The current FDA-approved, standard-of-care for frontline chronic lymphocytic leukemia (CLL) therapy includes continuous therapy with a Bruton tyrosine kinase inhibitor (BTKi) such as ibrutinib or acalabrutinib, with or without an anti-CD20 antibody, or one-year fixed duration therapy with venetoclax plus obinutuzumab. Now, because of non-overlapping mechanisms of action, BTKi and venetoclax combination strategies are being actively studied in the frontline setting. The goals of several recent trials are to utilize ibrutinib plus venetoclax (I plus V) strategies in time-limited designs with the goals to achieve deep response (i.e., undetectable minimal residual disease [uMRD]) and durable progression-free survival (PFS). Updated results of several I plus V combination studies1,2,3,4 were presented at ASH 2022, showing promising uMRD and PFS results. The main features of these important new reports are presented here to help provide some context on this combination for frontline CLL.
To begin with, we will summarize the key findings of the 4 abstracts evaluating I plus V at ASH 2022.
- In the MD Anderson I plus V phase 2 study, 120 patients (age ≥65, or TP53 disruption, or del 11q, or unmutated IGHV) were treated with ibrutinib and venetoclax (24 cycles of combination, with an additional 12 cycles allowed if MRD positive by cycle 24). The 4-year follow-up data showed that the rate of uMRD (<10-4 by multicolor flow cytometry) in the bone marrow (BM) was 52% and 64% after 12 and 24 cycles of combination therapy, respectively. The 4-year PFS rate was 94.5%.1
- The randomized phase 2 CAPTIVATE trial enrolled 164 patients (age <70), and 159 patients were treated with I plus V. After 12 cycles of combination therapy, the best uMRD (<10-4 by 8-color flow cytometry) rate was 75% in the peripheral blood (PB) and 68% in the BM.5 86 (58%) patients had confirmed uMRD (at least two uMRD in PB ≥3 months apart and confirmed in BM) and were randomized between ibrutinib versus placebo for continued treatment. With a median follow-up of 41 months post-randomization, the sustained uMRD rate at 1-, 2-, and 3-years post-randomization was 77%, 60%, and 63% in the ibrutinib arm, and 84%, 56%, and 58% in the placebo arm. The 4-year PFS rate was 95% in the ibrutinib arm and 88% in the placebo arm.2
- The randomized phase 3 GLOW trial randomized 211 patients (age ≥65, or CIRS >6, or CrCl <70mL/min, without TP53 disruption) between I plus V (12 cycles of combination) versus chlorambucil plus obinutuzumab (6 cycles). In the I plus V arm, at 3 months after end of treatment, the uMRD (<10-4 by next generation sequencing) rate was 54.7% in PB and 51.9% in BM.6 With 4 years of study follow-up, the sustained PB uMRD rate was 49% and 37.7% at 12 months and 27 months after end of treatment, respectively. The 42-month PFS rate was 74.6% in the I plus V arm.3
- The randomized phase 3 FLAIR trial enrolled patients fit for FCR chemoimmunotherapy (age ≤75) and without TP53 deletion by FISH (≤20%) and included ibrutinib (6 years maximum) versus I plus V (2-6 years based on uMRD results) arms. At the interim analysis with the first 274 patients reaching 2 years post-randomization, the uMRD (<10-4 by 8-color flow cytometry) rate within 2 years was 71.3% in PB and 65.4% in BM in the I plus V arm. No uMRD was observed in the ibrutinib arm.4
Collectively, these results demonstrated that time-limited therapy with I plus V can induce a reasonably high rate of uMRD that appeared to be somewhat sustained in the first few years after treatment discontinuation, and the early PFS results appear encouraging. Is there another side to this coin, however?
While these efficacy results are overall encouraging, an important question is how they compare to data of our current approved therapies, i.e., continuous BTKi-based therapy and fixed duration venetoclax plus obinutuzumab therapy. It is clear that I plus V can induce a much higher rate of uMRD compared to BTKi-based therapy alone, but longer followed-up of the I plus V studies are needed to evaluate the PFS data. Multiple frontline studies of BTKi-based therapy (RESONATE-2, iLLUMINATE, ECOG E1912, Alliance A041202, ELEVATE-TN) now have more mature data showing a PFS rate of 75-85% at 4-5 years. The median PFS in the RESONATE-2 study will be approaching 8 years.7 Long term follow-up data from the I plus V studies are important to determine whether time-limited therapy achieving uMRD can result in prolonged PFS comparable to that of continuous BTKi-based therapy. The comparison of I plus V with venetoclax plus obinutuzumab is perhaps more interesting. The CLL14 study 8 reported a PB uMRD (<10-4) rate of 61.1% using flow cytometry and 75.5% using allele-specific oligonucleotides PCR, and a 5-year PFS rate of 62.6% (reported at EHA 2022). The uMRD rates with I plus V do not appear substantially higher than the results of venetoclax plus obinutuzumab, and longer follow-up is needed to evaluate how the PFS results compare to each other, with the caveat that the four I plus V studies had different inclusion criteria and their patient populations may differ from the CLL14 study population. Certainly, these cross-trial comparisons are not ideal. The CLL17 (ibrutinib vs venetoclax plus obinutuzumab vs I plus V) and the MAJIC (acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab) trials will eventually address the questions of comparative efficacy and whether BTKi and venetoclax should be used in combination in the frontline.
The use of MRD in these important trials is crucial in helping to make treatment decisions and obviously impact on the clinical results. However, there is a great need to standardize the methodology, timing, and what sites (blood, bone marrow, or both) are being tested in these trials. There is also the issue of sensitivities of the MRD assay and what the cutoffs will be for determining MRD negativity.
Another important question in considering I plus V combination therapy is the optimal duration of therapy. An arbitrarily predetermined duration of therapy for all patients is likely, not ideal. Many patients achieve uMRD with only 6 cycles of combination therapy.1,3 On the other hand, the MD Anderson I plus V study showed deepening MRD responses from 1 year to 2 years and from 2 years to 3 years of combination therapy, suggesting some patients may benefit from additional therapy to achieve deeper responses.1 An MRD-guided approach in determining the duration of therapy is therefore plausible, and is being used in the FLAIR trial and the MAJIC trial. One caveat, though, is that uMRD might not be the best endpoint for all patients. In all the I plus V combination studies described above, uMRD rate was higher in patients with unmutated IGHV. 1,3,4,5 However, unmutated IGHV was still associated with inferior PFS in patients treated with I plus V in the GLOW trial!3 We would suggest that an MRD-guided approach may need to be utilized in combination with clinical treatment response and molecular risk adaptation.
Toxicity for the doublet approach also needs to be addressed. Compared to ibrutinib alone, I plus V can cause more cytopenia and GI toxicities.4 The doublet can be very difficult for elderly or frail patients to tolerate. In the GLOW trial,6 in the I plus V arm, 68.9% of the patients had ≥1 Grade 3 or above adverse events, including 34.9% with neutropenia, 15.1% with infections, 10.4% with diarrhea, 7.5% with hypertension, and 6.6% with atrial fibrillation. Importantly, 7 (6.6%) patients had treatment-associated mortality, mainly from cardiovascular and infectious complications, compared to only 2 (1.9%) patients in the chlorambucil plus obinutuzumab arm. This increased early mortality is very concerning and highlights the critical importance of careful patient selection when considering I plus V doublet treatment for CLL.