Breyanzi (lisocabtagene maraleucel)

P1/2, N=209, Recruiting, Juno Therapeutics, a Subsidiary of Celgene | Active, not recruiting --> Recruiting | Trial completion date: Jul 2026 --> Nov 2027 | Trial primary completion date: Jul 2026 --> Nov 2027

Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.

P1/2, N=20, Completed, Celgene | Recruiting --> Completed | N=121 --> 20 | Trial completion date: Dec 2024 --> Jan 2024 | Trial primary completion date: Dec 2024 --> Jan 2024

P=N/A, N=50, Recruiting, Bristol-Myers Squibb

P2, N=396, Recruiting, SWOG Cancer Research Network | Trial primary completion date: Dec 2024 --> Dec 2025

P3, N=0, Withdrawn, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company | N=200 --> 0 | Not yet recruiting --> Withdrawn

P2, N=27, Recruiting, Patrick C. Johnson, MD | Not yet recruiting --> Recruiting | Trial completion date: Sep 2029 --> Mar 2029 | Trial primary completion date: Sep 2024 --> Mar 2025

P=N/A, N=144, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Recruiting --> Active, not recruiting | N=240 --> 144 | Trial primary completion date: Jun 2028 --> Feb 2024

P3, N=300, Not yet recruiting, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

P1, N=57, Recruiting, NeoImmuneTech | Phase classification: P1b --> P1

P1, N=24, Recruiting, Fred Hutchinson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jan 2024 --> Dec 2024

P3, N=200, Not yet recruiting, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

P2, N=113, Completed, Celgene | Active, not recruiting --> Completed

We analyzed Medicare FFS claims data, focusing on the utilization patterns across three CAR-T products—Breyanzi, Kymriah, and Yescarta – which are indicated for the treatment of LBCL. CAR-T therapy for the treatment of LBCL has become more common within the Medicare population, primarily in the inpatient setting. This study helps understand providers' cost and associated patient care around CAR-T administration. The data shows that the average cost received by hospitals encompasses the expenses related to both the CAR-T drug and the medical services delivered to patients.

Liso-cel demonstrated high CR rate and deep, durable responses with low incidence of grade ≥3 CRS, NE, and infections in patients with heavily pretreated relapsed/refractory MCL, including those with high-risk, aggressive disease.

P2, N=104, Completed, Juno Therapeutics, a Subsidiary of Celgene | Active, not recruiting --> Completed | N=41 --> 104

In subgroup analyses including pts with R/R MCL and high-risk features, liso-cel showed clinically meaningful efficacy across subgroups with durable responses. Efficacy and safety were generally consistent with the overall population. While some subgroups had small numbers, results suggest a favorable benefit/risk profile for liso-cel in pts with R/R MCL and high-risk features, a population for whom effective treatment options are rarely available.

The most common treatments for CRS were tocilizumab (20%) and corticosteroids/tocilizumab (12%). This is the first large, multicenter, real-world study of patients with R/R LBCL who received commercial liso-cel in the US. Baseline characteristics of these patients showed a broader patient population than those eligible for the liso-cel registrational study. One-time infusion of liso-cel showed deep and durable responses in patients with R/R LBCL across a broad age range, including those with high-risk disease features.

"Adaptive Biotechnologies Corporation (Nasdaq: ADPT), a commercial stage biotechnology company that aims to translate the genetics of the adaptive immune system into clinical products to diagnose and treat disease, together with its collaborators will present data from more than 30 abstracts demonstrating the actionability of Adaptive’s next-generation sequencing (NGS)-based clonoSEQ^® test in assessing minimal residual disease (MRD) in blood cancer patients at the 65th Annual Meeting of the American Society of Hematology (ASH), December 9-12 in San Diego, California."

Although there were very few grade 3 events (n = 4) to assess, patients with grade 3 versus grade ≤ 2 CRS and/or NEs also had higher rates of utilization for some medications (eg, tocilizumab: 3/4 [75%] vs 28/75 [37%]; corticosteroids: 4/4 [100%] vs 19/75 [25%]). While most patients with R/R FL treated with liso-cel in the TRANSCEND FL study experienced treatment-emergent CRS and/or NEs, they were almost all of low severity (grade ≤ 2) and experienced as single events. Management costs for CRS/NEs, primarily related to facility HCRU, increased with greater AE severity and concurrency. The additional median cost for a patient with grade 3 versus grade ≤ 2 CRS or NEs was $22,586, representing an 88% increase in cost; however, this finding must be considered in the context of the small number of overall grade 3 events (n = 4) and ICU admissions (n = 1).

This economic analysis revealed lower overall per-patient weighted average costs associated with liso-cel compared with axi-cel and tisa-cel, primarily due to lower CRS and NE rates versus axi-cel and lower NE rates versus tisa-cel. In comparison with axi-cel and tisa-cel, liso-cel demonstrated robust economic and clinical value, with lower rates of CRS and/or NEs associated with substantial cost savings per AE event.

Included HCRU categories were: facility (standard inpatient admission, ICU stay), diagnostics (laboratory, imaging), medications (tocilizumab, corticosteroids, vasopressors), and procedures (dialysis, intubation). While most patients treated with liso-cel at DL2 in TRANSCEND CLL 004 experienced CRS and/or NEs, they were primarily of low severity. HCRU and associated costs for management of CRS and/or NEs after liso-cel infusion increased with AE severity. Although everyone in this study required hospitalization, ICU admissions were rare and only observed among patients who experienced both CRS and NEs.

Comparators were axicabtagene ciloleucel (Axi-cel), lisocabtagene maraleucel (Liso-cel), tisagenlecleucel (Tisa-cel), loncastuximab tesirine (Lonca), polatuzumab vedotin + bendamustine + rituximab (Pola-BR), rituximab + gemcitabine + oxaliplatin (R-GemOx), tafasitamab + lenalidomide, and epcoritamab. Over 3 years, the estimated cumulative per-patient cost of glofitamab is projected to be the lowest when compared with per-patient costs of other available T-cell engaging therapies, resulting in cost savings after its formulary adoption for the treatment of R/R DLBCL after ≥2 lines of therapy.

Three pts (20%) required tocilizumab (range, 0-1 doses), 4 (50%) required dexamethasone (median total dose, 5 mg; range, 0-200 mg), and 1 (12%) required high-dose methylprednisolone. While our primary endpoint was not reached at our planned interim analysis, we observed lower CRS rates and faster resolution of CRS in comparison to a real-world cohort of pts receiving liso-cel without prophylactic anakinra. To further enhance the preventative effects of anakinra, we plan to change the administration route from SC to intravenous, and to allow anakinra dose uptitration for the last 10 participants in the study.

Pts received lymphodepletion (LD) with cyclophosphamide 300 mg/m2/d and fludarabine 30 mg/m2/d for 3 days...Prior CD19 CAR T-cell product type was lisocabtagene maraleucel, n=4 (50%); axicabtagene ciloleucel, n= 3 (37%); or tisagenlecleucel, n=1...CONCLUSIONIn LBCL pts with disease relapse or progression after a first CD19 CAR T-cell therapy, we observed low response rates and lack of durable responses after treatment with the fully human scFv-bearing product JCAR021, prompting early study termination. Lower CAR T-cell expansion during manufacturing in CAR-exposed pts suggest pre-existing T-cell dysfunction as a potential mechanism of failure.

Eligible treatments included CAR T cell therapies (axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel), T cell engagers (mosunetuzumab, glofitamab, epcoritamab, odronextamab), phosphatidylinositol 3-kinase (PI3K) inhibitors (copanlisib, duvelisib, idelalisib), HSCT, yttrium-90 (90Y) ibritumomab tiuxetan, tazemetostat, and conventional therapies (immunochemotherapies, single- or multiagent chemo- or immunotherapies, and alkylating agents). This SLR demonstrated an evolving FL treatment landscape, with new agents such as CAR T cell therapies and T cell engagers exhibiting potential for improving effectiveness of treatment for patients in 3L+, 4L+, and 2L+ POD24 populations.

P2, N=213, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting

Over the past 3 years, three phase 2 studies has been conducted to evaluate the efficacy and safety of CAR T-cells in patients with R/R FL, specifically axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel).1-5 Although it’s not possible to make a direct comparison among these three studies because of different design and population, all of them demonstrated high efficacy with an overall response rates (ORR) ranging from 86-94%, even in patients with high risk disease. The safety profile seems to be slightly better with BiTEs than with CAR T-cells, especially compared to axi-cel. The debate about how to sequence CARs versus BiTEs is still being defined, and numerous questions are open about the right setting in which to prefer one therapy over the other.

"Foresight Diagnostics...announced today that six studies utilizing their patented PhasED-Seq technology will be presented at the 65th American Society of Hematology Annual Meeting and Exposition (ASH 2023) taking place December 9-12, 2023, in San Diego, California. Four of these studies have been accepted as oral presentations....Building upon these findings, Foresight and its partners will present new data at ASH 2023 that further supports the utility of Foresight's ultrasensitive PhasED-Seq MRD platform for accurate treatment response assessment."

Some patients received corticosteroids (30/130 [23.1%]) or tocilizumab (31/130 [23.8%]), and few required intravenous immunoglobulin (11/130 [8.5%]), vasopressors (4/130 [3.1%]), lumbar puncture (2/130 [1.5%]), or mechanical ventilation (1/130 [0.8%]). The majority of costs in the 6-month period after liso-cel infusion among patients with R/R FL in the TRANSCEND FL study were incurred in Month 1 and were facility related (IP and ICU hospitalizations and LOS). These findings, consistent with those previously reported for patients with LBCL treated with liso-cel, support that a single infusion of liso-cel is associated with significantly less HCRU and costs after the initial treatment period in the first month.

Axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel) are now FDA-approved for the treatment of tFL, but limited data are available on their clinical activity in patients (pts) with tFL since outcomes in those pts were not separately reported in registrational studies. CD19-targeting CAR-T cell therapy is effective for pts with relapsed/refractory tFL, including patients with characteristics of poor prognosis, with efficacy and toxicity profiles comparable to that observed in previous DLBCL studies. Unfortunately, pts who relapse post-CAR-T therapy have limited effective therapeutic options available, and this currently remains an unmet medical need within the field.

Methods Adult patients with primary or transformed LBCL treated with CD19-CAR-T cells, namely axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), between 2017 and 2022 were included in this single center retrospective study...Lymphodepletion was mostly cyclophosphamide and fludarabine (82.4%)...Additionally, we identified several factors that impact IR, which in turn shapes OS. In doing so, we show that CD4+ T lymphocytes are key players in disease response post-CAR-T and suggest that tracking CD4+ recovery following CAR-T may provide both diagnostic and therapeutic benefit.

Some medication usage was also higher among patients with grade ≥ 3 CRS/NE compared with grade ≤ 2 (tocilizumab: 10/16 [63%] vs 26/76 [34%]; corticosteroids: 15/16 [94%] vs 39/76 [51%]; vasopressors: 1/16 [6%] vs 2/76 [3%]). Over half of patients with R/R LBCL experienced any-grade CRS and/or NEs after liso-cel administration in TRANSFORM and PILOT, and the majority of these (83%) were low grade. Resource use and costs for management of AEs among patients with less severe CRS/NEs were relatively minimal compared with patients who had more severe CRS/NEs (with the exception of a few outliers). In general, HCRU and costs increased with greater severity.

Methods Samples were obtained from large B cell lymphoma (LBCL) patients that were part of the TRANSCEND-NHL-001 trial (NCT02631044, Abramson et al, Lancet 2020).Thirty-two patients with r/r B-cell lymphoma who received CAR-T cell treatment lisocabtagene maraleucel (16 responders (R) and 16 non-responders (NR)) were included in our analyses and (metabolically) analyzed by flow cytometry and extracellular flux analysis...More specifically, a higher abundance of memory phenotypes, metabolic activity and mitochondrial biogenesis of both harvested T cells and CAR-T product associates with improved clinical response. Combining metabolic, phenotypical and clinical characteristics and biomarkers of patient T cells (both pre- or post-production) shows the importance of the metabolic phenotype and fitness of T cell starting material, underlying the importance of early line CAR T therapy following diagnosis.

In these subgroup analyses including pts with R/R MCL and high-risk disease features (Ki-67 proliferation index ≥ 30%, TP53 mutation, blastoid morphology, and secondary CNS lymphoma), liso-cel demonstrated clinically meaningful efficacy across subgroups with durable responses. Efficacy and safety outcomes were generally consistent with the overall study population. While some subgroups were limited by small numbers, these results suggest a favorable benefit/risk profile for liso-cel in pts with R/R MCL and high-risk disease features, a pt population for whom effective treatment options are rarely available.

Background: For patients (pts) with R/R CLL/SLL after failure of Bruton tyrosine kinase inhibitor (BTKi) and B-cell lymphoma 2 inhibitor (BCL2i)–based treatment, there is no established standard of care and therefore there is a high unmet therapeutic need. In this exploratory analysis of pts with R/R CLL who had SD by iwCLL 2018 criteria after liso-cel treatment, greater liso-cel expansion, regardless of baseline tumor burden, correlated with blood uMRD status. Additionally, those with a PFS > 6 months achieved deeper clearance of blood sample-level MRD within 3 months of treatment versus those with a PFS ≤ 6 months, suggesting that MRD kinetics may identify pts with SD who can achieve durable disease control despite not achieving a response per iwCLL 2018 criteria. Further investigation is needed to better understand which subsets of pts with CLL who had SD may derive clinical benefit from liso-cel.

Patients with R/R MCL who were treated with liso-cel in the MCL cohort of TRANSCEND NHL 001 showed meaningful improvements across relevant aspects of health-related QOL, including symptoms and functioning. Clinically meaningful improvements were observed for all primary domains except for pain, and for many of the other PRO domains. These findings complement the clinical efficacy and safety data from the primary analysis of the MCL cohort of TRANSCEND NHL 001, further supporting the benefit of liso-cel in patients with R/R MCL.

In multivariable analyses, pre-LD LDH and largest lesion diameter were the only factors independently associated with response outcomes. We conclude that liso-cel is a robust alternative to other CD19 CAR-T products in older and frailer LBCL pts.

HCRU data were analyzed in the 6 months after infusion, including facility (eg, number of standard IP and ICU hospitalizations and length of stay [LOS]), procedures (eg, dialysis or intubation/mechanical ventilation), diagnostics (eg, imaging or laboratory tests), and medication use (eg, tocilizumab or corticosteroids). Among patients with R/R LBCL treated with liso-cel in the 2L TRANSFORM and PILOT trials, estimated median 6-month postinfusion costs were 68% lower for patients cared for in the OP versus IP setting. These results are consistent with a previous analysis of patients treated with liso-cel in the third-line setting (Palomba ML, et al. Leuk Lymphoma 2021); and thus, further support that OP postinfusion monitoring and care may allow health care systems to optimize HCRU and costs for patients with LBCL who receive CAR T cell therapy.

CAR T-cell products were axi-cel, n= 101 (25%); brexu-cel, n = 24 (6%); cilta-cel, n = 21 (5%); liso-cel, n = 46 (11%); ide-cel, n = 25 (6%); tisa-cel, 12 (3%); and investigational CD19 or CD20 CAR T-cell products, n = 174 (43%). A logistic regression model using pre-LD ANC, platelet, Hb, LDH, CRP, and ferritin showed improved discrimination and sensitivity compared to CAR-HEMATOTOX in our training set, but both models had low specificity (poor ability to "rule in" pts at risk of severe hematotoxicity) and thus low clinical utility at this time. We plan to further improve our predictive models by incorporating post-infusion biomarkers of systemic inflammation that we have previously shown to be associated with delayed count recovery after CAR T-cell therapy (Juluri, Blood Advances 2022).

Ide-cel (39%), liso-cel (36%), and axi-cel (17%) were the most used CAR-T cell products. All patients received lymphodepleting chemotherapy with fludarabine/cyclophosphamide...CONCLUSIONS In our comprehensive plasma proteomic profiles analysis, we identified cutoffs for IL3, IL6, IL5 and IL10 that may be predictive for CRS and ICANS regardless of CAR-T cell product. Our results are clinically applicable and may be used to recognize patients at risk for CRS and/or ICANS who may be eligible for prophylactic therapies.