Outcomes and Sequences of Targeted Therapies in CLL

Authored by Dr. Brian Koffman

Bottom Line:

In real world data, outcomes were equivalent in chronic lymphocytic leukemia patients whether they were first treated with venetoclax or a BTK inhibitor.

Who Performed the Research and Where Was it Presented:

Dr. Nadine Kutsch of Cologne Germany presented the abstract: “Outcomes and Treatment Sequences of Therapies with BCL2- and BTK Inhibitors in Chronic Lymphocytic Leukemia (CLL): An Analysis of Patient Data within the German CLL Study Group (GCLLSG) Registry” at the American Society of Hematology (ASH) Annual Meeting in December 2023 held in San Diego, CA.

Background:

Venetoclax, the only approved BCL2 inhibitor, and the few approved BTK inhibitors (BTKi) have revolutionized the care for CLL patients. However, there are unanswered CLL research questions concerning how these therapies are used outside of clinical trials and about their best sequencing.

Methods and Participants:

Real-world data from the German CLL Study Group (GCLLSG) registry was gathered from multiple sites in Germany to collect information on CLL patients with one or more first-line CLL treatments between July 1, 2014, and January 30, 2023. Patients who had been treated in a clinical trial were excluded.

Results:

• Patients:
  • 274 were treated with a venetoclax-based regimen as first therapy.
    • The median observation time from the first (before a BTK inhibitor) documented venetoclax treatment (irrespective if given as first-line or in a later therapy line) was 26 months.
    • The median age at the time of first treatment was 71 years.
    • 172 pts (62.8%) were male.
    • Based on genetic testing (unmutated IGHV status and/or a deletion of mutation TP53), 11 out of 58 (19.0%) that could be assessed were in the very high-risk group.
  • 915 pts were treated with a BTKi as first therapy (given before venetoclax).
    • The median observation time from the first documented treatment was 78 months for the BTKi cohort.
    • The median age was 72 when first treated.
    • 628 pts (68.6%) were male.
    • 46 out of 145 evaluable patient (31.7%) were in the very high-risk group.
  • 152 of 274 pts (55.5%) in the venetoclax cohort received venetoclax as first-line treatment.
  • 352 of 915 pts (38.5%) in the BTKi cohort received a BTKi as first-line treatment.
  • When looking at all 222 prior therapies before their first venetoclax treatment and the 1,090 treatments prior to first dose of a BTKi, chemoimmunotherapy (70.3% and 68.3%, respectively) and chemotherapy (10.4% and 17.8%, respectively) were the most frequent. This is not surprising as the data looked back ten years.
  • More significantly, subsequent therapy following the first of either venetoclax or BTKi treatment, most received a targeted therapy.
  • There were 37 subsequent therapies in 26 patient who first receive venetoclax:
    • 10 (27.0%) were given a second venetoclax-containing regimen
    • 13 (35.1%) a BTKi-containing regimen.
  • For those who took a BTKi first, 393 subsequent treatments were administered in 264 pts, of which:
    • 146 (37.2%) included venetoclax.
    • 106 (27.0%) a BTKi.
• Outcomes:
  • Median event-free survival (EFS) is defined as time from randomization to an “event” in this case, either progression of disease or death due to any cause.
  • For venetoclax treatment:
    • The EFS was 31.8 months, with an estimated two of three patients being event free at two years.
    • The median time to next treatment (TTNT) was 63.7 months.
    • The median overall survival (OS) was 96.5 months. It was estimated nine of ten patients were alive at two years for an OS rate of 89.5%.
    • When venetoclax was given as first-line treatment with no prior treatments, the estimated 2-year OS rate was 93.6% versus 86.5% when given in a later therapy line for the first time.
  • For those in the BTKi cohort:
  • The median EFS from start of first BTKi treatment was almost two years with almost half event free at two years.
  • The median TTNT was 68.4 months.
  • The median OS was 85.9 months with an estimated two-year OS rate of 84.9%.
  • Like venetoclax, BTKi worked better when given as first-line treatment, with the estimated two-year OS rate was 92.3% versus 81.3% when given in a later therapy line for the first time.

Conclusions:

When looking at EFS, TTNT and OS were similar between venetoclax and BTKi-based therapy, at least in those CLL patients studied in the GCLLSG registry between 2014 and 2023. While this CLL research does broadly suggest that it is clinically and statistically equivalent to start chronic lymphocytic leukemia treatment with either a BTKi or venetoclax, what it doesn’t tease out which subsets such as those with high-risk markers or of a certain age who might benefit from a particular sequencing. Treatment must be individualized and to best do that, more research is needed.

Links and Resources:

Watch my monologue here:

Read the actual ASH 2023 abstract here at Outcomes and Treatment Sequences of Therapies with BCL2- and BTK Inhibitors in Chronic Lymphocytic Leukemia (CLL): An Analysis of Patient Data within the German CLL Study Group (GCLLSG) Registry.

Stay strong. We are all in this together.

Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.