Othman, Tamer

Introduction: Brexucabtagene Autoleucel (brexu-cel) is the first CD19-targeting chimeric antigen receptor (CD19.CAR) T-cell therapy approved for the treatment of relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in adult (≥18 yo) patients (pts) based on results from the ZUMA-3 trial. However, data on the safety and efficacy of CAR-T cells in older pts (≥60 yo) remains limited, with only 8 pts >65 yo enrolled in the ZUMA-3 trial. We evaluated the treatment characteristics and outcomes with use of brexu-cel amongst patients ≥60 yo in the Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database. Methodology: ROCCA is a consortium of over 30 U.S.-based institutions with a database of adult pts with B-ALL who received brexu-cel as standard of care therapy. We identified pts ≥60 yo and further stratified them into two cohorts: 60-69 yo and ≥70 yo. Outcomes of interest included OS, PFS, ORR, and toxicities (CRS and ICANS). Both OS and PFS were calculated from the day of brexu-cel infusion. Response assessment occurred on day +28, and MRD evaluation was per institutional practices. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy criteria. Results: Of 280 brexu-cel recipients in the ROCCA database, 73 (26%) were ≥60 yo, of which 58 (79%) were between 60-69 yo and 15 (21%) were ≥70 yo. Among pts ≥60 yo, the median age at infusion was 65 (range 60-81). Pts were heavily pretreated with a median of 3 prior lines of therapy (range 2-9). Prior therapies included: allogeneic HSCT (38%), inotuzumab ozogamicin (41%), and blinatumomab (62%). Forty pts (55%) had Ph-negative B-ALL, 24 (33%) had Ph+ B-ALL and 9 (12%) had Ph-like B-ALL. When grouped by HCT-CI equal to 0, 1-2 or ≥3, a higher proportion of pts ≥60 yo had HCT-CI ≥3 (19% vs. 7% in <60 yo; p=0.004). Pre-apheresis, 33 pts (45%) had active disease (>5% marrow blasts or extramedullary disease), 34 (47%) were in CR (of whom 14 were MRD-negative) and 6 had unknown disease status. Following brexu-cel, 43 (59%) achieved MRD-negative CR, 20 (27%) had MRD + or CR with unknown MRD status, 6 (8%) had refractory disease and 5 had no disease evaluation available. The ORR was similar between pts 60-69 and ≥70 yo (MRD-negative CR rate: 58% vs 61%, r/r to brexu-cel: 9% vs 6%) and was comparable to pts <60 yo (MRD-negative CR 66%; r/r disease of 9%). The rate of all grade ICANS was higher in pts ≥70 (77%) than in pts 60-69 (47%) or pts <60 (49%), with grade 1-2 ICANS occurring at a significantly higher rate in pts ≥70 (44% vs. 20% in 60-69 and 20% in <60, p=0.049). Grade 3-4 ICANS were similar between the groups: 33%, 27% and 29% in the ≥70, 60-69, and <60 groups, respectively. Conversely, rates of CRS were similar across age groups (80-84%). There was no statistically significant difference in the rate of grade 3-4 CRS which was 17% in pts ≥70, 4% in pts 60-69, and 11% in pts <60 yo. With a median follow-up of 332 days (range 8-936 days) from infusion, pts ≥60 yo had a median PFS of 395 days compared to 547 days in pts <60 yo. Median PFS was lower in the ³70 yo (231 days) compared to 677 in the 60-69 yo cohort. No statistically significant difference was found between the <60 and ≥60groups in 6- and 12-month PFS rates (6 months PFS: 66% vs 64%, p=0.77 and 12 months PFS: 57% vs 57%, p=1.00). When pts ≥60 yo were stratified by age, pts ≥70 yo had similar 6-month PFS compared to other age groups but significantly lower 12-month PFS (38%; vs. 64% in pts 60-69and 57% in pts <60, p=0.001). Median OS was not reached in any of the age groups, and there was no statistically significant difference in 6-month OS (72% in ≥ 70 vs. 82% in the 60-69 vs. 82% in <60, p=0.14) or 12-months OS (61% in ≥ 70 vs. 69% in 60-69 vs. 73% in <60, p=0.18). Conclusion: This is the largest study to date of older B-ALL pts receiving CAR-T cells. We observed that older pts, particularly those aged 60-69, have similar outcomes to younger pts. However, pts ≥70 yo had lower median and 12-month PFS when compared to younger patients. Additionally, pts ≥70 yo had higher rates of grades 1-2 ICANS. An important limitation of this analysis is the potential selection bias among clinicians when selecting older patients for this treatment. Longer follow-up, including inclusion of additional pts ≥70 yo is needed to confirm these results, and further studies are needed to identify the optimal approach for use of CAR T-cell therapy in patients in this age group.

Background: Ph-like ALL is a high-risk subset of B-lineage ALL that responds poorly to standard chemotherapy regimens. While allogeneic hematopoietic cell transplantation (HCT) is routinely recommended for patients with Ph-like ALL, large multicenter data addressing its role is limited. Here, we conducted a multicenter study to evaluate the role of HCT in adolescent and young adult (AYA) and adult patients (pts) with Ph-like ALL and compare their outcomes to pts with Ph-pos and Ph-neg (non-Ph-like) ALL. Methods: The study included pts (age ≥18) with B-lineage ALL who received HCT in first complete remission (CR1) at 3 academic centers (MD Anderson Cancer Center, City of Hope and Mayo Clinic) between 2006 and 2021. Pts were divided into 3 main subgroups: Ph-like, Ph-pos and Ph-neg ALL. Ph-like ALL cases were identified using cumulative data obtained by targeted RNA sequencing, conventional cytogenetics, FISH studies, whole genome chromosomal microarray and flow cytometry. Measurable residual disease (MRD) prior to HCT was measured using flow cytometry with a sensitivity of 0.01% for Ph-neg and Ph-like ALL, and with a PCR assay for BCR::ABL1 for Ph-pos ALL. MRD-negativity was defined as <0.01%. Predictors of relapse were evaluated in univariate and multivariate analysis using Fine-Gray sub-distribution hazard models considering non-relapse mortality (NRM) as a competing risk. Results: 673 patients were identified, 83 (12.3%) had Ph-like ALL, of which 73% had CRLF2-alterations. The remaining patients were classified either as Ph-pos (N=271, 40.3%) or Ph-neg ALL (N=319, 47.4%). Patients with Ph-like ALL were younger (median age 40 years vs 48 and 46 years for Ph-pos and Ph-neg ALL, respectively, p=0.01), more likely to be of Hispanic ethnicity (69% vs 32% and 48% for Ph-pos and Ph-neg ALL respectively, p<0.001). Patients with Ph-like ALL were also more likely to have induction failure (24% vs 2% and 11% for Ph-pos and Ph-neg ALL, respectively, p=0.001). A summary of pts characteristics for each subgroup can be found in Table 1. The median follow-up was 30, 52 and 48 months for patients with Ph-like, Ph-pos and Ph-neg ALL, respectively. In univariate analysis, 3-yr OS and PFS did not differ significantly (66% and 59% vs 59% and 54%, p=0.1) between patients with Ph-like and Ph-neg ALL, respectively. Similarly, the cumulative incidence of relapse was comparable between patients with Ph-like and Ph-neg ALL (22% vs 20%, respectively, p=0.7). In contrast, the 3-yr OS (75%, p<0.001) and PFS (70%, p=0.001) were significantly higher and relapse rate significantly lower (12%, p=0.003) in pts with Ph-pos ALL compared with Ph-like or Ph-neg ALL (Figure 1). The inferior survival in patients with Ph-like and Ph-neg ALL was likely attributable to higher relapse rates (22% and 20% vs 12%, respectively, p=0.003) compared to Ph-pos ALL. Finally, the 3-yr NRM rate in patients with Ph-like ALL was comparable (20% vs 18% and 23%, respectively, p>0.1) to Ph-pos and Ph-neg ALL. We confirmed that the relapse rate in patients with Ph-like ALL was comparable to the rate in pts with Ph-neg ALL (HR=1.02, 95% CI 0.6-1.8, p=0.9) on multivariate analysis (MVA). Ph-pos ALL was associated with a significantly lower relapse rate compared with Ph-neg ALL (HR=0.4, 95% CI 0.3-0.7, p<0.001). MRD positivity prior to allo-HCT was the only additional significant predictor for relapse on MVA (HR=2.9, 95% CI 1.8-4.7, p<0.001). Conclusions: HCT appears to overcome the poor prognosis of patients with Ph-like ALL. Despite higher induction failure rates, patients with Ph-like ALL undergoing HCT in CR1 had similar outcomes to other Ph-neg ALL subsets. The impact of effective salvage therapy leading to MRD-negativity in CR1 in this group is under investigation and will be reported. Further studies are needed to assess the impact of different Ph-like alterations on HCT outcomes. Outcomes for patients with Ph-pos ALL are significantly better than other groups, likely due to the use of TKIs pre- and post-HCT.

Background: Maintenance therapy with brentuximab vedotin (BV) after autologous stem cell transplantation (ASCT) improved progression-free survival (PFS) among high-risk patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) in the phase III AETHERA trial. However, cHL treatment has changed significantly since that trial with frequent incorporation of BV and PD-1 inhibitors into earlier lines of therapy. The efficacy of BV maintenance may be different among pts who receive novel agents before ASCT. Methods: Pts with a diagnosis of R/R cHL who underwent ASCT between 2010 and 2022 were identified at 5 US transplant centers. Pts receiving no systemic post-ASCT maintenance or BV maintenance were included, while pts receiving investigational maintenance treatments were excluded. Medical records were reviewed to identify clinical variables. Results: 921 pts were identified. Median age was 32 yrs (IQR 24-44). 641 pts (70%) had primary refractory disease or relapsed within 12 months of frontline therapy, 326 (35%) had extranodal disease at relapse, and 173 (19%) had B symptoms at relapse. Pts received a median of 2 (1-9) lines of therapy before ASCT, including 295 (32%) who received ≥3 lines. 425 (46%) pts received BV before ASCT (including 24 pts as part of frontline treatment). 70 pts (8%) were BV-refractory (defined as failure to achieve an objective response to any BV-based treatment). 169 (18%) received a PD-1 agent with salvage treatment. 638 pts (69%) had a complete response on pre-ASCT positron emission tomography (PET). BEAM (71%) or CBV (21%) conditioning were used for most pts and 236 pts (26%) received peri-ASCT radiation. 224 pts (24%) received post-ASCT BV maintenance (including 37% of pts undergoing ASCT from 2015-2022). Compared to pts receiving no maintenance, pts receiving BV maintenance were more likely to have primary refractory/early relapsed disease (79% vs 67%, p<0.001), have received only 1 salvage regimen (79% vs 65%, p=0.001), and received BEAM conditioning (83% vs 67%, p<0.001). BV maintenance pts were less likely to receive peri-ASCT radiation (20% vs 28%, p=0.022). The median number of BV maintenance cycles was 10 (1-18) and the most common reason for discontinuation was neuropathy. Median post-ASCT follow-up was 4.9 yrs. 5-yr PFS and OS after ASCT were 70% (95% CI 67-74%) and 85% (83-88%), respectively. Because BV-refractory pts were much less likely to receive BV maintenance (p=0.0044) and had inferior PFS (HR 2.2, p<0.001) (and therefore would serve as a confounder), we excluded BV-refractory pts from additional analyses. Use of BV maintenance was associated with improved PFS (5-yr 81% vs 67%, HR 0.47 [0.33-0.69], p<0.001) and OS (5-yr 92% vs 83%, HR 0.38 [0.20-0.73], p=0.004). The benefit of BV maintenance depended upon pre-ASCT therapy. BV maintenance was associated with a significant improvement in PFS for pts who received no novel agents before ASCT (HR 0.41 [0.25-0.65], p<0.001), but not for BV-treated (HR 0.69 [0.38-1.25], p=0.22) or PD-1-treated pts (HR 0.63 [0.13-3.03], p=0.56) ( Figure). Among pts with 0-1 modified AETHERA risk factors, BV maintenance was not associated with a significant PFS benefit in any treatment subgroup (no novel agents, HR 0.50, p=0.087; BV-treated, HR 1.28, p=0.67; PD-1-treated, HR 2.97, p=0.44). For pts with 2+ modified AETHERA risk factors, BV maintenance significantly improved PFS in the no novel agent group (HR 0.35, p<0.001) but not in the BV-treated (HR 0.55, p=0.099) or PD-1 treated groups (HR 0.24, p=0.19). In multivariable analyses that included key variables (age, year of ASCT, conditioning regimen, peri-ASCT radiation, early relapse/primary refractory disease, B symptoms, extranodal sites, pre-ASCT PET, lines of therapy), BV maintenance was associated with a significant PFS benefit among pts who received no novel agents before ASCT (HR 0.27 [0.12-0.65], p<0.001), but not for pts treated with BV (HR 0.56 [0.28-1.10], p=0.091) or PD-1 blockade (HR 1.10 [0.22-5.56], p=0.91) before ASCT. Conclusions: In this large cohort, BV maintenance was associated with the clearest benefit among pts who received only chemotherapy before ASCT. We were unable to identify a significant improvement in PFS for pts receiving novel agents before ASCT (which could be due to insufficient power to detect a small benefit in this population), suggesting that if these pts benefit from BV maintenance, its impact is likely more limited.

Introduction: Single arm studies incorporating PD-1 blockade and/or brentuximab vedotin (BV) to salvage regimen have produced encouraging results in transplant-eligible relapsed/refractory classic Hodgkin lymphoma (R/R cHL) and are increasingly used in practice. As prospective randomized studies comparing PD1 based salvage to other salvage regimens are lacking, we conducted a retrospective study comparing post-transplant outcomes of R/R cHL patients who received PD1-based regimen and other novel and conventional regimen. Methods: Consecutive adult patients with R/R cHL who received salvage therapy and underwent autologous stem cell transplant (ASCT) between 2010 and 2021 at 5 United States academic institutions were included. Demographics and clinical variables were recorded at relapse by electronic health records review. Study Objectives were post-ASCT progression free survival (PFS) and overall survival (OS). Results: 981 pts of R/R cHL were identified. At relapse, median age was 31 (IQR: 21-43) years, 504 (52%) were male, 323 (49%) had advanced stage, 353 (41%) had extranodal disease (END), 185 (22%) had B symptoms, 345 (45%) were refractory to frontline therapy and 317 (32%) relapsed within a year of frontline therapy.308 (31%) received >1 line of salvage before ASCT. Patients were divided into 3 groups based on salvage therapy received: 1) 195 (20%) patients received a PD-1 agent with or without BV at any point before ASCT (PD-1 group), 2) 312 (32%) patients received BV at any point before ASCT without PD-1 (BV group), and 3) 474 (48%) patients received no novel agent before ASCT (chemo group). PFS was significantly higher in PD1 group (2-yr PFS 93.1 (CI 95: 89.4-96.9)%); compared to BV (2 yr PFS 73.9 (CI 95: 69.1-79.1)% , p <0.0001) or chemo groups (2 yr PFS 71.6 (CI 95: 67.6-75.9)% , p<0.0001). PFS was not different between the BV and chemo groups (p=0.88) (Figure 1). OS was not significantly different between PD-1 group (2 yr OS 96.2 % (CI 95: 93.2-99.2), p=0.06), BV group (2 yr OS 94.3% (CI 95: 91.7-97.0), p=0.2) and chemo group (2 yr OS 91.8% (CI 95: 89.3-94.4)). Amongst pts who were transplanted in complete metabolic response (CMR), we assessed post-ASCT PFS and OS based on salvage therapy received immediately before ASCT. Pts who received PD-1 as last salvage therapy had improved PFS compared to chemo (HR: 0.15 (CI 95: 0.07-0.3), p= <0.0001) and BV (HR: 0.2 (CI 95: 0.08-0.5), p= <0.001). Pts receiving PD-1 immediately before ASCT also had higher OS compared to those receiving chemo (HR: 0.2 (CI 95: 0.05-0.8), p= 0.02) but not BV (HR: 0.8 (CI 95: 0.4-1.3), p=0.1). There was no difference between BV and chemo group in regards to PFS and OS. In multivariable analysis that included time to relapse, B symptoms, END, pre-ASCT response, number of salvage therapy lines before ASCT, year of transplant and BV consolidation, PD-1 salvage therapy had significantly higher PFS compared to chemotherapy (HR: 0.3 (CI 95: 0.2-0.5), p= <0.001). BV group had significantly lower PFS (HR: 3.34 (CI 95: 1.8-6.0), group=0.002) compared to PD1 group. PFS was not different between BV and chemo group (p= 0.7). OS was similar between all 3 groups. Similar PFS and OS were seen among patients receiving PD-1 + BV (n=83) and PD-1 with or without chemo (n =112) (p=0.96 for PFS; p= 0.72 for OS); as well as for patients receiving PD-1 as part of their first salvage therapy (n=151) or later salvage treatments (n=44) (p=0.45 for PFS, p= 0.3 for OS). Patients who received PD1 based regimen as last salvage therapy pre-ASCT had significantly better PFS (HR: 6.8 (CI 95: 2.4-19.2), p= <0.0001) and OS (HR: 10.6 (CI 95: 2.5-44.8), p= 0.0001) compared to patients who received PD1 prior to their last line of salvage therapy per-ASCT. Conclusion: Receipt of PD-1 based salvage therapy at any point before ASCT is associated with significantly improved PFS compared to either BV or chemotherapy-based salvage treatments. In the subgroup of patients transplanted in CMR, PD1 based last salvage regimen were associated with higher PFS compared to chemotherapy and BV and higher OS compared to chemotherapy. PD1 based last salvage therapy pre-ASCT was associated with better survival compared to PD1 prior to last salvage therapy. Results of this study strongly support the use of PD-1 based salvage therapy for patients with R/R cHL. S.D., R.M., H.S contributed equally. R.S., M.M. contributed equally.