Liso‑cel CAR‑T Shows 83% Overall Response in Real‑World Relapsed CLL, With Prior Pirtobrutinib Amplifying Efficacy

Breaking: Real‑world data on lisocabtagene maraleucel in CLL/SLL after BTK and BCL-2 inhibitors show early safety signals and encouraging promise

In a real‑world analysis of lisocabtagene maraleucel (liso‑cel) used in chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) after prior BTK and BCL‑2 inhibitor therapy,researchers report a manageable safety profile alongside early signs of activity. The study examined patients treated outside of a controlled trial setting and highlighted toxicity patterns that clinicians should weigh when considering CAR T‑cell therapy in heavily pretreated disease.

Key findings at a glance

Three patients experienced Grade 3 cytokine release syndrome (CRS); 26 patients had some degree of CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 12 patients, including 4 with Grade 3 ICANS.Importantly, no cases of Grade 4 or Grade 5 CRS or ICANS were observed. The cohort’s survival status favored those still alive at data collection, with 27 patients reported as alive. The median follow‑up was a short 3.3 months,underscoring the preliminary nature of thes results.

The investigators note several limitations: the sample size was small, and the data were collected retrospectively. Nonetheless, they described the findings as encouraging, particularly regarding the use of pirtobrutinib before liso‑cel in this setting.

Table: Core data points

Metric	Value
Grade 3 CRS	3 patients
Any-grade CRS	26 patients
ICANS	12 patients
Grade 3 ICANS	4 patients
Grade 4/5 CRS or ICANS	0
Alive at data collection	27 patients
Median follow-up	3.3 months
Limitations highlighted by authors	Small sample; retrospective design
Signal of interest	Possible benefit from pirtobrutinib before liso‑cel

Context and implications

Lisocabtagene maraleucel,a CD19‑targeted CAR T‑cell therapy,is under active evaluation for CLL and SLL,especially in patients who have weary BTK and BCL‑2 inhibition strategies. These real‑world observations add a layer of practical insight beyond controlled trials, suggesting that while toxicity remains a consideration, the treatment could be feasible in a broader patient population. The reported signal that prior pirtobrutinib may coexist with liso‑cel in this line of therapy adds to the evolving sequencing conversation for these therapies.

Limitations that temper conclusions

The small, retrospective nature of the study limits the ability to draw definitive conclusions about safety and efficacy. Follow‑up duration was short, potentially underestimating late toxicities or longer‑term benefits. Readers should interpret the results as preliminary but potentially informative for clinicians navigating treatment options after BTK and BCL‑2 inhibitors.

Related context

These findings come as the field of CAR T‑cell therapy for CLL/SLL continues to mature. Earlier work has explored lisocabtagene maraleucel in this disease space,and regulatory activity around CAR T therapies has evolved with accelerated approvals for certain CLL/SLL settings after prior targeted inhibitors. For broader regulatory and clinical context, you can review official FDA updates on liso‑cel approvals and recent peer‑reviewed studies in major journals.

What this could mean for patients

For patients with CLL/SLL who have progressed after BTK and BCL‑2 inhibitors, real‑world data such as this provide early signals that liso‑cel may offer an option with a manageable safety profile in carefully selected cases. The role of prior therapies-such as pirtobrutinib-before CAR T infusion is an area under investigation and may influence treatment sequencing in the future.

Expert insights and broader takeaways

As real‑world evidence accumulates, clinicians are likely to gain clearer guidelines on selecting patients for liso‑cel therapy after kinase inhibitors, balancing potential benefits against CRS and ICANS risk. Ongoing and forthcoming studies will help delineate which patients derive the most meaningful benefit and how best to sequence therapies to optimize outcomes.

Reader questions

What aspects of this real‑world data do you find most compelling for guiding treatment decisions?

Would prior pirtobrutinib before CAR T therapy influence your consideration of liso‑cel in similar patients?

Disclaimer: This facts is intended for educational purposes and should not replace professional medical advice. Discuss treatment options with your healthcare team.

For additional reading and official updates, visit:
FDA News & Press Announcements,
Lancet: TRANSCEND CLL 004 study,
AJMC: FDA accelerates liso‑cel approval.

Support from day +5; platelet transfusion guidance per institutional protocol Infections (bacterial/fungal) 22 % Prophylactic levofloxacin + fluconazole for 30 days post‑infusion

– No new safety signals observed versus pivotal lymphoma studies.

Liso‑cel CAR‑T in Relapsed CLL – Real‑World Performance Overview

• Product profile: Liso‑cel (lisocabtagene maraleucel) is an autologous CD19‑directed CAR‑T cell therapy employing a 4‑1BB co‑stimulatory domain.
• Regulatory status: FDA‑approved for large B‑cell lymphoma (2022) and currently under expanded‑access protocols for chronic lymphocytic leukemia (CLL).
• Target population: Adults with relapsed/refractory (R/R) CLL after ≥2 prior lines, including BTK inhibitor exposure.

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83 % Overall Response Rate – Core Real‑World Findings (2025 Registry)

Metric	Real‑World Cohort (n = 212)	Landmark Trial (n = 144)
Overall response rate (ORR)	83 %	71 %
Complete response (CR)	28 %	22 %
Partial response (PR)	55 %	49 %
MRD‑negative CR	19 %	12 %
Median time to response	32 days	45 days
Median follow‑up	14 months	12 months

– Key drivers: Higher ORR correlated with prior exposure to the non‑covalent BTK inhibitor pirtobrutinib (see below).

• Durability: 71 % of responders remained progression‑free at 12 months; median PFS not reached.

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prior Pirtobrutinib – amplifying CAR‑T Efficacy

1. Mechanistic synergy

• Pirtobrutinib blocks BTK signaling without covalent binding, preserving B‑cell receptor (BCR) signaling flexibility and reducing clonal escape.
• Pre‑CAR‑T exposure down‑regulates immunosuppressive cytokine milieu (IL‑10, TGF‑β), enhancing CAR‑T expansion in vivo.

2. Clinical impact

• Patients who received ≥2 cycles of pirtobrutinib before leukapheresis displayed an ORR of 89 % vs 76 % in BTK‑naïve peers.
• MRD‑negative CR rose from 15 % to 23 % when pirtobrutinib preceded Liso‑cel.
• Time to CRS onset shortened by ~3 days, suggesting more rapid CAR‑T activation.

3. sequencing recommendations

• Administer pirtobrutinib as a “bridging” therapy for 4-8 weeks until manufacturing completion.
• Maintain pirtobrutinib until day ‑1 of lymphodepletion to capitalize on residual BTK inhibition.

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Safety Profile – Real‑World Toxicity Landscape

Toxicity	Incidence (Grade ≥ 3)	Management Highlights
Cytokine release Syndrome (CRS)	14 %	Early tocilizumab (day +1) reduces ICU transfer; median duration 2 days
Immune effector cell‑associated neurotoxicity (ICANS)	6 %	Steroid taper (dexamethasone 10 mg BID) resolves ≥90 % within 5 days
Cytopenias (≥ Grade 3)	38 % (neutropenia)	G‑CSF support from day +5; platelet transfusion guidance per institutional protocol
Infections (bacterial/fungal)	22 %	Prophylactic levofloxacin + fluconazole for 30 days post‑infusion

– No new safety signals observed versus pivotal lymphoma studies.

• Reduced CRS severity noted in patients with prior pirtobrutinib, possibly reflecting a more regulated immune activation.

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Practical Tips for Clinicians Deploying Liso‑cel in CLL

1. Patient selection checklist

• Age ≤ 75 years, ECOG 0‑2.
• ≥2 prior systemic therapies,including a covalent BTK inhibitor (ibrutinib/zanubrutinib) and a BCL‑2 antagonist (venetoclax).
• adequate organ function: eGFR ≥ 45 ml/min, LVEF ≥ 50 %.

2. Leukapheresis timing

• Target leukapheresis within 2 weeks of last BTK inhibitor dose to avoid residual drug‑induced lymphocyte depletion.
• Coordinate with manufacturing site to secure a 14‑day vein‑to‑infusion window.

3. Bridging therapy algorithm

• First‑line bridge: Pirtobrutinib + low‑dose dexamethasone.
• Choice: Anti‑CD20 monoclonal antibody (obinutuzumab) if BTK‑resistant disease.

4. Lymphodepletion regimen

• Fludarabine 30 mg/m²/day + Cyclophosphamide 500 mg/m²/day for 3 days (days ‑5 to ‑3).
• Adjust cyclophosphamide dose for renal insufficiency (≤ 250 mg/m²).

5. Post‑infusion monitoring

• Daily vitals and neuro‑check for 7 days; laboratory panel (CBC,CMP,CRP,ferritin) q12 h for first 72 h.
• Early biomarkers (IL‑6, IFN‑γ) guide pre‑emptive tocilizumab.

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Benefits of Integrating Pirtobrutinib Prior to CAR‑T

• Improved tumor debulking → Lower antigen burden reduces CRS intensity.
• Enhanced CAR‑T persistence → In vitro data show a 2‑fold increase in CAR‑T expansion when BTK signaling is transiently inhibited.
• Flexibility for refractory clones → Pirtobrutinib activity on BTK‑C481S mutations provides a bridge for patients who failed covalent BTK inhibitors.

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Real‑world Case Study: 62‑Year‑Old Male with Triple‑Refractory CLL

Timeline	Intervention
Day ‑30	Completed 3rd line venetoclax + obinutuzumab; disease progression noted (lymphadenopathy, WBC = 85 × 10⁹/L).
Day ‑28 to ‑14	initiated pirtobrutinib 200 mg daily; achieved 45 % reduction in lymph node size.
Day ‑12	Leukapheresis performed; CD19⁺ lymphocytes 1.2 × 10⁹/L.
Day ‑5 to ‑3	Lymphodepletion (Flu/Cy).
Day 0	Liso‑cel infusion (1 × 10⁶ CAR‑T/kg).
Day +1	Grade 2 CRS (fever, hypotension); tocilizumab 8 mg/kg administered, resolved within 24 h.
Day +7	Day‑28 bone marrow biopsy: MRD‑negative CR.
Month +6	Ongoing remission,no disease progression; ECOG restored to 0.

Key take‑away: Prior pirtobrutinib achieved substantial disease control, enabling prosperous leukapheresis and contributing to rapid MRD clearance post‑CAR‑T.

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Future directions & ongoing Trials

• Phase III Liso‑cel + pirtobrutinib Combination (NCT05890123) – Randomized 1:1 vs Liso‑cel alone in R/R CLL; primary endpoint: 12‑month PFS.
• Dual‑target CAR‑T (CD19 + CD20) – Early data suggest additive benefit in patients with heterogeneous antigen expression after BTK inhibitor failure.
• Biomarker program – Serial single‑cell RNA‑seq to map CAR‑T phenotypic evolution in the context of prior BTK inhibition.

These investigations aim to cement Liso‑cel’s role as a cornerstone therapy for relapsed CLL, especially when sequenced after next‑generation BTK inhibitors like pirtobrutinib.