Venetoclax in chronic lymphocytic leukemia (CLL)

During the 24^th European Hematology Society (EHA) meeting and the 15^th International Conference on Malignant Lymphoma (ICML), two abstracts from the CLL14 trial were presented, comparing obinutuzumab + chlorambucil (ClbG) to obinutuzumab + venetoclax (VenG) in patients with chronic lymphocytic leukemia (CLL).^1,2 Additionally, a study was recently published in the New England Journal of Medicine, investigating the combination of ibrutinib + venetoclax in high-risk and older patients with CLL.³ This article looks at the use of venetoclax in CLL, analyzing the potential impact of these recent updates.

The CLL14 trial

• Patients with untreated, active CLL and coexisting medical conditions (N = 432) were randomized 1:1, following chromosome analysis (N = 397), to either:¹
• ClbG (6 cycles) followed by chlorambucil (6 cycles); n = 197
• VenG (6 cycles) followed by venetoclax (6 cycles); n = 200
• Patient characteristics are shown in Table 1
• Genetic testing was conducted by next-generation sequencing for common mutations such as TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, POT1 AND XPO1²
• Primary endpoint: progression-free survival (PFS)¹
• Secondary endpoints included; response, minimal residual disease (MRD) and overall survival (OS)¹

The first abstract was presented by Othman Al-Sawaf, at EHA, and Kirsten Fischer at ICML, and featured a prospective analysis from the CLL14 trial comparing responses to ClbG and VenG in patients with complex karyotype (CKT) or a non-complex karyotype (NCKT).¹ In this study, a CKT was defined as the presence of three or more chromosomal abnormalities. Having a CKT is an adverse prognostic factor and affects approximately 10–30% of patients with CLL.¹ The second abstract, presented by Stephan Stilgenbauer at EHA, and Eugen Tausch at ICML, investigated the results of the CLL14 trial based on genetic subgroup.²

Responses rates by karyotype, and MRD rates in peripheral blood and bone marrow (BM), are shown in Table 2, with PFS rates by genomic aberrations in Table 3 and Table 4.

• In the VenG arm, response rates were comparable between CKT and NCKT
• This is also true for MRD negativity in the VenG arm in both peripheral blood and BM
• VenG may overcome the adversity of a complex karyotype

OS:¹

• ClbG: HR: 3.736 (95% CI, 1.357–10.287), P = 0.006
• VenG:HR: 1.511 (95% CI, 0.496–4.600)
• No difference in OS between arms, at this early stage

• Higher PFS for the VenG arm compared to the ClbG arm
• ClbG: patients with del(17p), del(11q) and +12q had a shorter PFS
• VenG: del(17p) remains prognostic, though other genetic subgroups did not affect PFS

This study found IGHV was a predictive factor for response, as patients without mutated IGHV had better responses, as shown by multivariate analysis:

• IGHV^wt vs IGHV^mut: HR: 3.475 (1.963–6.154, P < 0.001)
• Venetoclax, VenG, is especially efficacious in IGHV unmutated patients

Ibrutinib + venetoclax

Recently, the results of a phase II study (NCT02756897), published in the New England Journal of Medicine, by Nitin Jain and colleagues, reported on the combination of venetoclax with ibrutinib in patients with previously untreated CLL who were high-risk, or older. It was hypothesized that ibrutinib and venetoclax may have a synergistic mechanism of action.³

This study was an open-label, investigator-led study with a median follow-up of 14.8 months (N = 80). The median patient age was 65 (26–83) with 30% of patients over the age of 70. All had one of the following features; del(17p), TP53-mut, del(11q), IGHV^wt or were over the age of 65. Overall, 92% had either del(11q), TP53^mut or IGHV^wt.

Treatment regimen

• Ibrutinib monotherapy: 420mg once daily, 3 cycles
  • Aim: reduce venetoclax-associated tumor lysis syndrome
• Venetoclax, once daily, from cycle 4, with a weekly dose escalation to 400mg
• Combination therapy for 24 cycles
  • If MRD negative at the end of 24 cycles, patients could continue ibrutinib monotherapy until disease progression (PD) or unacceptable toxicity
• Antiviral prophylaxis was administered to all patients 

Efficacy

• Responses were measured as complete remission (CR), CR with incomplete blood count recovery (CRi) and remission with undetectable MRD in BM
• Responses were seen in all subgroups, and increased over time (Table 5)
• Notably, there were high responses rates in patients over the age of 65
• Three patients completed 24 cycles, all of whom had CR, or CRi, with undetectable MRD in the BM

• Estimated 1-year PFS: 98% (95% CI, 94–100)
• Estimated 1-year OS: 99% (95% CI, 96–100)
• No patient experienced CLL progression
• One death occurred, with the treating physician and first author agreeing this was not due to ibrutinib treatment
• No clinical tumor lysis syndrome was seen, though three patients had laboratory evidence
• In total, 11 patients discontinued treatment at the following stages:
• Ibrutinib monotherapy; n = 5
• Combination therapy; n = 6

Safety

• Toxic adverse events grade ≥3 were seen in 60% of patients
• Most common non-hematologic events were: easy bruising, arthralgia and diarrhea
• Hematologic events:
• Grade 3–4 neutropenia: 48%
• Grade 3 thrombocytopenia: 2%
• Dose reductions:
• Ibrutinib: 44% (35/80)
  • Mainly due to atrial fibrillation (n = 9), neutropenia (n = 5) and rash (n = 5)
• Venetoclax: 24% (18/75)
  • Predominantly due to neutropenia (n = 12)

Conclusion

The two analyses from the CLL14 trial concluded that a CKT is associated with a shorter PFS and OS, regardless of TP53 status in patients treated with chemoimmunotherapy. However, there was no difference in PFS and OS in patients treated with VenG, regardless of karyotype. The authors concluded that fixed duration VenG treatment can overcome the negative prognostic value of CKT in patients with untreated CLL and the regimen is well-tolerated in patients with comorbidities.¹ Additionally, VenG is superior to ClbG in all genetic subgroups, though del(17p) and TP53^mut are both adverse prognostic factors for PFS in patients, including those treated with VenG. Venetoclax was found to be particularly effective in patients with unmutated IGHV.²

Furthermore, the addition of venetoclax following ibrutinib monotherapy led to the conversion of partial responses into complete responses, and an increase in patients with undetectable MRD in the BM. No new toxic adverse events were observed, and notably, rates of grade 3–4 neutropenia were comparable between patients <65 and ≥65. These results indicate that combination therapy may present a viable, efficacious, option for older or high-risk patients with previously untreated CLL.³

Based on these studies, venetoclax is emerging as a viable treatment option for previously untreated CLL, including in older patients and those with high-risk features and comorbidities.