Molecular determinants of clinical outcomes in a real-world diffuse large B-cell lymphoma population.

Molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) underlies the variable outcomes achieved with immunochemotherapy. However, outcomes of gene expression profiling (GEP)-defined molecular subgroups in a real-world DLBCL population remain unknown. Here we examined the prevalence and outcomes of molecular subgroups in an unselected population of 1149 patients with de novo DLBCL in British Columbia, Canada. Evaluable biopsies were profiled by fluorescence in situ hybridization (FISH), immunohistochemistry, and digital GEP to assign cell-of-origin and the so-called "double-hit signature" (DHITsig)-a signature originally described as being characteristic for high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2). DHITsig was expressed in 21% of 431 germinal center B-cell-like (GCB)-DLBCL and all 55 Burkitt lymphomas examined. Reflecting this latter finding, DHITsig has been renamed the "dark zone signature" (DZsig). DZsigpos-DLBCL, non-DZsigpos GCB-DLBCL and activated B-cell-like (ABC)-DLBCL were associated with a 2 year overall survival of 57%, 89%, and 71%, respectively. 62% of DZsigpos tumors were negative for HGBCL-DH-BCL2 by FISH, but were associated with outcomes similar to HGBCL-DH-BCL2. A small group of HGBCL-DH-BCL2 that lacked DZsig expression had different molecular features compared with DZsig-expressing HGBCL-DH-BCL2 and were associated with favorable outcomes comparable to DLBCL, not otherwise specified. DZsigpos and ABC-DLBCL had a shorter diagnosis-to-treatment interval (DTI) than GCB-DLBCL, with this metric being associated with outcome. In conclusion, DZsig expression extends beyond HGBCL-DH-BCL2 and captures a poor-prognosis DLBCL subgroup with short DTI, including patients unidentifiable by routine FISH testing, that should be considered for treatment intensification or novel therapies in prospective trials.

Idecabtagene vicleucel chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma with renal impairment.

We evaluated patients with relapsed multiple myeloma with renal impairment (RI) treated with standard of care idecabtagene vicleucel (ide-cel), as outcomes with chimeric antigen receptor (CAR) T-cell therapy are unknown in this population. RI was defined as creatinine clearance (CrCl) <50 mL/min. CrCl of <30 mL/min or dialysis dependence were defined as severe RI. The study cohort included 214 patients, 28 (13%) patients with RI, including 11 patients severe RI (dialysis, N=1). Patients with RI were older, more likely to be female and had higher likelihood of having Revised International Staging System stage 3 disease. Rates and severity of cytokine release syndrome (89% vs. 84%, grade ≥3: 7% vs. 2%) and immune effector cell-associated neurotoxicity syndrome (23% vs. 20%) were similar in patients with and without RI, respectively. Patients with RI had higher incidence of short-term grade ≥3 cytopenias, although cytopenias were similar by 3 months following CAR T-cell therapy. Renal function did not worsen after CAR T-cell therapy in patients with RI. Response rates (93% vs. 82%) and survival outcomes (median progression-free survival: 9 vs. 8 months; P=0.26) were comparable in patients with and without RI, respectively. Treatment with ide-cel is feasible in patients with RI, with a comparable safety and efficacy profile as patients without RI, with notable exception of higher short-term high-grade cytopenias.

Long-term results of PET-guided radiation in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP.

Consolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) remains controversial, with routine practice continuing to include RT in patients with initial bulky disease or residual masses. Positron emission tomography (PET)-computed tomography is a sensitive modality for detecting the presence of residual disease at the end of treatment (EOT). A PET-guided approach to selectively administering RT has been the policy in British Columbia since 2005. Patients with advanced-stage DLBCL diagnosed from 1 January 2005 to 1 March 2017 and treated with at least 6 cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab), who underwent EOT PET, were included in this analysis. Those with complete metabolic response (PET-negative [PET-NEG]) were observed; those with PET-positive (PET-POS) scans were offered consolidative RT, when feasible. Of the patient records reviewed, 723 were identified, with median follow-up of 4.3 years: 517 (72%) were PET-NEG; 206 (28%) were PET-POS. Time to progression (TTP) and overall survival (OS) at 3 years were 83% vs 56% and 87% vs 64%, in patients with PET-NEG and PET-POS scans, respectively. PET-POS patients with nonprogressing disease treated with consolidative RT (109 and 206; 53%) had outcomes approaching those of PET-NEG patients, with 3-year estimates of 76% and 80% for TTP and OS. PET-NEG patients who had bulky disease (≥10 cm) at diagnosis had outcomes indistinguishable from those without bulk, despite the omission of RT. These data suggest that patients with advanced-stage DLBCL who are PET-NEG at EOT and receive no RT have excellent outcomes. 18F-fluorodeoxyglucose-PET can reliably guide selective administration of consolidative RT, even in patients with initially bulky disease.

The impact of MYC and BCL2 structural variants in tumors of DLBCL morphology and mechanisms of false-negative MYC IHC.

When the World Health Organization defined high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) as a clinical category, rearrangements were the only structural variant (SV) incorporated. An "atypical double-hit" category has been proposed, encompassing tumors with concurrent MYC and BCL2 SVs other than cooccurring translocations (ie, copy number variations [CNVs]). Although the identification of a gene expression signature (DHITsig) shared among tumors harboring MYC and BCL2 rearrangements (HGBL-DH/TH-BCL2) has confirmed a common underlying biology, the biological implication of MYC and BCL2 CNVs requires further elucidation. We performed a comprehensive analysis of MYC and BCL2 SVs, as determined by fluorescent in situ hybridization (FISH), in a cohort of 802 de novo tumors with diffuse large B-cell lymphoma morphology. Although BCL2 CNVs were associated with increased expression, MYC CNVs were not. Furthermore, MYC and BCL2 CNVs, in the context of atypical double-hit, did not confer a similar gene expression profile as HGBL-DH/TH-BCL2. Finally, although MYC immunohistochemistry (IHC) has been proposed as a screening tool for FISH testing, 2 mechanisms were observed that uncoupled MYC rearrangement from IHC positivity: (1) low MYC messenger RNA expression; and (2) false-negative IHC staining mediated by a single-nucleotide polymorphism resulting in an asparagine-to-serine substitution at the 11th amino acid residue of MYC (MYC-N11S). Taken together, these results support the current exclusion of MYC and BCL2 CNVs from HGBL-DH/TH and highlight the ability of a molecular-based classification system to identify tumors with shared biology that FISH and IHC fail to fully capture.

Factors associated with refractoriness or early progression after idecabtagene vicleucel in patients with relapsed/refractory multiple myeloma: U.S. Myeloma Immunotherapy Consortium real world experience.

While response rates and survival outcomes have been very promising for idecabtagene vicleucel (ide-cel), a proportion of patients do not respond or relapse early after this B-cell maturation antigen (BCMA) targeted CAR T-cell therapy. Understanding the characteristics of these patients is important for patient selection and development of novel strategies to improve outcomes. We evaluated factors associated with early progression (progression or death due to myeloma ≤ 3 months after CAR T infusion) in patients treated with standard of care ide-cel at 11 US academic centers. Among 211 patients that received ide-cel, 43 patients had a progressive event ≤ 3 months of infusion. Patients with a history of extramedullary disease, prior BCMA targeted therapy, elevated ferritin at lymphodepletion, use of bridging therapy, Hispanic ethnicity, plasma cell leukemia and t(4;14) were more likely to progress ≤ 3 months of infusion (p < 0.05). Of these risk factors for early progression identified in univariate analyses, history of extramedullary disease, prior BCMA targeted therapy, elevated ferritin at lymphodepletion, plasma cell leukemia, and t(4;14) were associated with worse progression-free survival (PFS) in multivariable analysis. Presence of three or more of these factors had a significant negative impact on PFS (p < 0.001; median PFS for ≥ 3 factors, 3.2 months vs. 0 factors, 14.1 months). This study helps identify patients at high risk of early progression after CAR T who may benefit from specific interventions pre and post CAR T to improve outcomes.

Outcomes of Hodgkin variant Richter transformation in chronic lymphocytic leukaemia and small lymphocytic lymphoma in British Columbia.

Hodgkin variant Richter transformation (HvRT) is a rare and challenging complication of chronic lymphocytic leukaemia (CLL) for which information on prognostic factors and treatment approaches remain limited. We analysed characteristics and survival outcomes of a population-based cohort of 32 patients with HvRT identified in British Columbia over a 40-year period. Median interval from CLL diagnosis to HvRT was 5.6 years (range, 0-33.6), with five cases diagnosed concurrently. Most patients (80%) had treatment for CLL prior to HvRT. Median age at HvRT was 71 years (range, 51-86) and the majority of patients had high-risk disease, including stage 3-4 in 87% and International Prognostic Score (IPS) ≥ 4 in 65%. Two-year progression-free (PFS) and overall survival (OS) from HvRT were 47% (95% CI: 29%-64%) and 57% (95% CI: 38%-72%), respectively. OS from HvRT was significantly worse in those with anaemia (p = 0.02), elevated lactate dehydrogenase (p = 0.04), high IPS (p = 0.04), and worse performance status (p = 0.001). For those treated with curative-intent ABVD/ABVD-like therapy, 2-year PFS and OS were 70% (95% CI: 45%-85%) and 74% (95% CI: 49%-89%), respectively. In this real-world population-based cohort, HvRT was associated with poor clinical outcomes overall; however, those able to tolerate curative-intent therapy had similar survival to older patients with de novo HL.

Clinicopathological characteristics and long-term outcomes of plasmablastic lymphoma in British Columbia.

Plasmablastic lymphoma (PBL) is an aggressive and rare subtype of non-Hodgkin lymphoma with no standard-of-care therapy. We reviewed all patients diagnosed with histologically confirmed PBL in British Columbia, Canada between 1997 and 2019. Overall, 42 patients were identified, including 15 (36%) positive for HIV and nine (21%) on chronic immunosuppression. Curative-intent treatment consisting primarily of cyclophosphamide, doxorubicin, vincristine and prednisone was administered to 31 patients, of which 74% achieved response, however 61% relapsed after a median of 7.5 months. At a median follow-up of eight years for the whole cohort, five-year progression-free survival (PFS) and overall survival (OS) were 18% [95% confidence interval (CI): 6%, 30%] and 22% (95% CI: 8%, 36%) with median eight and 15 months respectively. There were no differences in relapse rate (p = 0.962), PFS (p = 0.228) or OS (p = 0.340) according to immune status. For those treated with curative intent, five-year PFS and OS were 24% (95% CI: 8%, 40%) and 31% (95% CI: 13%, 49%) with median 18 and 27 months respectively. In this population-based cohort of PBL patients spanning 20 years, survival outcomes were poor. Ultimately, further research is needed to develop more effective treatment strategies and to improve survival for patients.

Outcome of primary mediastinal large B-cell lymphoma using R-CHOP: impact of a PET-adapted approach.

Cure rates for primary mediastinal large B-cell lymphoma (PMBCL) have improved with the integration of rituximab. However, the type of primary therapy and role of radiotherapy (RT) remains ill-defined. Herein, we evaluated the outcome of PMBCL primarily treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and the impact of an end-of-treatment (EOT) 18F-fluorodeoxyglucose positron emission tomography (PET) scan to guide consolidative RT. Patients ≥18 years of age with PMBCL treated with curative intent rituximab-chemotherapy were identified. Prior to 2005, patients were recommended to receive R-CHOP + RT (RT era). Beginning in 2005, EOT PET was used to guide RT and only those with a PET-positive scan received RT (PET era). In total, 159 patients were identified, 94% were treated with R-CHOP and 44% received RT (78% in RT era, 28% in PET era). The 5-year time to progression (TTP) and overall survival (OS) for the entire cohort were 80% and 89%, respectively, similar across treatment eras. Overall, 10% had refractory disease. In total, 113 patients had an EOT PET scan: 63% negative and 37% positive with a 5-year TTP of 90% vs 71% and 5-year OS of 97% vs 88%, respectively. For those with Deauville (D)-scored PET scans (n = 103), the 5-year TTP for PET-negative cases by Deauville criteria (D1-D3, DX) was 91%, with inferior outcomes for D5 vs D4 (5-year TTP 33% vs 87%, P = .0002). Outcomes for PMBCL treated with RCHOP are favorable and use of a PET-adapted approach reduces RT in the majority of patients. A small proportion have refractory disease and may benefit from an alternate treatment.

Early progression after bendamustine-rituximab is associated with high risk of transformation in advanced stage follicular lymphoma.

Despite widespread use of bendamustine and rituximab (BR) as frontline therapy for advanced-stage follicular lymphoma (FL), little is known about the risk of early progression or incidence of histological transformation. We performed a retrospective analysis of a population-based cohort of 296 patients with advanced-stage FL treated with frontline BR and maintenance rituximab. As previously demonstrated, outcomes with this regimen are excellent, with 2-year event-free survival estimated at 85% (95% confidence interval [95% CI], 80-89) and 2-year overall survival 92% (95% CI, 88-95). Progression of disease within 24 months (POD24) occurred in 13% of patients and was associated with a significantly inferior outcome with 2-year overall survival of 38% (95% CI, 20-55). The only significant risk factor for POD24 at baseline was elevated lactate dehydrogenase (P < .001). Importantly, the majority of POD24 patients (76%) had transformed disease. Compared with a historical cohort treated with rituximab, cyclophosphamide, vincristine, and prednisone, event-free survival has improved and the risk of POD24 has decreased, but a higher proportion of patients with POD24 harbor transformation. The overall incidence of transformation appears unchanged. The presence of occult or early transformation is the main driver of POD24 in FL patients treated with frontline BR. Identification of biomarkers and improved management strategies for transformation will be crucial to improving outcomes.

COVID-19 and myeloma: what are the implications for now and in the future?

The pandemic has affected every aspect of myeloma care. Immediate focus is minimising risk of contracting coronavirus disease 2019 (COVID-19) and the sequelae of infection. However, what does the future hold for our patients? What lessons will be taken forward to tackle myeloma in the fiscally constrained future? If we embrace the challenges that will emerge in the post-pandemic environment, the treatment delivered to patients could be more cost-effective and better tailored than before. Healthcare delivery post-COVID-19 will not return to how it was, and now is the time to invest in novel strategies to deliver the best possible outcomes for patients.

A tale of two antibodies: obinutuzumab versus rituximab.

While rituximab has dramatically improved outcomes for patients with CD20+ malignancies for two decades, responses are not universal and resistance can develop. Obinutuzumab was developed to potentiate activity and overcome resistance. Pre-clinical data suggests obinutuzumab is superior to rituximab at effecting B cell depletion; however recent phase III clinical trial results have been mixed. The decision of which antibody to employ will probably be further complicated by the approval of a subcutaneous preparation of rituximab and several anti-CD20 biosimilars. Clinicians are now challenged with deciding whether to switch to obinutuzumab in approved settings, accepting the potential for increased toxicity and probable increased cost. The benefit conferred by obinutuzumab over rituximab may be context-specific and vary based on histological subtype and immune integrity. This comprehensive review will explore the preclinical differences, investigate the proposed pathogenesis of rituximab resistance, compare the employed dosing strategies and interrogate available clinical results to help inform practice.

Anti-CD20 Directed Therapy of B Cell Lymphomas: Are New Agents Really Better?

PURPOSE OF REVIEW: Since its initial approval in 1997, rituximab has revolutionized the treatment of CD20-positive lymphoproliferative disorders. Now, over two decades later, second-generation molecules are emerging that may have key biological advantages compared to rituximab, as well as biosimilars that may be more cost-effective. Clinicians, health policy makers, and payers will now need to critically appraise the available evidence for these competitors and decide which anti-CD20 to use. RECENT FINDINGS: Evidence has emerged directly comparing rituximab IV to a subcutaneous preparation, and head-to-head comparisons of rituximab versus next-generation anti-CD20 monoclonal antibodies have also been published. Trials comparing rituximab with newly developed biosimilars have also allowed for registration of these agents. In this review, we will present an overview of anti-CD20 monoclonal antibody development, discuss the mechanistic and clinical evidence for rituximab, as well as the novel compounds, and provide commentary on the possible advantages and limitations of these agents.

The role of inflammation in leukaemia.

Acute leukaemias are a group of malignancies characterised by the invasion of the bone marrow by immature haematopoietic precursors and differentiation arrest at various maturation steps. Multiplicity of intrinsic and extrinsic factors influences the transformation and progression of leukaemia. The intrinsic factors encompass genetic alterations of cellular pathways leading to the activation of, among others, inflammatory pathways (such as nuclear factor kappa B). The extrinsic components include, among others, the inflammatory pathways activated by the bone marrow microenvironment and include chemokines, cytokines and adhesion molecules. In this chapter, we review the role of inflammatory processes in the transformation, survival and proliferation of leukaemias, particularly the role of nuclear factor kappa B and its downstream signalling in leukaemias and the novel therapeutic strategies that exploit potentially unique properties of inflammatory signalling that offer interesting options for future therapeutic interventions.

Utilizing 3D Models to Unravel the Dynamics of Myeloma Plasma Cells' Escape from the Bone Marrow Microenvironment.

Recent therapeutic advancements have markedly increased the survival rates of individuals with multiple myeloma (MM), doubling survival compared to pre-2000 estimates. This progress, driven by highly effective novel agents, suggests a growing population of MM survivors exceeding the 10-year mark post-diagnosis. However, contemporary clinical observations indicate potential trends toward more aggressive relapse phenotypes, characterized by extramedullary disease and dominant proliferative clones, despite these highly effective treatments. To build upon these advances, it is crucial to develop models of MM evolution, particularly focusing on understanding the biological mechanisms behind its development outside the bone marrow. This comprehensive understanding is essential to devising innovative treatment strategies. This review emphasizes the role of 3D models, specifically addressing the bone marrow microenvironment and development of extramedullary sites. It explores the current state-of-the-art in MM modelling, highlighting challenges in replicating the disease's complexity. Recognizing the unique demand for accurate models, the discussion underscores the potential impact of these advanced 3D models on understanding and combating this heterogeneous and still incurable disease.

Frontline therapy with bendamustine rituximab (BR) and rituximab cyclophosphamide vincristine prednisone (RCVP) confers similar long-term outcomes in patients with treatment naïve Waldenström macroglobulinemia in a real-world setting: a population-based analysis.

We report on outcomes of 111 patients with treatment naïve Waldenström macroglobulinemia (TN WM) treated with frontline bendamustine-rituximab (BR) (n = 57) or rituximab-cyclophosphamide-vincristine-prednisone (RCVP) (n = 54). Median follow-up was 60.7 months (range 1.9-231.6). Median progression-free survival (PFS) was 60.5 months (95% CI 47.6-73.4) for BR and 79.0 months (95% CI 31.3-126.8) for RCVP (p = .96). Median overall survival (OS) was not reached for BR and 153.4 months (95% CI 114.5-192.4) for RCVP (p = .37). While overall and major response rates did not differ between treatment groups, BR had numerically higher rate of very good partial response or better response (51% vs. 37%, p = .30) and complete response (26% vs. 13%, p = .13). RCVP confers comparable outcomes to BR in a real-world population of TN WM patients and remains an effective regimen, particularly when tolerance or frailty is an issue, or in resource-limited settings.

Safety and efficacy of anti-BCMA CAR-T cell therapy in older adults with multiple myeloma: A systematic review and meta-analysis.

INTRODUCTION: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy is transforming the care of patients with relapsed/refractory multiple myeloma (MM). Unfortunately, despite being a disease of older adults these patients remain under-represented in most pivotal clinical trials. We performed a systematic review and proportion meta-analysis of prospective clinical trials and observational studies of anti-BCMA CAR-T therapy in patients with MM with the aim to determine the efficacy and safety of this therapy in older adults (≥65 years). MATERIALS AND METHODS: We searched the Pubmed, Scopus, Web of Science (WOS), Ovid, Embase, CENTRAL, and CINAHL databases through September 9, 2022 and abstracts from the American Society of Hematology (ASH) Annual Meeting 2022. Primary outcome measures included overall response rate (ORR), rates of cytokine release syndrome (CRS), and immune cell-effector-associated neurotoxicity syndrome (ICANS). study was registered with PROSPERO (study number: CRD42022334287). RESULTS: After screening 2218 references, 14 studies were included for data extraction, with a total of 558 patients, 26.2% (n = 146) of whom were older adults. The pooled ORR amongst this population was 93%, which was comparable to the ORR of 86% amongst younger patients. In older adults, the rates of CRS (any grade) and grade ≥ 3 were 95% and 21%, respectively. For younger patients, the pooled rate of CRS (any grade) and grade ≥ 3 CRS was 91% and 20%, respectively. The rate of ICANS (any grade) in older adults was 15%, which was higher than that observed in those <65 years. CONCLUSION: Older adults experience comparable outcomes to younger patients with anti-BCMA CAR-T therapy, albeit with numerically higher rates of neurotoxicity.

Simple Score of Albumin and CRP Predicts High-Grade Toxicity in Patients with Multiple Myeloma Receiving CAR-T Therapy.

Administration of chimeric-antigen receptor T-cell (CAR-T) therapy is complex and associated with unique toxicities. Identifying patients at risk for inferior outcomes is important for individualized management. The Glasgow-prognostic score (GPS) is a simple score shown to be highly prognostic of outcomes in the setting of traditional chemotherapy or checkpoint inhibitor administration. We sought to evaluate the value of the GPS to predict outcomes of patients with relapse refractory multiple myeloma (RRMM) receiving anti-BCMA CAR-T therapy. We included all patients treated with commercial CAR-T therapy for RRMM between 5/1/2021 and 2/1/2023 at the Moffitt Cancer Center. The GPS (CRP >1 mg/dL, 1 point; albumin <3.5, 1 point) was calculated for all patients at lymphodepletion (day -6) and patients were grouped as high-risk GPS (score = 2) or low-risk GPS (0 or 1). The primary endpoint was overall survival (OS) at day 100. A total of 139 pts were included, with a median follow-up of 6.7 months (95% CI, 6.2 to 8.9 months). Pts were treated with either idecabtagene vicleucel (83%) or ciltacabtagene autoleucel (17%). In total, 14% were classified with high-risk GPS, with significantly increased risk for grade 3 cytokine release syndrome (P = .003) and ICANS of any grade (P < .001). Patients in the high-risk GPS group had significantly lower day-100 OS (68.4% versus 97.3%, P < .001), OS at 6 months (56% versus 91.8% P = .0019) and PFS at 6 months (38.3% versus 72.3%, P = .03). The association of GPS with day-100 OS remained significant in a multivariable model. In conclusion, the GPS identifies a group of high-risk patients with RRMM receiving CAR-T therapy who experience increased rates of immune-mediated toxicity and are at higher risk for early mortality.

Impact of extramedullary multiple myeloma on outcomes with idecabtagene vicleucel.

Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). However, the outcomes with ide-cel in patients with extramedullary disease (EMD) remain incompletely characterized. We included patients with RRMM treated with ide-cel between May 2021 and April 2023 across 11 US academic institutions. Visceral or soft tissue lesions non-contiguous from bone was classified as EMD. Time-to-event analyses were performed from date of ide-cel infusion. Among 351 patients, 84 (24%) had EMD prior to infusion. The median follow-up from ide-cel infusion was 18.2 months (95% CI: 17-19.3). The day 90 overall response rates (ORR) were 52% vs. 82% for the EMD and non-EMD cohorts, respectively (p < 0.001). The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p < 0.0001) for the non-EMD cohort. In a multivariable analysis, EMD was an independent predictor of inferior PFS [hazard ratio 1.5 (1.1-2.2), p = 0.02]. The median overall survival was 14.8 months [95% CI: 9-Not reached (NR)] vs. 26.9 months (26.3 vs. NR, p = 0.006) for the EMD and non-EMD cohorts, respectively. Extramedullary disease represents an independent predictor of inferior day 90 ORR and PFS among patients treated with ide-cel.