Outcomes of patients aged ≥26 years with relapsed or refractory B-cell acute lymphoblastic leukemia in ZUMA-3 and historical trials.

Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 CAR T-cell therapy approved in the USA and European Union (EU) for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL; aged ≥26 years in EU). Here, outcomes for patients with R/R B-ALL aged ≥26 years in ZUMA-3 treated with brexu-cel were compared with historical standard-of-care (SOC) therapy. After median follow-up of 26.8 months, the overall complete remission (CR) rate among patients treated with brexu-cel in Phase 2 (N = 43) was 72% and median overall survival (OS) was 25.4 months (95% CI, 15.9-NE). Median OS was improved in Phase 2 patients versus matched historical SOC-treated patients. Compared with aggregate historical trial data, Phase 1 and 2 patients had improved OS versus blinatumomab, inotuzumab, and chemotherapy in a matching-adjusted indirect comparison (MAIC) study. These data demonstrate clinical benefit of brexu-cel relative to SOC in patients ≥26 years with R/R B-ALL.

Autologous Hematopoietic Cell Transplantation Consolidation for First Response is Associated With Longer Survival Among Patients With Nodal Peripheral T Cell Lymphoma.

Nodal peripheral T cell lymphomas (PTCLs) are challenging subsets of non-Hodgkin lymphomas characterized by their heterogeneity and aggressive clinical behavior. Given the mixed outcomes reported in previous studies, the efficacy of autologous hematopoietic cell transplantation (auto-HCT) as a consolidation strategy following initial chemotherapy response remains uncertain. This study aims to evaluate the impact of upfront auto-HCT consolidation on overall survival (OS) and event-free survival (EFS) among patients with nodal PTCL who achieved a complete or partial response to initial chemotherapy. A retrospective cohort study was conducted at Moffitt Cancer Center, involving 123 patients with nodal PTCL treated between February 2005 and February 2021. Patients were stratified into 2 groups based on whether they received auto-HCT as part of their initial treatment strategy. Kaplan-Meier method and Cox proportional hazard models were used for statistical analysis to compare OS and EFS between groups. Patients undergoing auto-HCT after first response demonstrated significantly longer median OS (12.3 versus 4.3 yr; P = .035) and EFS (6.2 versus 2.2 yr; P = .003) compared to those who did not. Multivariate analyses indicated that auto-HCT at first response and younger age at diagnosis were favorable prognostic factors. The findings suggest that upfront auto-HCT consolidation can significantly improve long-term outcomes in patients with nodal PTCL, supporting the strategy of early auto-HCT consideration and referral following initial chemotherapy response. These results underscore the importance of integrating upfront auto-HCT into the treatment paradigm for nodal PTCL, emphasizing early referral to transplantation services to optimize patient outcomes.

Baseline Serum Inflammatory Proteins Predict Poor CAR T Outcomes in Diffuse Large B-cell Lymphoma.

A subset of patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 chimeric antigen receptor (CAR) T-cell therapy have poor clinical outcomes. We report serum proteins associated with severe immune-mediated toxicities and inferior clinical responses in 146 patients with DLBCL treated with axicabtagene ciloleucel. We develop a simple stratification based on pre-lymphodepletion C reactive protein (CRP) and ferritin to classify patients into low-, intermediate-, and high-risk groups. We observe that patients in the high-risk category were more likely to develop grade ≥3 toxicities and had inferior overall and progression-free survival. We sought to validate our findings with two independent international cohorts demonstrating that patients classified as low-risk have excellent efficacy and safety outcomes. Based on routine and readily available laboratory tests that can be obtained prior to lymphodepleting chemotherapy, this simple risk stratification can inform patient selection for CAR T-cell therapy. SIGNIFICANCE: CAR T-cell therapy has changed the treatment paradigm for patients with relapsed/refractory hematologic malignancies. Despite encouraging efficacy, a subset of patients have poor clinical outcomes. We show that a simple clinically applicable model using pre-lymphodepletion CRP and ferritin can identify patients at high risk of poor outcomes. This article is featured in Selected Articles from This Issue, p. 80.

Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis.

Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single-cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single-cell RNA sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. These findings define ALL with MyM as a high-risk disease that can arise from antecedent CH and offer new mechanistic insights to develop better therapeutic and preventative strategies. SIGNIFICANCE: CH is a precursor lesion for lymphoblastic leukemogenesis. ALL with MyM has distinct genetic and clinical characteristics, associated with adverse survival outcomes after chemotherapy. CH can precede ALL years before diagnosis, and ALL with MyM is enriched with activated T cells that respond to immunotherapies such as blinatumomab. See related commentary by Iacobucci, p. 142.

Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3.

BACKGROUND: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported. METHODS: Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×106 CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided. RESULTS: Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7-58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups.Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22). CONCLUSIONS: In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.

Chimeric antigen receptor T-cell therapy for adult B-cell acute lymphoblastic leukemia: state-of-the-(C)ART and the road ahead.

Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has recently been added to the armamentarium in the battle against B-cell acute lymphoblastic leukemia (B-ALL). In this review, we discuss the trials that led to US Food and Drug Administration approval of CAR T-cell therapies in patients with B-ALL. We evaluate the evolving role of allogeneic hematopoietic stem cell transplant in the CAR T-cell era and discuss lessons learned from the first steps with CAR T-cell therapy in ALL. Upcoming innovations in CAR technology, including combined and alternative targets and off-the-shelf allogeneic CAR T-cell strategies are presented. Finally, we envision the role that CAR T cells could take in the management of adult patients with B-ALL in the near future.

Outcomes of CD19-Directed Chimeric Antigen Receptor T Cell Therapy for Transformed Nonfollicular Lymphoma.

CD19-directed chimeric antigen receptor (CAR) T cell (CAR-T) therapy with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) are approved for the treatment of relapsed or refractory large B cell lymphoma (LBCL), including de novo diffuse LBCL (DLBCL), primary mediastinal B cell lymphoma (PMBCL), and transformed follicular lymphoma (tFL). Transformed nonfollicular lymphomas (tNFLs), including transformed marginal zone lymphoma (tMZL) and transformed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) were not included in their respective pivotal studies. This study was conducted to evaluate the outcomes of axi-cel and tisa-cel in tNFL patients, including those who received ibrutinib concomitantly through apheresis, lymphodepletion, and CAR-T infusion. This single-center retrospective study included all patients with tCLL/SLL, tMZL, tFL, and DLBCL/PMBCL treated with CAR-T therapy outside of a clinical trial setting from November 2017 to May 2021 at Moffitt Cancer Center, Tampa, Florida. We analyzed and compared outcomes in patients with tCLL/SLL or tMZL and patients with DLBCL/tFL. The study included 134 patients who received a total of 136 CAR-T treatments (111 with axi-cel and 25 with tisa-cel). Ninety patients had de novo DLBCL/PMBCL, 23 had tFL, and 21 had tNFL (12 with tMZL and 9 with tCLL/SLL). The overall response and complete response rates were 66.7% and 55.6%, respectively, for tCLL/SLL and 92.9% and 71.4% for tMZL. The overall response and complete response rates were not different between tNFL and DLBCL/tFL (P = .92 and .81, respectively). At a median follow-up of 21.3 months, the median progression-free survival (PFS) for tCLL/SLL was 5.4 months (95% confidence interval [CI], .8 month to not assessable [NA]); for tMZL, the median PFS was not reached (NR) (95% CI, 2.3 months to NA); and for DLBCL/tFL, the median PFS was 14.3 months (95% CI, 5.6 months to NA) (P = .58). The estimated 1-year PFS rate was 29.6% (95% CI, 5.2% to 60.7%) for tCLL/SLL, 50.0% (95% CI, 22.9% to 72.2%) for tMZL, 42.7% (95% CI, 22.4% to 61.6%) for tNFL, and 53.0% (95% CI, 42.3% to 62.5%) for DLBCL/tFL. The median overall survival was NR (95% CI, 9.2 months to NA) for tCLL/SLL, 27.1 months (95% CI, 8.5 months to NA) for tMZL, and NR (95% CI, 17.4 months to NA) for DLBCL/tFL (P = .79). Compared to the DLBCL/tFL cohort, tNFL patients were more likely to develop immune effector cell-associated neurologic syndrome (ICANS) and to receive tocilizumab (P = .04 and .01, respectively, after controlling for CAR-T product) and with a possibly higher incidence of grade ≥3 cytokine release syndrome (CRS) (P = .07). Two patients in the tNFL cohort died of treatment-related toxicity after receiving axi-cel. Six tNFL patients received ibrutinib concurrently with tisa-cel, with 1 case of grade ≥3 CRS/ICANS that rapidly resolved and no other severe toxicities. Our case series supports the use of CD19 CAR-T therapy in relapsed/refractory tCLL/SLL and tMZL. The concurrent use of ibrutinib and tisa-cel in tNFL was associated with manageable toxicity in tNFL.

Sequencing antigen-targeting antibodies and cellular therapies in adults with relapsed/refractory B-cell acute lymphoblastic leukemia.

The recent approvals of four CD19-or CD22-targeted therapies for B-cell acute lymphoblastic leukemia (B-ALL) have transformed the treatment of relapsed/refractory (r/r) disease. Adults with r/r B-ALL are usually eligible for all options, but there are no studies directly comparing these agents, and the treating physician must decide which to select. Each therapy has notable activity as a single agent but has limitations in particular settings, and the optimal choice varies. These therapies can be complementary and used either sequentially or concomitantly. Here, we review the current landscape of antigen-targeted therapies for r/r B-ALL and discuss considerations for their use.

Pneumococcal Conjugate Vaccine Does Not Induce Humoral Response When Administrated Within the Six Months After CD19 CAR T-Cell Therapy.

CD19 targeted chimeric antigen receptor-modified T cell therapy (CAR-T) leads to B cell aplasia and low serum immunoglobulin levels. Long-lived CD19-negative plasma cells may persist through the therapy and generate antibodies. There is a paucity of data describing how CAR-T impacts the persistence of antibodies against vaccine-related antigens and the degree to which CAR-T recipients may respond to vaccines. We characterized the effect of CAR-T on pneumococcal immunoglobulin G (IgG) titers and determine whether pneumococcal conjugate vaccine (PCV13) administered after CAR-T develops long-term humoral protection against pneumococcus. A retrospective chart review was performed to identify CAR-T recipients who had serum pneumococcal IgG titers drawn before (baseline) or at days +90, +180, +270, +360, or +540 after CAR-T. We then determined whether they received PCV13 vaccination at these timepoints. IgG concentration ≥1.3 µg/mL was considered protective for that serotype, and patients with ≥6/11 tested vaccine-specific serotypes meeting this threshold were deemed to have humoral protection against pneumococcus. Absolute pneumococcal IgG titers and the proportion of patients with humoral protection, stratified by serotype, and vaccination status were compared by paired nonparametric t-tests. Absolute counts for lymphocyte, CD4 T-cell, and CD19 cell and total IgG level, along with the rate of invasive pneumococcal infections, were measured at these timepoints. A total of 148 CAR-T recipients with pneumococcal IgG titers measured for at least one of the defined time points were identified. At baseline, 25% (19/76) patients with evaluable pneumococcal IgG titers met the definition of humoral protection. Among 44 patients with paired pneumococcal IgG titers at baseline and day+90, absolute IgG titers of all serotypes decreased (geometric mean = 0.41 and 0.32 µg/mL, respectively; P < .001). Thirteen patients were vaccinated following the titer blood draw at day+90 and had paired pneumococcal IgG titers at day+90 and day180. Absolute IgG titers of all vaccine specific serotypes in these vaccinated patients decreased from day+90 to day+180 (geometric mean = 0.36 and 0.29 µg/mL, respectively; P = .03). The proportion of patients meeting the criteria of humoral protection remained the same at day+180 despite vaccination at day+90. The results were similar among 8 patients vaccinated at day+180, as well as 7 patients consecutively vaccinated at day+90 and day+180 with corresponding pneumococcal IgG titers. When all vaccine-specific pneumococcal IgG titers were pooled together by timepoint regardless of vaccination status, the proportion of patients with humoral protection decreased until day+540. Some patients developed humoral protection after vaccination at day+360, maintained seroprotective IgG titers from baseline, or developed protection after receiving intravenous immunoglobulin treatment secondary to recurrent infections. Our study demonstrated that few large B cell lymphoma patients had humoral protection against pneumococcus at baseline, and existing IgG titers decreased after CAR-T. PCV13 vaccination at day+90 or day+180 after CAR-T did not increase humoral protection against pneumococcus. Only at day+540 was there evidence of humoral protection against pneumococcus in a modest proportion of patients. Clinical trials are needed to determine the optimal timing of vaccination, before or after CAR-T, to develop protective immunity against Streptococcus pneumoniae infections.

Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study.

BACKGROUND: Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care. METHODS: Adults with R/R B-ALL received a single infusion of KTE-X19 (1 × 106 CAR T cells/kg). Long-term post hoc subgroup assessments of ZUMA-3 were conducted. Outcomes from matched patients between historical clinical trials and ZUMA-3 patients were assessed in the retrospective historical control study SCHOLAR-3. RESULTS: After 26.8-months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients (N = 55) in phase 2 was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients (N = 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 (N = 49) and matched historical controls (N = 40) was 25.4 and 5.5 months, respectively. CONCLUSIONS: These data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult R/R B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population. TRIAL REGISTRATION: NCT02614066.

Cost-Effectiveness of KTE-X19 for Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in the United States.

INTRODUCTION: Despite currently available treatments for adults with relapsed/refractory acute lymphoblastic leukemia (R/R ALL), survival outcomes remain poor, highlighting the need for new therapeutic strategies. This study estimates the cost-effectiveness of KTE-X19 to treat adults with R/R ALL from a US payer perspective. METHODS: The model had two components: a decision-tree, where pre-infusion costs for patients who ultimately did not receive KTE-X19 are accounted for, followed by a partitioned survival analysis, where all KTE-X19 infused patients would enter the three-state (pre-progression, progressed disease, death) model. Comparators included current standard of care treatments, i.e., blinatumomab (BLIN), inotuzumab ozogamicin (INO), and salvage chemotherapy (CHEMO). Both standard parametric and mixture cure models were used to model survival. Efficacy, safety, healthcare resource utilization, and health state utility inputs were derived from the ZUMA-3 trial (NCT02614066) and literature. Cost inputs were derived from literature or publicly available sources. Outcomes and costs were discounted 3% annually. Results of KTE-X19 versus comparators are reported as total and incremental life-years (LYs), quality-adjusted life-years (QALYs), costs, and resulting incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses (PSA) and key scenario analyses were also performed. RESULTS: In the base case, incremental QALYs for KTE-X19 were 2.44, 3.26, and 4.61 versus BLIN, INO, and CHEMO, respectively. Incremental costs were $50,913, $251,532, and $432,027, respectively, resulting in ICERs of $20,843/QALY (versus BLIN), $77,271/QALY (versus INO), and $93,768/QALY (versus CHEMO). Deterministic sensitivity analysis results were most sensitive to subsequent allogeneic stem cell transplant rates and post-progression utilities. PSA found that KTE-X19 is 78.4%, 74.0%, and 75.4% likely to be cost-effective versus BLIN, INO, and CHEMO, respectively. Across most scenarios, at a willingness-to-pay (WTP) threshold of $150,000/QALY, KTE-X19 was cost-effective versus all treatments. CONCLUSIONS: Compared to current options for adults with R/R ALL, KTE-X19 is cost-effective, driven primarily by improved survival.

Several treatments for adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) have been approved in the past decade in the US, including blinatumomab (BLIN) and inotuzumab ozogamicin (INO). However, despite the high costs associated with these treatments, survival for patients remains poor. KTE-X19, an autologous anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy, approved by the Food and Drug Administration in October 2021, has potential to improve survival, but its economic value has not yet been determined. This model comprehensively evaluated the long-term clinical and economic value of KTE-X19 versus current treatments, including BLIN, INO, and salvage chemotherapy (CHEMO). Inputs were derived from key clinical trials, the literature, and other publicly available sources. The model used the perspective of a US third party payer over a patient lifetime. Compared to BLIN, INO and CHEMO, KTE-X19 resulted in improved quality of life as measured with incremental quality-adjusted life years (QALYs) of 2.44 (vs BLIN), 3.26 (vs INO), and 4.61 (vs CHEMO). Treatment with KTE-X19 had incremental costs of $50,913 (vs BLIN), $251,532 (vs INO), and $432,027 (vs CHEMO). KTE-X19 was found to provide good value for money based on incremental cost-effectiveness ratios of $20,843/QALY (vs BLIN), $77,271/QALY (vs INO), and $93,768/QALY (vs CHEMO). These values are well below the commonly accepted thresholds to determine economic value. Results were also found to be robust across sensitivity and scenario analyses.

Change in Patients' Perceived Cognition Following Chimeric Antigen Receptor T-Cell Therapy for Lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy can lead to durable responses in patients with relapsed/refractory hematologic malignancies. Immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS) are common and may place patients at risk for longer-term cognitive impairment. This study examined changes in cognition in the first year after CD19-directed CAR T-cell therapy for lymphoma, as well as CAR T-cell therapy-specific risk-factors (e.g., ICANS, CRS) and nonspecific risk factors (e.g., baseline quality of life, frailty) for worsening cognition. Patients' perceived cognition was assessed at baseline and at days 90 and 360. Clinical variables were abstracted from medical records. Piecewise mixed models were used to examine acute change (i.e., within 90 days) and longer-term change (i.e., from 90 days to 360 days) in cognition, as well as to explore risk factors for worsening cognition. Among 118 participants (mean age 61, 59% male), mean levels of perceived cognition did not change from baseline to day 90 (P> .05) but worsened from day 90 to day 360 in global cognition and in the domains of memory, language, organization, and divided attention (P< .05). Although statistically significant, changes were small (d values 0.15-0.28). Greater baseline fatigue, anxiety, and depression were associated with worse global cognition at day 90 (P< .01). Patients with more severe ICANS post-CART reported worse global cognition at day 360 (P< .05), although there were no differences in perceived cognition by severity of CRS (P> .05). Other putative risk factors were not associated with acute or longer-term changes in perceived cognition (P> .05). CAR T-cell therapy recipients reported delayed deterioration in several cognitive domains, although changes were small. These findings may be useful when educating future patients on what to expect when receiving CAR T-cell therapy.

Change in Neurocognitive Performance Among Patients with Non-Hodgkin Lymphoma in the First Year after Chimeric Antigen Receptor T Cell Therapy.

The success of chimeric antigen receptor (CAR) T cell therapy in treating patients with relapsed/refractory hematologic malignancies is leading to a growing number of survivors treated with this regimen. To our knowledge, no previous studies have examined neurocognitive performance in adult CAR T cell therapy recipients, despite high rates of neurotoxicity and cytokine release syndrome (CRS) in the acute treatment period. This study examined changes in neurocognitive performance in the first year after CAR T cell therapy for non-Hodgkin lymphoma (NHL). Putative risk factors for worsening neurocognitive performance (eg, neurotoxicity, CRS) were explored as well. Neurocognition was assessed before initiation of CAR T cell therapy and at 30, 90, and 360 days post-treatment. Clinical variables were abstracted from medical records. Mixed models were used to examine change in total neurocognitive performance (TNP) and cognitive domains (ie, attention, executive function, verbal ability, immediate and delayed memory, and visuospatial abilities). Among 117 participants (mean age, 61 years; 62% male), TNP and executive function declined slightly on average from baseline to day 90 and then improved from day 90 to day 360 (P < .04). Small but significant linear declines in visuospatial ability on average were also observed over time (P = .03). Patients who had 4 or more lines of previous therapy and those with worse neurotoxicity (but not CRS) demonstrated worse TNP. CAR T cell therapy recipients reported transient or persistent deterioration in several cognitive domains, although changes were slight. These findings may be useful when educating future patients on what to expect when receiving CAR T cell therapy.

Assessment of Clonotypic Rearrangements and Minimal Residual Disease in Lymphoid Malignancies.

CONTEXT.­: Measurable (minimal) residual disease (MRD) is an independent prognostic factor for survival outcomes in patients with lymphoid and plasma cell malignancies and has been incorporated into consensus criteria regarding treatment response, strategy, and clinical trial endpoints. clonoSEQ (a next-generation sequencing [NGS]-MRD assay) uses multiplex polymerase chain reaction and NGS to identify clonotypic rearrangements at the immunoglobulin (Ig) H, IgK, IgL, T-cell receptor (TCR)-ß, and TCR-γ loci, as well as translocated B-cell lymphoma 1/IgH and 2/IgH sequences for MRD assessment. Additionally, it can be used to confirm diagnoses of cutaneous T-cell lymphoma (CTCL). OBJECTIVE.­: To review the technical aspects of our experience using the clonoSEQ Assay in routine clinical practice. DESIGN.­: In this single-center experience, 390 patients with lymphoid and plasma cell malignancies were assessed with the NGS-MRD Assay at a central laboratory. RESULTS.­: Median time from arrival of the shipment to initiation of the assay (defined as captured in Adaptive's secure tracking system) was 2.1 hours. Overall, 317 patients had 1 or more samples submitted for sequence identification. Of these, 290 (91.5%) had trackable sequences identified. The median calibration rate of samples by malignancy (where n ≥ 10 samples, excluding CTCL samples) was 88.1%, across a variety of fresh and archived sample sources (177 of 201 samples). TCR-ß and/or TCR-γ clonotypes were identified in 40 of 95 samples (42.1%) from 66 patients with suspected CTCL. CONCLUSIONS.­: This NGS-MRD Assay is a valuable and sensitive tool for monitoring MRD in patients with plasma cell and lymphoid malignancies and assisting in the diagnosis of CTCL.

Response and resistance to CDK12 inhibition in aggressive B-cell lymphomas.

Despite significant progress in the treatment of patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), the prognosis of patients with relapsed disease remains poor due to the emergence of drug resistance and subsequent disease progression. Identification of novel targets and therapeutic strategies for these diseases represents an urgent need. Here, we report that both MCL and DLBCL are exquisitely sensitive to transcription-targeting drugs, in particular THZ531, a covalent inhibitor of cyclin-dependent kinase 12 (CDK12). By implementing pharmacogenomics and a cell-based drug screen, we found that THZ531 leads to inhibition of oncogenic transcriptional programs, especially the DNA damage response pathway, MYC target genes and the mTOR-4EBP1-MCL-1 axis, contributing to dramatic lymphoma suppression in vitro. We also identified de novo and established acquired THZ531-resistant lymphoma cells conferred by over-activation of the MEK-ERK and PI3K-AKT-mTOR pathways and upregulation of multidrug resistance-1 (MDR1) protein. Of note, EZH2 inhibitors reversed resistance to THZ531 by competitive inhibition of MDR1 and, in combination with THZ531, synergistically inhibited MCL and DLBCL growth in vitro. Our study indicates that CDK12 inhibitors, alone or together with EZH2 inhibitors, offer promise as novel effective approaches for difficult-to-treat DLBCL and MCL.

Patterns and Predictors of Failure in Recurrent or Refractory Large B-Cell Lymphomas After Chimeric Antigen Receptor T-Cell Therapy.

PURPOSE: Chimeric antigen receptor T-cell (CAR T) therapy is capable of eliciting durable responses in patients with relapsed/refractory (R/R) lymphomas. However, most treated patients relapse. Patterns of failure after CAR T have not been previously characterized, and may provide insights into the mechanisms of resistance guiding future treatment strategies. METHODS AND MATERIALS: This is a retrospective analysis of patients with R/R large B-cell lymphoma who were treated with anti-CD19 CAR T at a National Cancer Institute-designated Comprehensive Cancer Center between 2015 and 2019. Pre- and posttreatment positron emission/computed tomography scans were analyzed to assess the progression of existing (local failures) versus new, nonoverlapping lesions (de novo failures) and identify lesions at a high risk for progression. RESULTS: A total of 469 pretreatment lesions in 63 patients were identified. At a median follow-up of 12.6 months, 36 patients (57%) recurred. Most (n = 31; 86%) had a component of local failure, and 13 patients (36%) exhibited strictly local failures. Even when progressing, 84% of recurrent patients continued to have a subset of pretreatment lesions maintain positron emission/computed tomography resolution. Lesions at a high risk for local failure included those with a diameter ≥5 cm (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.55-3.55; P < .001), maximum standardized uptake value ≥10 (OR, 2.08; 95% CI, 1.38-3.12; P < .001), or those that were extranodal (OR, 1.49; 95% CI, 1.10-2.04; P = .01). In the 69 patients eligible for survival analysis, those with any lesion ≥5 cm (n = 46; 67%) experienced inferior progression-free survival (hazard ratio, 2.41; 95% CI, 1.15-5.04; P = .02) and overall survival (hazard ratio, 3.36; 95% CI, 1.17-9.96; P = .02). CONCLUSIONS: Most patients who recur after CAR T experience a component of local progression. Furthermore, lesions with high-risk features, particularly large size, were associated with inferior treatment efficacy and patient survival. Taken together, these observations suggest that lesion-specific resistance may contribute to CAR T treatment failure. Locally directed therapies to high-risk lesions, such as radiation therapy, may be a viable strategy to prevent CAR T failures in select patients.

KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study.

BACKGROUND: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies. METHODS: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 106 CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066. FINDINGS: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p<0·0001) had complete remission or complete remission with incomplete haematological recovery, with 31 (56%) patients reaching complete remission. Median duration of remission was 12·8 months (95% CI 8·7-not estimable), median relapse-free survival was 11·6 months (2·7-15·5), and median overall survival was 18·2 months (15·9-not estimable). Among responders, the median overall survival was not reached, and 38 (97%) patients had MRD negativity. Ten (18%) patients received allo-SCT consolidation after KTE-X19 infusion. The most common adverse events of grade 3 or higher were anaemia (27 [49%] patients) and pyrexia (20 [36%] patients). 14 (25%) patients had infections of grade 3 or higher. Two grade 5 KTE-X19-related events occurred (brain herniation and septic shock). Cytokine release syndrome of grade 3 or higher occurred in 13 (24%) patients and neurological events of grade 3 or higher occurred in 14 (25%) patients. INTERPRETATION: KTE-X19 showed a high rate of complete remission or complete remission with incomplete haematological recovery in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia, with the median overall survival not reached in responding patients, and a manageable safety profile. These findings indicate that KTE-X19 has the potential to confer long-term clinical benefit to these patients. FUNDING: Kite, a Gilead Company.