CLL/SLL

EHA 2019 | Ibrutinib in early and late CLL: news from EHA

At the 24th annual Congress of the European Hematology Association (EHA), Amsterdam, NL, use of ibrutinib in early and late chronic lymphocytic leukemia (CLL) was discussed. On Friday 14 June 2019 session, Arnon P Kater from the University of Amsterdam, Amsterdam, NL, presented on the safety of venetoclax and ibrutinib in patients with relapsed/refractory (R/R) CLL from the phase II VISION/ HOVON 141 (HOV141) trial.1 While Petra Langerbeins from the University of Cologne, Köln, DE, on Sunday 16 March 2019, discussed the results of phase III CLL12 trial on ibrutinib versus placebo in patients with asymptomatic, treatment-naive early-stage CLL.2

Ibrutinib is a therapy designed to target Bruton’s tyrosine kinase, which is essential for the survival of CLL leukemia cells. Therefore, unlike standard chemotherapy, ibrutinib is directed specifically against cancer cells and should not affect normal cells. Ibrutinib-based therapy is already a standard of care for R/R patients with CLL and is becoming popular as a frontline for high risk or older patients. However, questions remain regarding its toxicity profile and its efficacy for asymptomatic patients with intermediate to very high risk of progression.

Ibrutinib in indolent disease

Currently, it is not clear whether patients with inactive indolent CLL would benefit from early treatment. The placebo-controlled, double-blind phase 3 study, CLL12, aimed to assess whether ibrutinib, would benefit asymptomatic, treatment-naive patients with increased risk of progression, in terms of improved efficacy with low toxicity.

Table 1. Study design and patient characteristics.

Trial number

NCT02863718

Treatment

Ibrutinib (420 mg daily) or placebo

Patient population

Asymptomatic Binet A patients with intermediate to very high risk of progression

Endpoints

Primary

EFS

Secondary

PFS, TFS, TTNT, ORR, and safety

Patients

Ibrutinib n = 182

Placebo n = 181

Median age (range)

Ibrutinib 64 years (38–85)

Placebo 64 years (36–80)

EFS, event free survival as time to symptomatic progression, CLL treatment and/or death; ORR, overall response rate; PFS, progression free survival; TFS, treatment-free survival; TTNT, time to next treatment;

Key findings
  • Primary median EFS was not reached (NR) in the ibrutinib arm and was 47.8 months in the placebo arm (HR 0.25; 95% CI, 0.14–43; P<0.0001)
  • Median PFS was NR with ibrutinib arm and 14.8 months with the placebo (HR 0.18; 95% CI, 0.12–27)
  • TTNT was also longer in the ibrutinib arm (HR 0.21; 95% CI, 0.11–39)
 Tolerability and safety
  • Median treatment duration - ibrutinib 21 cycles and placebo 18 cycles
  • 1% of patients discontinued treatment in the ibrutinib arm versus 45.9% in the placebo arm
  • Main reasons for discontinuation were:
  • PD - for 45% of patients on placebo and 2% on ibrutinib
  • AE - for 26% of patients on placebo and 52% on ibrutinib
  • Non-compliance - for 8% of patients on placebo and 10% on ibrutinib
  • Other - for 2% of patients on both placebo and ibrutinib

AEs of clinical interest with significant difference between study arms:

  • bleeding - 27.6% in the ibrutinib arm and 9.6% in the placebo arm (P = 0.0001; CTC ≥ 3 3.2 and 1.2, respectively)
  • atrial fibrillation - 17.8% in the ibrutinib arm and 7.3% in the placebo arm (P = 0.003; CTC ≥ 3 6.5 and 1.7, respectively)
  • hypertensive disorders – 9.7% in the ibrutinib arm and 3.9% in the placebo arm (P = 0.04; CTC ≥ 3 6.5 and 1.7, respectively)

Table 2. Adverse events (AEs) affecting ≥ 5% of study population.

 

Ibrutinib

(n=185)

Placebo

(n=178)

Any grade AEs (%)

152 (82.2)

151 (84.8)

AEs > grade 3 (%)

80 (43.2)

69 (38.8)

Serious side effects (approx. %)

Infections

Neoplasms

Cardiac disorders

Nervous system disorders

Musculoskeletal disorders

 

11

6

9

5

5

 

12

11

7

4

4

AEs leading to interruption (%)

Arrhythmias

Bleeding

77 (41.6)

18

8

38 (21.3)

0

1

Fatal AEs* (%)

Treatment related

4 (2.2)

0

5 (2.8)

0

*, death of unknown cause (n=4), infection (n=2), cardiac failure (n=1). 

Ibrutinib in R/R CLL

Although ibrutinib has proven feasibility in R/R CLL, existing treatment options are either based on continuous treatment or fixed-duration of treatment, regardless of response. This approach may result in unnecessary prolonged treatment, or development of resistance. Post-treatment minimal residual disease (MRD) predicts outcome in patients on chemo-immunotherapy. The rationale behind the HOV141, a prospective, multi-center study, was to evaluate the feasibility of MRD to guide treatment in patients with R/R CLL after induction therapy with the combination of ibrutinib and venetoclax.

Table 3. Study design and patient characteristics.

Trial number

NCT03226301

Treatment

Induction

 

Ibrutinib (420 mg daily) pre-treatment for 2 cycles, followed by combination of ibrutinib + venetoclax (final dose 400 mg daily) for 15 cycles

Maintenance

Patients with uMRD after the induction randomised to ibrutinib or observation

Patient population

Predominantly male (71%) patients with creatinine clearance ≥30 ml/min, with previously treated CLL, of which were 33% Binet stage C

Endpoints

Primary

PFS at 12 months after therapy

Secondary

MRD eradication*, ORR, OS, and safety

Patients

n = 207 (data from first 51 patients included here)

Median age (range)

67 (40–83)

*, <0.01% CLL cells; MRD, minimal residue disease by flow cytometry <10-4; OS, overall survival; uMRD, undetectable MRD; 

Key findings
  • After 9 cycles of ibrutinib plus venetoclax 61% of patients achieved complete remission (CR)
    • 6% CR had incomplete hematologic recovery
    • partial response was seen in 29% of patients
    • 4% had unknown clinical response
  • MRD status at the end of cycle 9 and 12 are described in table 4.

Table 4. Percentage of patients with MRD result by time point (n = 42)

 

Baseline

End of cycle 9

End of cycle 12

uMRD

<10-4

-

33%

52%

Low MRD+

(10-4–10-2)

-

43%

31%

High MRD+

(≥10-2)

100%

24%

17%

NA, not available; uMRD, undetectable minimal residue disease;

Tolerability and safety 
  • All of 51 patients completed the first 2 cycles with ibrutinib alone, 48 completed cycle 3 with ibrutinib and escalation of venetoclax, 43 completed all 9 cycles
  • Main reasons for discontinuation were; treatment of other malignancy, refusal to continue, and excessive toxicity (2 patients each)
  • One patient died of unknown cause and one was intolerant to ibrutinib

AEs of clinical interest:

  • Tumor lysis syndrome (TLS) - 10% of patients with laboratory TLS without clinical toxicity during the venetoclax escalation, these patients had increased baseline risk of TLS
  • Bleeding (grade 2) - 8% of patients during cycles 2, 6 and 9
  • Atrial fibrillation (grade 2) - 8% of patients during cycles 4 to 6

Table 5. Adverse events (AEs).

Any grade AEs

N = 147

AEs > grade 3 occurring in >5% population

N = 55

Side effects (%)

Neutropenia

Infections

Metabolism and nutrition disorders

Gastrointestinal disorders

Blood and lymphatic system disorders (excluding anemia)

 

36

20

8

8

6

Summary

Overall, the data presented shows that ibrutinib improved EPS, PFS, and TTNT in high-risk patients with asymptomatic, treatment-naive early-stage CLL, when compared with placebo control. The toxicity profiles were comparable between both study arms with the exception of increased risk of atrial fibrillation, bleeding, and hypersensitive disorders in the ibrutinib arm. Similarly, in patients with the R/R CLL, the combination of ibrutinib and venetoclax, improved remission rates, increased levels of uMDR proportionally to the number of therapy cycles, and was well tolerated. 

Infection was a common AE in both studies, bleeding and atrial fibrillation were more prevalent in indolent patients, while TLS was only reported in R/R patients. Therefore, the data suggest that ibrutinib offers benefit in asymptomatic, early-stage CLL patients with increased risk of progression, as well as in later stages in the R/R setting, with good toxicity profiles.

References
  1. Kater AP, et al. Safety analysis of venetoclax and ibrutinib for patients with relapsed/refractory chronic lymphocytic leukemia (r/r cll): second interim analysis from the phase II VISION HO141 trial. Abstract #S108: 24th EHA Congress, Amsterdam, NL  
  2. Langerbeins P, et al. Ibrutinib versus placebo in patients with asymptomatic, treatment-naïve early stage chronic lymphocytic leukemia (CLL): primary endpoint results of the phase 3 double-blinded randomized CLL12 trial. Abstract #LB2602: 24th EHA Congress, Amsterdam, NL

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