Tag: Non-Hodgkin Lymphoma

Real-World Outcomes with CD20×CD3 Bispecific Antibodies in Relapsed/Refractory Large B-Cell Lymphoma: Insights from the Multicenter REALBiTE Consortium

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SUMMARY: The American Cancer Society estimates that in 2026, about 79,320 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,970 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas in the United States and more than 25,000 cases of DLBCL are diagnosed each year in the United States, accounting for more than 25 percent of all lymphoma cases. The incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population.

Background
DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher 5-year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless of molecular subtype, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL. Approximately 30-40% of patients experience disease progression or relapse during the first 2 years and attempts to improve on R-CHOP regimen have not been successful.

Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL), including Diffuse Large B-Cell Lymphoma (DLBCL), remains a challenging disease state with historically poor outcomes after multiple lines of therapy. CD20×CD3 Bispecific Antibodies (BsAbs), including Epcoritamab (EPKINLY®) and Glofitamab (COLUMVI®), represent a major therapeutic advance by redirecting endogenous T cells to malignant B cells through off-the-shelf immune engagement. Pivotal trials demonstrated encouraging response rates, leading to regulatory approvals in the United States. However, clinical trials often enroll selected patients with favorable performance status and limited comorbidity, underscoring the need for robust Real-World Evidence (RWE) to better understand effectiveness, durability, and outcomes in routine practice.

Study Design and Patient Population
The REALBiTE Consortium conducted a large multicenter retrospective analysis across 21 U.S. academic centers, evaluating patients with R/R DLBCL treated with commercially available Epcoritamab or Glofitamab between January 2023 and October 2024, with updated follow-up through May 2025.

Across multiple analyses, more than 300 patients were evaluated, reflecting a heavily pretreated, high-risk population:

  • Over half were primary refractory to frontline therapy
  • A substantial proportion had double-hit or triple-hit lymphoma
  • Approximately 60% had prior CAR T-cell therapy, many of whom were CAR T-refractory
  • Nearly 70% would have been ineligible for registrational trials due to comorbidities, disease burden, or performance status

This cohort therefore represents a realistic cross-section of patients encountered in contemporary lymphoma practice.

Efficacy Outcomes in the Real World
Despite high-risk features, Overall Response Rates (ORR) with BsAbs in routine practice were comparable to pivotal clinical trials:

  • ORR approximately 51–54%
  • Complete Response (CR) rates ranging from 23–33%

However, response durability was limited:

  • Median Progression-Free Survival (PFS): ~2.5–2.6 months
  • Median Overall Survival (OS): ~7.7–7.8 months
  • Six-month PFS and OS rates were approximately 36% and 60%, respectively

These findings highlight a key real-world gap: while BsAbs induce meaningful initial responses, early disease progression remains common, particularly in biologically aggressive disease.

Predictors of Progression and Resistance
Several baseline clinical and biologic factors were associated with inferior outcomes:

  • Double-hit or triple-hit lymphoma
  • High International Prognostic Index (IPI)
  • Poor performance status (ECOG ≥2)
  • Primary refractory disease
  • Refractoriness to the line of therapy immediately preceding BsAbs

Importantly, loss or absence of CD20 expression emerged as a critical resistance mechanism. Among patients with paired biopsies, nearly 90% lost CD20 expression following BsAb therapy, with rapid progression thereafter. Additionally, undetectable CD20 by immunohistochemistry prior to BsAb initiation was strongly associated with inferior PFS and OS, underscoring the clinical relevance of confirming target antigen expression before treatment.

Safety and Causes of Mortality
Progressive lymphoma was the leading cause of death, accounting for more than 80% of fatalities, followed by infections. Treatment-related deaths due to Cytokine Release Syndrome (CRS) or Immune effector Cell–Associated Neurotoxicity Syndrome (ICANS) were infrequent, reinforcing the manageable safety profile of BsAbs in experienced centers. Notably, infection-related mortality occurred early and late, highlighting the need for vigilance with immune suppression and supportive care.

Outcomes After Progression on Bispecific Antibodies
Disease progression following BsAb therapy was often rapid, with a median time to progression of approximately 1.5 months. Nearly half of progressing patients received no further anti-lymphoma therapy, reflecting clinical decline and limited salvage options.

Among patients who did receive subsequent treatment:

  • Chemoimmunotherapy was most commonly used but achieved modest responses (~30%)
  • Loncastuximab tesirine showed limited activity
  • CAR T-cell therapy, when feasible, demonstrated the most favorable outcomes, with ORRs around 50% and high CR rates
  • Allogeneic hematopoietic cell transplantation, used as consolidation in selected responders, resulted in encouraging short-term disease control, with many patients remaining progression-free at follow-up

Nevertheless, overall post-BsAb survival remained poor, with median OS after salvage therapy of less than 4 months.

Clinical Implications
These Real-World Data confirm that Epcoritamab and Glofitamab are active therapies in heavily pretreated R/R LBCL, even among patients excluded from clinical trials. However, the short duration of benefit in most patients emphasizes the aggressive biology of this population and the urgent need for improved sequencing strategies.

Key clinical takeaways include:

  • Assessment of CD20 expression prior to BsAb initiation is critical
  • Early identification of patients unlikely to benefit may help guide alternative strategies
  • Clinical trial enrollment, novel combinations, or consolidation approaches (CAR T or allogeneic transplant) should be strongly considered for eligible responders
  • Durable remissions, while uncommon, do occur, suggesting that a subset of patients can derive long-term benefit with appropriate selection

Conclusion
The REALBiTE Consortium provides the most comprehensive real-world assessment to date of CD20×CD3 bispecific antibodies in R/R LBCL. While Response Rates mirror those seen in pivotal trials, real-world PFS and OS are shorter, reflecting broader patient inclusion and aggressive disease biology. These findings reinforce the transformative potential of BsAbs while highlighting the need for better predictive biomarkers, rational combinations, and optimized sequencing to improve long-term outcomes for this challenging patient population.

Outcomes following disease progression after epcoritamab or glofitamab in the real-world outcomes of bispecific T-cell engagers (REALBiTE) multi-center, retrospective cohort study. Brooks T, Mian A, Nedved A, et al. Blood. 2025;146(suppl 1):402. doi:10.1182/blood-2025-402

JAYPIRCA® (Pirtobrutinib)

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The FDA on December 3, 2025, granted traditional approval to JAYPIRCA® for adults with relapsed or refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor. In 2023, FDA granted accelerated approval to JAYPIRCA® for adults with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. JAYPIRCA® is a product of Eli Lilly and Company.

FDA Approves Pirtobrutinib in Relapsed/Refractory CLL/SLL

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SUMMARY: The FDA on December 3, 2025 granted traditional approval to Pirtobrutinib (JAYPIRCA®) for adults with relapsed or refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor. In 2023, FDA granted accelerated approval to Pirtobrutinib for adults with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

The American Cancer Society estimates that for 2025, about 23,690 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4460 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM).

The 3 covalent BTK inhibitors (cBTKi) presently approved by the FDA for CLL/SLL include Ibrutinib (IMBRUVICA®) Acalabrutinib (CALQUENCE®), and Zanubrutinib (BRUKINSA®). Although covalent BTK inhibitors have dramatically improved outcomes for patients with CLL or SLL, they are not curative. Despite the efficacy of covalent BTK inhibitors, treatment failure often occurs through development of resistance or intolerance.

Pirtobrutinib (JAYPIRCA®) is a next-generation, highly selective, reversible, non-covalent BTK inhibitor (BTKi), developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. Pirtobrutinib is 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies, and inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology. Pirtobrutinib is well tolerated and demonstrated encouraging efficacy and safety in early-phase studies, leading to FDA accelerated approval in December 2023 for patients with CLL/SLL who have received ≥2 prior lines of therapy, including both a BTKi and a BCL-2 inhibitor.

Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) in the post–covalent Bruton Tyrosine Kinase Inhibitor (cBTKi) setting remains a major therapeutic challenge. No prospective, randomized trials have previously evaluated treatment options in this population, and real-world data suggest poor outcomes, particularly after sequential covalent BTKi and BCL-2 inhibitor exposure. The present FDA approval was based on the BRUIN CLL-321 study.

Study Design
BRUIN CLL-321 is the first global, randomized, multicenter, Phase III trial conducted exclusively in patients with R/R CLL/SLL previously treated with a cBTKi.

  • Design: Open-label, 1:1 randomization to Pirtobrutinib 200 mg PO daily (N=119) vs. investigator’s choice (IC) of Idelalisib plus Rituximab (IdelaR-N=82) or Bendamustine plus Rituximab (BR-N=37).
  • Population: 238 patients; median 3 prior therapies; 50% had prior Venetoclax; high prevalence of high-risk genomic features (del[17p]/TP53 mutation ~54%, complex karyotype up to 72%).
  • Endpoints: Primary endpoint was Independent Review Committee (IRC)–assessed Progression-Free Survival (PFS). Secondary endpoints included Time to Next Treatment or death (TTNT), Overall Survival (OS), Overall Response Rate (ORR), and Safety.

Patients could cross over from IC to Pirtobrutinib upon confirmed progression, and treatment beyond IRC-defined progression was permitted if clinical benefit was maintained.

Efficacy Outcomes

  • PFS: Median 14.0 months with Pirtobrutinib vs. 8.7 months with IdelaR/BR (HR = 0.54; P =0.0002), representing a 46% reduction in the risk of progression or death.
  • TTNT: Median 24.0 months with Pirtobrutinib vs. 10.9 months with IC (HR = 0.37), reflecting sustained clinical benefit beyond protocol-defined progression in many patients.
  • OS: No statistically significant difference at final analysis (HR = 1.09), likely influenced by crossover (75.8% of eligible IC patients switched to Pirtobrutinib).
  • Subgroup Benefit: PFS improvement was consistent across key high-risk subgroups, including those with del(17p)/TP53 mutation, complex karyotype, and unmutated IGHV.

Safety Profile
Pirtobrutinib was generally well tolerated:

  • Grade ≥3 adverse events (AEs): 57.7% with Pirtobrutinib vs. 73.4% with IC.
  • Discontinuations due to AEs: 17.2% vs. 34.9%, respectively.
  • Class-related BTKi toxicities (atrial fibrillation, hypertension, major bleeding) were infrequent, with rates comparable to or lower than background incidence in CLL populations.
  • No cases of Richter transformation were reported in the Pirtobrutinib arm, versus three in the IC group.

Clinical Implications
The BRUIN CLL-321 trial establishes Pirtobrutinib as a new standard of care option for patients with CLL/SLL previously treated with cBTKi, offering:

  • Significant PFS improvement in a population with historically poor prognosis.
  • Prolonged TTNT, which may be more reflective of real-world benefit than PFS alone.
  • Favorable safety profile supporting long-term tolerability.

These findings also raise important considerations for sequencing strategies, including potential use of Pirtobrutinib prior to Venetoclax in certain patients, pending further prospective data (e.g., BRUIN-322 trial).

Takeaway for Practice:
For CLL/SLL patients progressing after cBTKi therapy, Pirtobrutinib offers a meaningful advancement, providing durable disease control with a manageable toxicity profile. BRUIN CLL-321 delivers the first randomized evidence supporting treatment in this setting, addressing a long-standing gap in the therapeutic landscape.

Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or Bendamustine/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor–Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321). Sharman JP, Munir T, Grosicki S, et al. J Clin Oncol. 2025;43:2538-2549

 

 

Tafasitamab Plus Lenalidomide and Rituximab Improves Outcomes in Relapsed/Refractory Follicular Lymphoma: Results from the Phase III inMIND Trial

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SUMMARY: The FDA on June 18, 2025, approved Tafasitamab-cxix (MONJUVI®) with Lenalidomide and Rituximab for adults with Relapsed or Refractory Follicular Lymphoma (FL).

The American Cancer Society estimates that in 2025, about 80,350 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,390 individuals will die of this disease. Indolent Non-Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL).

Follicular Lymphoma is the most indolent form and second most common form of all NHLs, and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas and the average age of diagnosis is 65 years. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance Rituximab (RITUXAN®). This can result in a median Progression Free Survival (PFS) of 6-8 yrs and a median Overall Survival (OS) of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years, with prognosis worsening after each subsequent relapse. Immunotherapy-based approaches are increasingly favored, yet durable disease control remains elusive, particularly among patients with high-risk features such as progression within 24 months of initial therapy (POD24) or resistance to anti-CD20 monoclonal antibodies.

Lenalidomide in combination with Rituximab (R²) is an established option after at least one prior line of therapy. Tafasitamab, a humanized anti-CD19 monoclonal antibody with both direct cytotoxic and immune-mediated mechanisms of action, has previously demonstrated efficacy in Diffuse Large B-Cell Lymphoma in combination with Lenalidomide (L-MIND trial). The Phase III inMIND study (NCT04680052) was designed to evaluate whether adding Tafasitamab to the R² backbone could improve outcomes in patients with Relapsed or Refractory (R/R) FL. This study was powered to assess PFS in patients with FL only.

Study Design and Methods
inMIND was a randomized, double-blind, placebo-controlled, global Phase III trial that enrolled 548 patients with Grade 1–3A FL or Marginal Zone Lymphoma. All patients had received at least one prior systemic therapy, including an anti-CD20 monoclonal antibody, and required treatment for Relapsed or Refractory disease. Key eligibility criteria included age 18 years or older, CD19+/CD20+ disease, and ECOG performance status 2 or less. Patients were stratified by POD24 status, refractoriness to prior therapy, and number of prior treatment lines (1 vs >1).

Participants were randomized 1:1 to:

  • Tafasitamab + Lenalidomide + Rituximab (Tafa arm)
  • Placebo + Lenalidomide + Rituximab (control arm)

A total of 548 patients were randomized (Tafa, n=273; Placebo, n=275). Baseline characteristics were balanced between arms:

  • Median age: 64 years
  • 79% with intermediate/high-risk FLIPI scores
  • 83% with high tumor burden (GELF criteria)
  • 32% with POD24
  • 43% refractory to prior anti-CD20 therapy

Tafasitamab (12 mg/kg IV) or placebo was administered on days 1, 8, 15, and 22 of cycles 1–3, and days 1 and 15 of cycles 4–12. All patients received standard dosing of Lenalidomide plus Rituximab for up to twelve 28-day cycles.

  • Primary endpoint: investigator-assessed Progression-Free Survival (PFS) in patients with FL.
  • Key secondary endpoints: Complete metabolic Response (PET-CR), Overall Response Rate (ORR), Duration of Response (DOR), Time To Next Treatment (TTNT), Overall Survival (OS), and safety.

At a median follow-up of 14.1 months:

  • Primary endpoint met: Tafasitamab significantly reduced the risk of progression, relapse, or death by 57%.
    • Median PFS: 22.4 months (Tafa) vs 13.9 months (placebo)
    • Hazard ratio (HR) 0.43; 95% CI 0.32–0.58; P < 0.0001
  • Independent Review Committee (IRC) confirmation: median PFS not reached with Tafasitamab vs 16.0 months with placebo (HR 0.41; P < 0.0001).
  • Response outcomes:
    • PET-CR rate: 49.4% vs 39.8% (P = 0.029)
    • ORR: 83.5% vs 72.4% (P = 0.0014)
    • DOR: 21.2 vs 13.6 months (HR 0.47; P < 0.0001)
    • TTNT: not reached vs 28.8 months (HR 0.45; P < 0.0001)
  • Overall Survival (immature): trend favoring Tafasitamab (HR 0.59; 95% CI 0.31–1.13).

Subgroup Analyses
PFS benefit with Tafasitamab was consistent across all prespecified groups, including POD24 patients, those refractory to prior anti-CD20 therapy and patients with ≥2 prior lines of therapy

Safety Profile
Adverse events were manageable and consistent with known profiles of the combination components.

  • Grade 3/4 adverse events occurred in 71% (Tafa) vs 69.5% (placebo).
  • Most common Grade 3/4 events: neutropenia (40% vs 38%), pneumonia (8% vs 5%), thrombocytopenia (6% vs 7%).
  • COVID-19 infections were slightly more frequent in the Tafasitamab arm (6% vs 2%).
  • Treatment discontinuation due to adverse events occurred in 11% (Tafa) vs 7% (placebo).
  • On-study deaths were less frequent in the Tafasitamab arm (5.5% vs 8.5%).

Importantly, Tafasitamab did not interfere with the administration of Lenalidomide or Rituximab and dose reductions and treatment interruptions were comparable across arms.

Clinical Implications
The inMIND trial is the first phase III study to validate a dual-antibody approach targeting both CD19 and CD20 in FL. The addition of Tafasitamab to R² not only extended PFS by nearly nine months but also improved depth of response and delayed the need for subsequent therapy, without introducing unexpected toxicities.

For high-risk patients, including those with POD24 or anti-CD20–refractory disease, these results are particularly impactful, addressing a long-standing gap in treatment outcomes.

As novel immunotherapies such as bispecific antibodies and CAR T-cell therapies are integrated earlier in the treatment paradigm, questions about sequencing and immune fitness will become increasingly relevant. Nonetheless, Tafasitamab plus R² emerges from inMIND as a practical, chemotherapy-free regimen that can be delivered in both community and academic settings, representing a potential new standard of care for patients with R/R FL.

Key Takeaways

  • inMIND met its primary endpoint, showing a 57% risk reduction in progression, relapse, or death with Tafasitamab + R² vs R² alone.
  • Benefits were consistent across high-risk subgroups, including POD24 and anti-CD20–refractory patients.
  • Secondary endpoints (ORR, CR, DOR, TTNT) also significantly favored Tafasitamab.
  • Safety profile was manageable and aligned with expectations.
  • Longer follow-up will clarify OS benefit, but current findings strongly support the role of Tafasitamab in improving outcomes for patients with Relapsed/Refractory Follicular Lymphoma.

Tafasitamab Plus Lenalidomide and Rituximab for Relapsed or Refractory Follicular Lymphoma: Results from a Phase 3 Study (inMIND). Sehn LH, Luminari S, Scholz CW, et al. Blood (2024), Volume 144, Supplement 2: LBA-1. https://doi.org/10.1182/blood-2024-212970

Pirtobrutinib in Relapsed/Refractory CLL/SLL after Prior cBTKi: Phase III BRUIN CLL-321 Results

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SUMMARY: The American Cancer Society estimates that for 2025, about 23,690 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4460 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM).

The 3 covalent BTK inhibitors (cBTKi) presently approved by the FDA for CLL/SLL include Ibrutinib (IMBRUVICA®) Acalabrutinib (CALQUENCE®), and Zanubrutinib (BRUKINSA®). Although covalent BTK inhibitors have dramatically improved outcomes for patients with CLL or SLL, they are not curative. Despite the efficacy of covalent BTK inhibitors, treatment failure often occurs through development of resistance or intolerance.

Pirtobrutinib (JAYPIRCA®) is a next-generation, highly selective, reversible, non-covalent BTK inhibitor (BTKi), developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. Pirtobrutinib is 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies, and inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology. Pirtobrutinib is well tolerated and demonstrated encouraging efficacy and safety in early-phase studies, leading to FDA accelerated approval in December 2023 for patients with CLL/SLL who have received ≥2 prior lines of therapy, including both a BTKi and a BCL-2 inhibitor.

Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) in the post–covalent Bruton Tyrosine Kinase Inhibitor (cBTKi) setting remains a major therapeutic challenge. No prospective, randomized trials have previously evaluated treatment options in this population, and real-world data suggest poor outcomes, particularly after sequential covalent BTKi and BCL-2 inhibitor exposure.

Study Design
BRUIN CLL-321 is the first global, randomized, multicenter, Phase III trial conducted exclusively in patients with R/R CLL/SLL previously treated with a cBTKi.

  • Design: Open-label, 1:1 randomization to Pirtobrutinib 200 mg PO daily (N=119) vs. investigator’s choice (IC) of Idelalisib plus Rituximab (IdelaR-N=82) or Bendamustine plus Rituximab (BR-N=37).
  • Population: 238 patients; median 3 prior therapies; 50% had prior Venetoclax; high prevalence of high-risk genomic features (del[17p]/TP53 mutation ~54%, complex karyotype up to 72%).
  • Endpoints: Primary endpoint was Independent Review Committee (IRC)–assessed Progression-Free Survival (PFS). Secondary endpoints included Time to Next Treatment or death (TTNT), Overall Survival (OS), Overall Response Rate (ORR), and Safety.

Patients could cross over from IC to Pirtobrutinib upon confirmed progression, and treatment beyond IRC-defined progression was permitted if clinical benefit was maintained.

Efficacy Outcomes

  • PFS: Median 14.0 months with Pirtobrutinib vs. 8.7 months with IdelaR/BR (HR = 0.54; P =0.0002), representing a 46% reduction in the risk of progression or death.
  • TTNT: Median 24.0 months with Pirtobrutinib vs. 10.9 months with IC (HR = 0.37), reflecting sustained clinical benefit beyond protocol-defined progression in many patients.
  • OS: No statistically significant difference at final analysis (HR = 1.09), likely influenced by crossover (75.8% of eligible IC patients switched to Pirtobrutinib).
  • Subgroup Benefit: PFS improvement was consistent across key high-risk subgroups, including those with del(17p)/TP53 mutation, complex karyotype, and unmutated IGHV.

Safety Profile
Pirtobrutinib was generally well tolerated:

  • Grade ≥3 adverse events (AEs): 57.7% with Pirtobrutinib vs. 73.4% with IC.
  • Discontinuations due to AEs: 17.2% vs. 34.9%, respectively.
  • Class-related BTKi toxicities (atrial fibrillation, hypertension, major bleeding) were infrequent, with rates comparable to or lower than background incidence in CLL populations.
  • No cases of Richter transformation were reported in the Pirtobrutinib arm, versus three in the IC group.

Clinical Implications
The BRUIN CLL-321 trial establishes Pirtobrutinib as a new standard of care option for patients with CLL/SLL previously treated with cBTKi, offering:

  • Significant PFS improvement in a population with historically poor prognosis.
  • Prolonged TTNT, which may be more reflective of real-world benefit than PFS alone.
  • Favorable safety profile supporting long-term tolerability.

These findings also raise important considerations for sequencing strategies, including potential use of Pirtobrutinib prior to Venetoclax in certain patients, pending further prospective data (e.g., BRUIN-322 trial).

Takeaway for Practice:
For CLL/SLL patients progressing after cBTKi therapy, Pirtobrutinib offers a meaningful advancement, providing durable disease control with a manageable toxicity profile. BRUIN CLL-321 delivers the first randomized evidence supporting treatment in this setting, addressing a long-standing gap in the therapeutic landscape.

Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or Bendamustine/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor–Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321). Sharman JP, Munir T, Grosicki S, et al. J Clin Oncol. 2025;43:2538-2549

 

 

ADCETRIS® (Brentuximab vedotin)

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The FDA on February 11, 2025, approved ADCETRIS® in combination with Lenalidomide and a Rituximab product for adult patients with relapsed or refractory Large B-Cell Lymphoma (LBCL), including Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified (NOS), DLBCL arising from indolent lymphoma, or High-Grade B-Cell Lymphoma (HGBL), after two or more lines of systemic therapy, who are ineligible for autologous Hematopoietic Stem Cell Transplantation (auto-HSCT) or CAR T-cell therapy. ADCETRIS® is a product of Seagen Inc., a subsidiary of Pfizer.