Management of patients with CLL after venetoclax discontinuation

One of the hallmarks of chronic lymphocytic leukemia (CLL) is the uncontrolled proliferation of B cells coupled with a failure of apoptosis due to overexpression of anti-apoptotic Bcl-2. Venetoclax-based therapies targeting the Bcl-2 pathway became a standard of care for patients with CLL.^1-3 However, little is known about the optimal treatment regimen after discontinuation of venetoclax or the impact of venetoclax resistance on the efficacy of subsequent therapies. This is particularly important considering the early use of venetoclax-based therapies⁴ in the treatment of patients with CLL supported by the data from MURANO and CLL14 clinical trials.

Anthony R. Mato, Memorial Sloan Kettering Cancer Center, New York, US, and colleagues, aimed to address those knowledge gaps in a multicenter retrospective study of patients with CLL who had discontinued venetoclax and received subsequent therapy. The results were presented during the 61st American Society of Hematology (ASH) Annual Meeting & Exposition, Orlando, US.⁵ Here we provide a summary of the data reported at the meeting. Data presented at the ASH meeting may supersede the data in the published abstract.

Methods

• Retrospective analysis of data collected from patients with CLL who discontinued venetoclax for any reason
• Patients were divided into cohorts depending on the subsequently used treatment
  • BTK inhibitor (BTKi)
  • PI3K inhibitor (PI3Ki)
  • Cellular therapy
• Primary objectives were
  • Overall response rate (ORR)
  • Progression-free survival (PFS) defined as the time from post-venetoclax therapy to disease progression, death or censored at last follow-up
• Exploratory analysis
  • PFS2 defined as PFS from the start of venetoclax treatment to progression on ibrutinib therapy, death or last follow-up
• Survival was estimated using the Kaplan-Meier method and analyses were stratified by prior BTKi exposure and discontinuation reason

Results

• In total, data from 326 patients across 31 international centers were analyzed (patient characteristics presented in Table 1)

Table 1. Patient characteristics

Baseline characteristics

Results

Available data (n)

Age at CLL diagnosis, median (range), years

58 (32–88)

326

Age at venetoclax start, median (range), years

66 (38 –91)

324

Male, (%)

69

326

White race, (%)

87

325

CLL characteristics, (%)

Rai stage ≥ 3

Del(17p)

TP53 mutated

TP53 disruption (del17p or TP53 mutated)

Complex karyotype (≥ 3 abnormalities)

NOTCH1 mutated

IGHV non-mutated

 

64

47

45

56

39

18

82

 

318

312

221

312

279

103

171

Therapy prior to venetoclax

Lines of therapy, median (range)

Prior ibrutinib (%)

Prior BTKi (%)

Prior idelalisib (%)

 

3 (0–11)

60

61

19

 

326

324

324

324

• Majority of patients (96%) had received venetoclax in the relapsed/refractory setting, with 67% administered in clinical practice rather than as a part of a clinical trial
• Venetoclax monotherapy was given to 73% of patients
• The highest dose of 400 mg was given to 73% of patients
• Median number of cycles of anti-CD20 antibody n= 6 (1–12)
• ORR to venetoclax was 69%, including 28% complete response (CR)
• Median time to best response was 9 months (1–60)
• Reasons for venetoclax discontinuation and responses to the subsequent therapies are outlined in Table 2 and Table 3

Table 2. Venetoclax discontinuation

Allo-HSCT, allogeneic hematopoietic stem cell transplantation

Overall discontinuation rate, (%)

100

Reasons for discontinuation, (%)

CLL progression

Adverse event

Richter’s transformation

Patient preference

Planned allo-HSCT

 

38

14

14

8

6

Following discontinuation

Treatment with next line of therapy

Alive and untreated

Died prior to subsequent therapy

 

58

19

23

• Post-venetoclax treatment with BTKi induced higher ORR in BTKi-naïve patients compared with BTKi-exposed/resistant (p= 0.001) (Table 3)
  • BTKi treatment of BTKi-naïve patients after venetoclax discontinuation resulted in durable response (median PFS was 32 months after 10.5 months median follow-up)
  • The response of BTKi-exposed patients depended on the reason for discontinuation (median PFS was 4 months in patients resistant to BTKi vs not reached in BTKi-intolerant patients after 7.7 months follow-up)
• Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after venetoclax showed efficacy (PFS not reached)
• PI3Ki and CAR T-cell therapy in post-venetoclax setting did not produce a durable response (median PFS of 4 months and 9 months, respectively)

Table 3. Response to subsequent therapies following venetoclax discontinuation

acalabr, acalabrutinib; BTKi, Bruton tyrosine kinase inhibitor; CAR T-cell, chimeric antigen receptor T cell; CR, complete response; Nc BTKi, non-covalent BTKi; ORR, overall response rate; PD, progressive disease, PI3Ki, phosphoinositide 3-kinase inhibitor; PR, partial response; PR-L, partial response with lymphocytosis; SD, stable disease; ven, venetoclax

Post-ven
therapy

BTKi

PI3Ki

CAR T- cell therapy

Anti-CD20 antibody

Agent

Ibrutinib
Acalabr

Ibrutinib
Acalabr
Nc BTKi

Ibrutinib
Acalabr
Nc BTKi

Idelalisib
Duvelisib

Anti-CD19

Rituximab
Obinutuzumab
Ofatumumab

Prior exposure

BTKi-naïve

BTKi-exposed
BTKi-resistant

BTKi- exposed
BTKi-intolerant

PI3Ki-
naïve
BTKi-exposed

BTKi-exposed

–

Number of patients

44

20

10

17

18

19

ORR (%)

CR

PR

PR-L

SD

PD

83.9

9

56.8

18.1

11.6

4.5

53

6.6

26.4

20

20

27

70

20

30

20

–

30

46.9

5.9

35.2

5.8

23.7

29.4

66.6

33.3

33.3

0

5.7

27.7

32

16

16

0

32

37

• Discontinuation rates of subsequent therapies varied between treatments:
  • BTKi in BTKi-naïve patients – 38% (mainly due to CLL progression 21.4%, adverse event, transformation, planned cellular therapy, or other, all ~ 14%)
  • BTKi in BTKi-exposed patients – 38% (mainly due to CLL progression 66.6% and sudden death on treatment 16.6%)
  • PI3Ki – 78% (mainly due to CLL progression 58.3%, adverse event 25%, or transformation 16.7%)
  • Anti-CD20 antibodies – 72% (mainly due to CLL progression 62%, adverse event, or other both ~ 15%)
  • There were no discontinuations on CAR T-cell therapy
• PFS2 for patients treated with venetoclax followed by ibrutinib was not reached with a median follow-up of 22 months (24-month PFS was 78%)

Conclusion

The data support the early use of venetoclax in the course of CLL and demonstrate the importance of prior treatment exposure and reasons for discontinuation in decision making on the subsequent line of therapy. BTKi in patients who were BTKi-naïve or previously responsive and allo-HSCT were the most effective post-venetoclax treatments.

However, the author highlighted the limitations of the study, including a more heavily pretreated patient population, with a high number of patients who received venetoclax monotherapy, which might not be representative of patients seen in everyday clinical practice. As true venetoclax discontinuation might not have been captured and the relatively short follow-up, direct comparisons between therapies should not be made.