registration: NCT03575351 (TRANSFORM study) ( ClinicalTrials.gov )

Background: ctDNA clearance after frontline DLBCL tx has shown strong prognostic value for favorable outcomes, with the potential to improve MRD-driven therapeutic strategies and establish MRD as a surrogate endpoint in future studies (Roschewski M, et al. Blood 2022; Goldstein J, et al. Blood 2023). However, further study is needed to evaluate the association of this noninvasive approach with efficacy outcomes after 2L LBCL tx. We previously reported ctDNA analysis after liso-cel infusion in TRANSFORM (NCT03575351; Stepan L, et al. Blood 2023;142[suppl 1]). Here, we describe the predictive value of pre-tx and on-tx ctDNA levels for durable clinical benefit (CR and event-free survival [EFS]) in both liso-cel and SOC arms from TRANSFORM (Kamdar M, et al. J Clin Oncol 2024), evaluating ctDNA as an earlier surrogate for conventional clinical outcomes. Methods: Baseline (prerandomization) and longitudinal ctDNA levels were assessed in randomized pts treated with liso-cel or SOC in TRANSFORM using the phased variant enrichment and detection sequencing assay (PhasED-Seq; Foresight Diagnostics). Phased variants were identified from baseline plasma samples for longitudinal ctDNA monitoring at multiple on-tx time points, as previously described (Stepan L, et al. Blood 2023;142[suppl 1]). Randomization was defined as study Day 1. Association of ctDNA levels with response per independent review committee using Lugano 2014 criteria and EFS was investigated at various predefined time points, including Day 43 (after 2 cycles of salvage immunochemotherapy for SOC; Day 15 after liso-cel infusion), Day 64 (after 3 cycles of salvage immunochemotherapy for SOC; 1 month after liso-cel infusion), and Day 126 (within 2 months after ASCT; 3 months after liso-cel infusion). To assess the surrogacy value of ctDNA, ctDNA-MRD dynamics and ctDNA clearance were investigated within both arms. Results: In pooled analyses combining the liso-cel and SOC arms, higher baseline ctDNA levels (above the median) were associated with shorter EFS (P = 0.05). Pts achieving Day 126 CR had substantial reductions in ctDNA burden vs baseline, while pts with PD or stable disease had persistently high ctDNA levels vs baseline. Achieving undetectable ctDNA at different time points was associated with significantly longer EFS in pooled analyses, observed as early as study visit Day 43, with the strongest association at Day 126. HR (95% CI) for inferior EFS was 3.0 (1.6-5.7) at Day 43, 3.8 (2.1-7.0) at Day 64, and 4.2 (2.3-7.7) at Day 126 in pts with detectable vs undetectable ctDNA. In the analysis by tx arm, consistent with the pooled analyses, ctDNA clearance was associated with EFS benefit at all measured time points with either liso-cel or SOC. Significantly more pts achieved undetectable ctDNA with liso-cel vs SOC during the study (39/63 [62%] vs 25/65 [38%], respectively; P = 0.013), consistent with superior EFS (primary endpoint) with liso-cel in TRANSFORM. All pts in the SOC arm with evaluable ctDNA at Day 126 (n = 28) had received high-dose chemotherapy (HDCT)/ASCT. However, pts with undetectable ctDNA in the liso-cel vs SOC arm had longer EFS at all predefined time points and had statistically longer EFS at Day 126 (SOC vs liso-cel: HR, 3.9 [95% CI, 1.4-10.6]), indicating a deeper and more durable response with liso-cel vs SOC. In pts with CR, ctDNA showed significant predictive value beyond the response assessment at all time points in the liso-cel arm with a HR (95% CI) of 3.8 (1.3-11.0) at Day 64 and 7.0 (2.0-24.3) at Day 126 for EFS in pts with detectable ctDNA vs undetectable ctDNA. Among pts in the SOC arm who experienced subsequent PD despite achieving CR (all received HDCT/ASCT) and undetectable ctDNA at Day 126, serial ctDNA assessment showed consistent reversion to detectable ctDNA at later time points. Conclusions: ctDNA data from TRANSFORM confirm the value of ctDNA as a biomarker for disease burden monitoring and early prediction of durable clinical benefit after 2L LBCL treatment. Furthermore, longitudinal ctDNA molecular response results agree with previously reported clinical efficacy data and confirm the superiority of liso-cel with deeper responses over the historical SOC in 2L LBCL. ctDNA may have a key role as a surrogate endpoint in future LBCL studies, including after CAR T cell therapies.

Background: Two CAR T cell therapies, liso-cel and axi-cel, demonstrated superior efficacy over salvage chemotherapy and autologous transplant as 2L therapy in transplant-intended pts with high-risk R/R LBCL, yet no head-to-head comparisons have been performed. A previous MAIC in the 2L setting with a median follow-up of 17.5 mo for liso-cel and 24.9 mo for axi-cel showed comparable efficacy and more favorable safety outcomes for liso-cel with lower rates of all-grade and grade ≥ 3 cytokine release syndrome (CRS) and neurological events (NEs) (Abramson JS, et al. Blood 2022). Here, we present updated results with long-term follow-up for liso-cel and axi-cel. Methods: MAICs were used to estimate population-adjusted relative treatment effects associated with liso-cel for event-free survival (EFS), PFS, ORR, and CR rate (TRANSFORM; NCT03575351; N = 184; data cutoff date: October 2023) vs axi-cel (ZUMA-7; NCT03391466; N = 359; data cutoff date: January 2023) and safety (TRANSFORM, n = 183; ZUMA-7, n = 338). Pts were excluded from the TRANSFORM data set if they did not meet ZUMA-7 eligibility criteria (ie, matching). Individual pt data (IPD) for pts remaining in the TRANSFORM data set were weighted using a method-of-moments propensity score model to match the marginal distribution (ie, mean, variance) of clinical factors among pts from ZUMA-7 (ie, adjustment). Baseline characteristics and outcome measures were revised to align with those defined in ZUMA-7. Efficacy comparisons were anchored through the common comparator, standard of care (SOC; with similar protocol-defined salvage chemotherapy regimens in both trials, followed by high-dose chemotherapy and autologous transplant in responders). Hazard ratios (HRs) were used to compare time-to-event outcomes (EFS, PFS), and odds ratios were used to compare binary outcomes (ORR, CR rate, safety). Selection and rank ordering of the treatment effect modifiers were guided by analysis of the TRANSFORM IPD and clinical experts. Factors to match (ie, pts from TRANSFORM were removed) and adjust (ie, pts from TRANSFORM were reweighted) for efficacy and safety comparisons were reported previously (Abramson JS, et al. Blood 2022). Safety comparisons were unanchored due to the absence of CAR T cell-associated toxicities in the SOC arms. Bridging chemotherapy was allowed in TRANSFORM but not in ZUMA-7; it was not possible to adjust for this factor given sample size constraints. Results: Median study follow-up time was 33.9 mo for liso-cel and 47.2 mo for axi-cel. Efficacy outcomes were comparable between therapies in the unmatched/unadjusted comparison. For liso-cel vs axi-cel, respectively, median (95% CI) EFS was 29.5 mo (9.5‒not reached [NR]) vs 8.3 mo (4.5‒15.8) with HR (95% CI) of 0.94 (0.60‒1.46), and median (95% CI) PFS was 29.5 mo (10.3‒NR) vs 14.7 mo (5.4‒43.5) with HR of 0.90 (95% CI, 0.56‒1.47). Median ORR was 87% vs 83% with odds ratio (95% CI) of 1.41 (0.58‒3.40), and CR rate was 74% vs 65% with odds ratio (95% CI) of 0.95 (0.44‒2.03). After matching with ZUMA-7 for pt eligibility, the TRANSFORM sample size was 158; matching and adjusting for the selected effect modifiers resulted in an effective sample size of 80 for the primary efficacy scenario comparisons (sample size for ZUMA-7 and median efficacy values for axi-cel were unchanged). After matching and adjustment, efficacy outcomes remained comparable between therapies. Median (95% CI) EFS for liso-cel was NR (6.21‒NR) with HR (95% CI) of 0.75 (0.43‒1.33), and median (95% CI) PFS was NR (9.4-NR) with HR (95% CI) of 0.68 (0.37‒1.23). ORR was 85% with odds ratio (95% CI) of 1.63 (0.60‒4.44), and CR rate was 68% with odds ratio (95% CI) of 0.94 (0.40‒2.22). For safety, MAIC results demonstrated lower odds ratios (95% CI) of grade ≥ 3 serious treatment-emergent adverse events (TEAEs; 0.49 [0.27‒0.90]), CRS (any grade, 0.09 [0.04‒0.18]; grade ≥ 3, 0.09 [0.01‒0.75]), and NEs (any grade, 0.08 [0.03‒0.18]; grade ≥ 3, 0.21 [0.06‒0.68]) for liso-cel vs axi-cel. Conclusions: Results from this updated MAIC of liso-cel and axi-cel for the 2L treatment of R/R LBCL showed comparable efficacy, with more favorable safety outcomes for liso-cel. Liso-cel demonstrated a better safety profile with lower rates of grade ≥ 3 serious TEAEs and lower rates of all-grade and grade ≥ 3 CRS and NEs compared with axi-cel.

Introduction: TRANSFORM (NCT03575351) is a multinational, phase 3 study that compared efficacy and safety of liso-cel versus SOC, including overall survival (OS) as a key secondary endpoint, as a 2L treatment for patients (pt) with relapsed/refractory (R/R) large B-cell lymphoma who were eligible for transplant. The study design permitted pts treated with 2L SOC to receive liso-cel as third line (3L) treatment if protocol-defined conditions were met and requested by investigators. The intention-to-treat (ITT) analysis of OS for liso-cel versus SOC in TRANSFORM addressed a specific research question that did not account for treatment switching. Additionally, as real-world use of chimeric antigen receptor (CAR) T cell therapies in 3L may be less common compared with TRANSFORM, the ITT analysis may provide a conservative estimate of the treatment effect for liso-cel versus SOC on OS. Here, we conducted a complementary analysis of OS to adjust for crossover and estimate the relative effect of liso-cel versus SOC in the absence of 3L CAR T cell therapy. Methods: An external control arm based on external data from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) phase 3 study (NCT00137995) was created using the inverse probability of treatment weighting (IPTW) method. CORAL provided relatively mature survival data and reflects OS in the absence of CAR T cell therapies, which were not available at the time CORAL was conducted. After aligning inclusion/exclusion criteria of the 2 studies, 258 pts from CORAL were retained. To control for confounding, the 2L SOC cohort from CORAL was weighted to match the baseline distributions of prognostic factors and treatment effect modifiers of the liso-cel population in TRANSFORM. Relative efficacy was estimated by fitting a weighted Cox regression model to survival data for the external SOC arm from CORAL and the liso-cel arm from TRANSFORM. Results: After population adjustment via IPTW, the effective sample size (ESS) for SOC (CORAL) was 43.6% of the unadjusted sample size. The IPTW approach generally reduced imbalances in baseline characteristics between the 2 populations. The adjusted hazard ratio (HR; 95% CI) for liso-cel versus SOC was 0.50 (0.32–0.78), indicating that liso-cel was associated with a survival benefit in comparison with SOC in the absence of treatment switching (Table). Conclusions: These analyses demonstrated that liso-cel is associated with prolonged OS in comparison with SOC under a scenario of no 3L CAR T cell therapy, and the consideration of external data is a suitable alternative to existing statistical methods to adjust for treatment switching. The research was funded by: This study was funded by Bristol Myers Squibb. All authors contributed to and approved the abstract; writing and editorial assistance were provided by Emily Burke, PhD, of The Lockwood Group (Stamford, CT, USA), funded by Bristol Myers Squibb. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. F. Morschhauser Consultant or advisory role: Roche, Gilead, Abbvie Other remuneration: Membership on an entity's Board of Directors or advisory committees: Roche, Gilead, Novartis, BMS, Abbvie, Genmab, Miltenyi, Allogene therapeutics, AstraZeneca, Janssen H. Ghesquieres Consultant or advisory role: Gilead Sciences, Roche Honoraria: Gilead Sciences, Roche, Takeda Educational grants: Abbvie M. Kamdar Consultant or advisory role: AstraZeneca, Adaptive Biotechnologies, Abbvie, BeiGene, ADC Therapeutics, Syncopation Life Sciences, Bristol-Myers Squibb, Genetech/Roche Research funding: Novartis Other remuneration: Speakers' Bureau: Seattle Genetics F. F. Liu Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb C. Chandler Employment or leadership position: Conor Chandler is employed by Evidera, an independent research company that provides consulting services to life science companies; in his salaried position, he works with a variety of companies and is precluded from receiving payments or honoraria directly from these organizations for services rendered. Evidera received payment from Bristol Myers Squibb for the conduct of this study. A. Crotta Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb S. L. Klijn Employment or leadership position: Bristol Myers Squibb Consultant or advisory role: Bayer, Bristol Myers Squibb, Kite, Janssen - Payments made to OPEN Health Stock ownership: Bristol Myers Squibb A. Elsada Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb A. Previtali Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb I. Proskorovsky Employment or leadership position: Full-time employee of Evidera, which received funding from Bristol Myers Squibb to conduct this research. N. Schmitz Honoraria: Allogene Educational grants: Allogene, Miltenyi Other remuneration: Grants from Janssen, AstraZeneca, Abbvie J. S. Abramson Consultant or advisory role: Celgene, Novartis, Abbvie, Kite, Genetech, EMD Serono, MorphoSys, Alimera Sciences, Karyopharm Therapeutics, Bristol-Myers Squibb, C4 Therapeutics, BeiGene, AstraZeneca, Incyte, Bluebird Bio, Kymera, Epizyme, Genmab, MustangBio, Ono Pharmaceutical, Century Therapeutics, Lilly, Caribou Biosciences, Janssen, Takeda Honoraria: Regeneron, AstraZeneca, Janssen, Bristol-Myers Squibb Research funding: Seattle Genetics, AI Therapeutics, Bristol-Myers Squibb/Celgene

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.

Background: Pts with LBCL that is refractory to or has relapsed after 1L therapy and who are not intended for HSCT have poor outcomes and limited treatment options. Liso-cel is an autologous CD19-directed CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. In PILOT (NCT03483103), an open-label, single-arm, multicenter, phase 2 study in TNI pts with 2L R/R LBCL, liso-cel demonstrated high response rates and durable responses, with no new safety signals identified in 2L (Sehgal et al. Lancet Oncol 2022). In the current study, we assessed the comparative effectiveness of liso-cel in PILOT versus an external control cohort of pts with R/R LBCL who received conventional 2L chemotherapy regimens in the real-world clinical setting. Methods: PILOT enrolled pts with R/R LBCL at any time after only 1L of chemoimmunotherapy containing an anthracycline and a CD20-targeted agent and with confirmed PET-positive disease, who were considered TNI by their physician, and who met ≥ 1 prespecified TNI criterion. The primary endpoint for PILOT was ORR. Secondary endpoints included CR rate, duration of response (DOR), PFS, event-free survival (EFS), and OS. The real-world external control cohort was derived from a global, noninterventional, retrospective, observational study using multiple sources (COTA, Guardian Network, and clinical sites via electronic case report forms) representing pts with R/R LBCL across academic and community clinical settings in the US, Europe, and Japan. In the real world, intention to receive HSCT or not was not documented and was substituted with receipt of HSCT in this analysis. The real-world qualifying comparator cohort (QCC) included pts with R/R LBCL who received 1L treatment containing an anthracycline and CD20-targeted agent and any 2L treatment except HSCT and met PILOT eligibility criteria. The primary endpoint for this study was ORR in the PILOT cohort versus the QCC. EFS was defined in this study as time from index date to first documentation of disease progression/relapse, start of new anticancer therapy, or any-cause death, whichever occurred first. The index and data cut-off dates, respectively, were the day of liso-cel infusion and 09/24/2021 for the PILOT cohort and the start of 2L therapy and 12/31/2020 for the QCC. The study period was Jul 2018 to Sept 2021. Endpoint analyses were performed with adjustment using the propensity score methodology of trimmed stabilized inverse probability of treatment weighting to balance pts in the QCC to the PILOT cohort according to baseline characteristics. Highly prognostic baseline characteristics (based on literature and medical review) with ≤ 30% missing values in both PILOT and the real-world cohort were included in balancing: age, sex, years from initial diagnosis to index date, ECOG performance status, Ann Arbor disease stage, refractory versus relapsed, duration of CR after 1L therapy, and bulky disease. All tests were conducted assuming a 2-tailed test of significance and alpha level set a priori at 0.05, with no adjustment for multiplicity. Results: In the PILOT cohort (n = 61) and QCC (n = 273), respectively, median (range) age was 74 (53‒84)/74 (21‒93) years, 79%/77% of pts were aged ≥ 70 years, 26%/24% had ECOG performance status of 2, 23%/8% had CrCl (Cockcroft and Gault) < 60 mL/min, 3%/2% had left ventricular ejection fraction < 50%, 2%/5% had aspartate aminotransferase > 2 × upper limit of normal (ULN), 0%/3% had alanine aminotransferase > 2 × ULN, and 66%/53% had Stage III or IV disease. In the QCC, the most common conventional 2L chemotherapy regimens were rituximab plus ifosfamide, carboplatin, and etoposide (R-ICE; 15%), bendamustine plus rituximab (12%), and rituximab plus gemcitabine and oxaliplatin (11%). Pts who received R-ICE might have been intended to proceed to HSCT but did not because of lack of response to R-ICE; however, intention to receive HSCT cannot be verified based on retrospective real-world data. There was a statistically significant difference in adjusted ORR, CR rate, median DOR, EFS, PFS, and OS in favor of the PILOT cohort versus the QCC (Table). Conclusions: In pts with R/R LBCL who met prespecified TNI criteria, the difference in efficacy outcomes with liso-cel in PILOT versus conventional 2L chemotherapy regimens in the real world was statistically significant in favor of liso-cel, further supporting liso-cel as a new 2L therapy for pts with R/R LBCL who are not intended for HSCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lisocabtagene maraleucel (liso-cel) has shown promising efficacy in clinical trials for patients with relapsed/refractory large B-cell lymphoma (LBCL). We present health-related quality of life (HRQOL) results from the TRANSFORM study, the first comparative analysis of liso-cel vs standard of care (SOC) as second-line therapy in this population. Adults with LBCL refractory or relapsed =12 months after first-line therapy and eligible for autologous stem cell transplantation were randomized 1:1 to the liso-cel or SOC arms (3 cycles of immunochemotherapy in which responders proceeded to high-dose chemotherapy and autologous stem cell transplantation). HRQOL was assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - 30 items and the Functional Assessment of Cancer Therapy-Lymphoma subscale. Patients with baseline and =1 postbaseline assessment were analyzed (liso-cel, n = 47; SOC, n = 43). The proportion of patients with meaningful improvement in global health status/quality of life (QOL) was higher, whereas deterioration was lower in the liso-cel arm vs SOC arm from day 126 to month 6. Mean change scores showed meaningful worsening in global health status/QOL at month 6, fatigue at day 29 and month 6, and pain at month 6 with SOC; mean scores for other domains were maintained or improved in both arms. Time to confirmed deterioration favored the liso-cel arm vs SOC arm in global health status/QOL (median: not reached vs 19.0 weeks, respectively; hazard ratio, 0.47; 95% confidence interval, 0.24-0.94). HRQOL was either improved or maintained from baseline in patients with relapsed/refractory LBCL in the liso-cel arm vs SOC arm as second-line treatment. This study is registered at clinicaltrials.gov as #NCT0357531.

Background: Two chimeric antigen receptor (CAR) T cell therapies, liso-cel and axi-cel, demonstrated superior efficacy over salvage chemotherapy and autologous transplant for chemotherapy sensitive disease as 2L therapy in transplant-intended pts with high-risk R/R LBCL, yet no head-to-head clinical trials have compared CAR T cell therapies. A previous MAIC report showed comparable efficacy and an improved safety profile of liso-cel vs axi-cel in 3L+ R/R LBCL (Maloney et al. J Hematol Oncol 2021). Here we conducted a MAIC of treatment effects in the 2L setting for liso-cel vs axi-cel in pts with R/R LBCL. Methods: MAICs were used to estimate population-adjusted relative treatment effects associated with liso-cel for event-free survival (EFS), PFS, ORR, and CR rate (TRANSFORM; NCT03575351; N = 184) vs axi-cel (ZUMA-7; NCT03391466; N = 359), as well as safety (TRANSFORM, N = 183; ZUMA-7, N = 338). Pts from TRANSFORM were excluded from this analysis if they did not satisfy eligibility criteria specified in ZUMA-7 (ie, matching). Individual pt data (IPD) for pts who remained in the TRANSFORM data set were weighted using a method-of-moments propensity score model to match the marginal distribution (ie, mean, variance) of clinical factors among pts from ZUMA-7 (ie, adjustment). Baseline characteristics and outcome measures were revised to align with those defined in ZUMA-7. Efficacy comparisons were anchored through the common comparator, standard-of-care (SOC; with similar protocol-defined salvage chemotherapy regimens in both trials, followed by high-dose chemotherapy and autologous transplant in responders). Hazard ratios (HRs) were used to compare time to event outcomes (EFS, PFS), and odds ratios (OR) were used to compare binary outcomes (ORR, CR rate, safety). Selection and rank-ordering of the treatment effect modifiers were guided by analysis of the TRANSFORM IPD and by a panel of expert clinicians. Factors to match (ie, pts from TRANSFORM were removed) and adjust (ie, pts from TRANSFORM were re-weighted) for efficacy included: central nervous system involvement, absolute lymphocyte count at screening, age, sex, geographic region, secondary age-adjusted International Prognostic Index (sAAIPI) score, sum of the product of perpendicular diameters at baseline, R/R status to 1L therapy, double/triple-hit status, and disease histology. Safety comparisons were unanchored, owing to the absence of CAR T cell-associated toxicities in the SOC arms; factors for safety MAIC included: LVEF < 50% and bilirubin > 1.5 mg/dL at screening, age, and sAAIPI score. Notably, bridging chemotherapy was allowed in TRANSFORM but not in ZUMA-7; it was not practically possible to adjust for this factor given sample size constraints. Results: Unmatched and unadjusted comparisons showed no differences in median (95% CI) EFS for liso-cel (10.1 mo [6.1‒not reached]) vs axi-cel (8.3 mo [4.5‒15.8]; HR, 0.94 [0.58‒1.52]). After matching with ZUMA-7 for pt eligibility, the TRANSFORM sample size was 157; matching and adjusting for the selected effect modifiers resulted in an effective sample size of 69 for the primary efficacy scenario comparisons (sample size unchanged for ZUMA-7). MAIC primary scenario efficacy results for these populations showed no differences (Table). Median (95% CI) EFS after matching and adjustment was 9.5 mo (5.95‒not reached) for liso-cel. Results were consistent for other efficacy parameters of PFS, ORR, and CR rate. Sensitivity scenario comparisons that included additional adjustment factors led to similar results. MAIC safety results demonstrated lower odds of key CAR T cell-associated AEs with liso-cel vs axi-cel: cytokine release syndrome (CRS) any grade (OR, 0.09 [95% CI: 0.04‒0.19]), CRS grade ≥ 3 (OR, 0.10 [0.01‒0.81]), neurological events (NE) any grade (OR, 0.10 [0.04‒0.22]), and NEs grade ≥ 3 (OR, 0.21 [0.06‒0.69]). Conclusions: Findings from this comparative analysis of liso-cel and axi-cel for the 2L treatment of R/R LBCL show comparable efficacy of liso-cel and axi-cel, with more favorable safety outcomes for liso-cel where lower rates of all-grade and grade ≥ 3 CRS and NEs were observed. These results indicate liso-cel may have a better safety profile than axi-cel in 2L+ R/R LBCL and are consistent with those from the 3L+ MAIC analysis. This MAIC will be updated with the TRANSFORM primary analysis dataset when available. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Key Points • Liso-cel significantly improved EFS, CR rate, and PFS vs chemotherapy ± ASCT as a second-line treatment for LBCL.• Liso-cel was well tolerated as a second-line therapy, with low rates of any grade or severe cytokine release syndrome and neurological events.

Background Patients with large B-cell lymphoma (LBCL) primary refractory to or relapsed within 12 months of first-line therapy are at high risk for poor outcomes with current standard of care, platinum-based salvage immunochemotherapy and autologous haematopoietic stem cell transplantation (HSCT). Lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has previously demonstrated efficacy and manageable safety in third-line or later LBCL. In this Article, we report a prespecified interim analysis of liso-cel versus standard of care as second-line treatment for primary refractory or early relapsed (within 12 months after response to initial therapy) LBCL. Methods TRANSFORM is a global, phase 3 study, conducted in 47 sites in the USA, Europe, and Japan, comparing liso-cel with standard of care as second-line therapy in patients with primary refractory or early (<= 12 months) relapsed LBCL. Adults aged 18-75 years, Eastern Cooperative Oncology Group performance status score of 1 or less, adequate organ function, PET-positive disease per Lugano 2014 criteria, and candidates for autologous HSCT were randomly assigned (1:1), by use of interactive response technology, to liso-cel (100 x 10(6) CAR(+) T cells intravenously) or standard of care. Standard of care consisted of three cycles of salvage immunochemotherapy delivered intravenously-R-DHAP (rituximab 375 mg/m(2) on day 1, dexamethasone 40 mg on days 1-4, two infusions of cytarabine 2000 mg/m(2) on day 2, and cisplatin 100 mg/m(2) on day 1), R-ICE (rituximab 375 mg/m(2) on day 1, ifosfamide 5000 mg/m(2) on day 2, etoposide 100 mg/m(2) on days 1-3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), or R-GDP (rituximab 375 mg/m(2) on day 1, dexamethasone 40 mg on days 1-4, gemcitabine 1000 mg/m(2) on days 1 and 8, and cisplatin 75 mg/m(2) on day 1)-followed by high-dose chemotherapy and autologous HSCT in responders. Primary endpoint was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. Efficacy was assessed per intention-to-treat (ie, all randomly assigned patients) and safety in patients who received any treatment. This trial is registered with ClinicalTrials.gov, NCT03575351, and is ongoing. Findings Between Oct 23, 2018, and Dec 8, 2020, 232 patients were screened and 184 were assigned to the liso-cel (n=92) or standard of care (n=92) groups. At the data cutoff for this interim analysis, March 8, 2021, the median follow-up was 6.2 months (IQR 4.4-11.5). Median event-free survival was significantly improved in the liso-cel group (10.1 months [95% CI 6.1-not reached]) compared with the standard-of-care group (2.3 months [2.2-4.3]; stratified hazard ratio 0.35; 95% CI 0.23-0.53; stratified Cox proportional hazards model one-sided p<0.0001). The most common grade 3 or worse adverse events were neutropenia (74 [80%] of 92 patients in the liso-cel group vs 46 [51%] of 91 patients in the standard-of-care group), anaemia (45 [49%] vs 45 [49%]), thrombocytopenia (45 [49%] vs 58 [64%]), and prolonged cytopenia (40 [43%] vs three [3%]). Grade 3 cytokine release syndrome and neurological events, which are associated with CAR T-cell therapy, occurred in one (1%) and four (4%) of 92 patients in the liso-cel group, respectively (no grade 4 or 5 events). Serious treatment-emergent adverse events were reported in 44 (48%) patients in the liso-cel group and 44 (48%) in the standard-of-care group. No new liso-cel safety concerns were identified in the second-line setting. There were no treatment-related deaths in the liso-cel group and one treatment-related death due to sepsis in the standard-of-care group. Interpretation These results support liso-cel as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL. Copyright (C) 2022 Elsevier Ltd. All rights reserved.

Background: Pts with previously treated R/R aggressive LBCL have compromised health-related QOL (HRQOL). Liso-cel is an autologous, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In a prespecified interim analysis of TRANSFORM (NCT03575351), a randomized, open-label, pivotal trial, liso-cel demonstrated statistically significant and clinically meaningful improvement in the primary endpoint of event-free survival and key secondary endpoints (complete response rate and progression-free survival) in adults with R/R LBCL after failure of first-line (1L) immunochemotherapy compared with SOC, with no new safety signals. Here we present results of the pt-reported outcomes (PRO) analysis from TRANSFORM.

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children, representing approximately 75% of all pediatric acute leukemias. With current treatments, 20% of patients (pts) fail to respond to or relapse after initial chemotherapy (CT). Most children who relapse once experience a second relapse, and succumb to their disease, thus making recurrent ALL a leading cause of death by cancer in children. Allogeneic stem-cell transplant (SCT) is the preferred treatment option for pts relapsing after first line CT; however, up to 50% of pts with relapsed/refractory (r/r) disease do not qualify for SCT. Moreover, pts with an early relapse (within 12 months) after CT, experience poor outcomes with SCT, with a reported 3-year disease free survival of 21% to 29%. Pts who relapse after SCT have few therapeutic options. Several new strategies to treat r/r pts are in late stage development including chimeric antigen receptor T cells targeting CD19. In this analysis from one of the world's largest observational databases on hematopoietic cell transplantation maintained by CIBMTR, we assessed characteristics and current outcomes among pts with B-ALL who have relapsed after allogenic SCT, to better understand the clinical burden in this population. Methods: The primary objective of this non-interventional study was to evaluate the overall survival (OS) of pediatric B-ALL pts who relapse after first SCT. The study population included pts aged 3 to 21 years who underwent their first SCT between 2009 and 2013 for r/r B-cell ALL. OS was defined as the time from date of post-transplant relapse to the date of death due to any reason. Results: A total of 1349 children receiving a first transplant, with a mean age of 12.1 ± 5.2 years at time of transplant, were evaluated. Most pts were male (n = 820, 60.8%). Four hundred pts received SCT from an HLA-matched sibling (29.7%) and 947 (70.2%) from an unrelated adult (n = 571) or cord blood (n = 376) donor. Of the 1349 transplanted pts, 399 relapsed. OS at 6 months post relapse in the 399 pts was 55.8%, 95% CI [51-61%]; at one year 38.8%, 95% CI [34-44%]; at 3 years 23.2%, 95% CI [18-29%] and at 5 years, 20.3%, 95% CI [14-28%]. The median survival time after relapse post first SCT was 7.5 months with a median follow-up of 23 months. Seventy-one (17.8%) pts who relapsed underwent a second SCT, with a median OS time from second SCT of 12.9 months, 95% CI [9.7%, 22.6%]. The 3-year and 5-year OS probability after second SCT was 34.4%, 95% CI [21-48%] and 23%, 95% CI [7-45%], respectively. Conclusions: Post-transplant relapse is associated with poor outcomes even among those who are able to undergo a second SCT with 3-year OS as low as 23% (7.5 months median survival time) post first SCT and 34% post second SCT. New therapies are needed as alternative treatments for relapsed and refractory pediatric ALL pts.