Topline Presentation Points 
Front Line CLL (0:33-14:34)


Long term results of A041202 (Woyach, ASH 2021)- Ibrut with or without R vs BR in an older patient population (incl. high risk disease)  

Key Takeaways: 

  • Continued advantage of Ibrut-based regimens compared with BR chemoimmunotherapy 
    • At median 55-month follow-up, results continued to show a PFS advantage for the 2 Ibrut-containing regimens over BR 
    • No PFS difference between the 2 Ibrut-containing regimens suggest that R does not add benefit to ibrut when given in this manner  
    • Significant interaction effect between treatment group and TP53 abnormalities on PFS 
  • BTKi (particularly Ibrut) are associated with atrial fibrillation.  
    • Also true for hypertension 

Dr. Mato discussed management of cardiovascular AE’s with BTKi in more depth with Drs. Peter Anglin, Christine Chen, and Versha Banerji during the CLL Panel. Select highlights from this discussion included:

Monitoring for afib:

  • Close clinical screening and thorough cardiac assessment prior to BTKi
  • There is a need for better questionnaires/tools for monitoring long-term

Real-world experience with newer BTKi’s (acala and zanu):

  • Differences in incidence of afib seen in clinical trial has translated to practice, especially with acala (there is much less experience with zanu currently)

Phase III FLAIR Trial (Hillmen et al. ASH 2021) 

Key Takeaways: 

  • Ibrut + R Is superior to FCR  
    • In sub group analysis PFS was also shown in IGHV unmutated  
  • FCR associated with increased risk for secondary cancers vs Ibrut+R 
  • for patients with pre-existing hypertension or cardiac disorders, the relative risk of sudden unexplained or cardiac deaths is elevated to 18.7% in Ibrut-containing arms  

Phase III SEQUOIA Trial (Tam et al. ASH 2021)- Zanubrutinib (covalent 2nd gen BTKi) versus BR in treatment naive CLL/SLL 

Key Takeaways: 

  • 24 month PFS per IRC assessment 85.5% vs 69.5% BR 
  • PFS per IRC assessment by IGHV status, shows BR inferior for unmutated 
  • AE’s of interest 
    • rates of atrial fibrillation quite low  
    • higher rate of neutropenia’s in B+R arm, infection rates similar 

Phase III GAIA (CLL13) trial (Eichhorst et al. ASH 2021)- VEN time-limited combination treatments (RVe, GVe, GIVe) vs standard chemoimmunotherapy (CIT: FCR/BR) 

Key Takeaways: 

  • uMRD results 
    • GIVe 92.2% vs CIT 52% 
    • GVe 86.5% vs CIT 52% 
    • RVe 57% vs CIT 52% 
  • AEs – triplet therapy increases incidence of febrile neutropenia, infections, and TLS 
    • Is risk worth benefit? 
  • Awaiting data on PFS  

Phase II CAPTIVATE Study (Ghia et al. ASH 2021)- Ibrut + Ven for frontline CLL  

Key Takeaways: 

  • 2 cohorts: MRD and Fixed Duration (FD) 
  • For patients with uMRD at end of 15-month therapy – no value in Ibrut maintenance 
  • If uMRD not confirmed, Ibrut maintenance only 
  • Too early for retreatment data, but for patients who have progressed after fixed treatment Ibrut+Ven, most patients are apt to respond to Ibrut 

Phase III GLOW Study (Munir et al. ASH 2021)- MRD outcomes after Ibrut induction followed by fixed duration Ibrut+Ven vs Clb+Obin in elderly or unfit patients 

Key Takeaways: 

  • Superior PFS with Ibrut+Ven vs Clb+Obin was maintained with median 34.1 mos of follow-up 
  • 84.5% of patients had sustained uMRD < 10⁻⁴ and 80.4% had sustained uMRD < 10⁻⁵ with Ibrut+Ven
Relapsed/Refractory CLL – focus on BTK resistance (14:35 – 19:45)
  • About half of patients discontinue frontline or salvage ibrutinib, either due to resistance or intolerance 
  • Venetoclax is the most effective standard option for these patients, but remission duration is limited 
  • Alternative and less effective treatment options include PI3K inhibitors and chemoimmunotherapy 

Phase II study evaluating the addition of ublituximab and umbralisib (U2) to ibrutinib (Roeker et al. ASH 2021)

Key Takeaways: 

  • Aim: Achieving uMRD for 2 consecutive cycles and enter into treatment free observation from all therapies 
  • Most patients able to stop treatment  
    • Proportion achieving uMRD 77%  
    • 7.4 months – medium time point to uMRD  
  • AE’s – Grade3/4 events quite low  

Phase I/II BRUIN Study (Mato et al. ASH 2021) Updated results of Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi  

Key Takeaways: 

  • Updated data suggests efficacy in BTK and BCL2 pre-treated with ORR of 68% 
  • Median PFS not yet reached  
  • BTK C481 mutation status not a predictor of benefit 
  • Safety profile- No DLTs reported and MTD not reached  

Phase II – Preliminary efficacy and safety of MK-1026 Nemtabrutinib (Woyach et al. ASH 2021) 

Key Takeaways: 

  • Heavily pretreated population– median 4 lines of prior therapy 
    • 63% with C481 mutation and 23.5% have Del(17p) 
  • ORR 57.9% 
  • 93.9% any decrease in lymph node volume, 69.7% with decrease of > 50% 
  • Median duration of response not yet reached 
COVID-19 (19:45 – 22:37)

Trials covered:

  • Humoral Response to mRNA vaccines (Bagacean et al ASH 2021)
  • Cellular immune response to mRNA vaccines (Itchaki, ASH 2021) 

Key Takeaways from above trials: 

  • Patients with CLL have an impaired immune response to COVID19 vaccination, particularly if on active therapy 
  • Both anti-CD20 monoclonal antibodies and BTK/BCL2 inhibitors significantly impact immune response to COVID19 vaccination 
  • A 3rd dose of vaccine (booster) can increase immunity in these patients 
  • About 24% of patients with no humoral response can have an optimal cellular response to COVID19 vaccine 
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