With an updated median follow-up of 34.1 months, the 30-month progression-free survival (PFS) was 80.5% with ibrutinib plus venetoclax versus 35.8% for chlorambucil plus obinutuzumab in elderly or unfit patients with chronic lymphocytic leukemia (CLL) in the first line. These new findings evaluating the efficacy and safety of ibrutinib plus venetoclax as a potential fixed-duration treatment in adult patients were presented at the American Society of Hematology (ASH) annual meeting, held in Atlanta, Georgia from 11-14 December, 2021. Physician’s Weekly spoke with Dr. Talha Munir (Leeds Teaching Hospitals NHS Trust, UK) who presented these results [1].
The phase 3 GLOW study (NCT03462719) is a randomized, open-label trial that evaluated the efficacy and safety of first-line, fixed-duration ibrutinib plus venetoclax compared with chlorambucil plus obinutuzumab in elderly patients (≥65 years) with CLL, or patients ages 18-64 with a cumulative illness rating scale (CIRS) score >6 or creatinine clearance <70 mL/min. Cytogenetics excluded patients with del(17p) or pathogenic TP53 mutations. A total of 211 patients were randomized to receive either ibrutinib plus venetoclax (n= 106), or chlorambucil plus obinutuzumab (n=105).
New secondary endpoint data from the Phase 3 GLOW study showed that fixed-duration treatment with ibrutinib plus venetoclax resulted in undetectable minimal residual disease (uMRD) responses that were deeper compared to patients treated with chlorambucil plus obinutuzumab, and an additional analysis showed that uMRD responses were better sustained during the first year post-treatment.
The prespecified secondary endpoint was the rate of undetectable minimal residual disease (uMRD) responses, which was reported with cutoffs of < 10-4 and < 10-5, and was assessed at 3 and 12 months after end of treatment in either study arm. The authors reported that the PFS rate during the first-year post-treatment was sustained >90% with ibrutinib plus venetoclax, independent of BM or PB MRD status 3 months after end of treatment.
The authors reported that they observed deeper responses at end of treatment and better sustained uMRD responses during the first year post-treatment with all-oral, once-daily fixed-duration ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab. Further, responses were proportionally deeper at the level of < 10-5 in the ibrutinib plus venetoclax arm versus chlorambucil plus obinutuzumab arm in both peripheral blood (PB) and bone marrow (BM). Additional follow-up is warranted to confirm the long-term impact of MRD status on PFS.
With ibrutinib plus venetoclax, deep responses < 10-5 were seen in patients with unmutated IGHV CLL, and depth of response was mirrored in peripheral blood (49.1%) and bone marrow (45.5%).
Physician’s Weekly spoke interviewed Dr. Munir for specifics and context.
PW: What can we learn about older versus younger populations of patients?
Dr. Munir: This GLOW trial was a study primarily for elderly and unfit patients. I was looking at the comparison of the experimental arm, which is a combination of ibrutinib with venetoclax for fixed duration therapy, which is 3 months of ibrutinib followed by 12 months of a combination of ibrutinib with venetoclax versus chlorambucil obinutuzumab, which was the standard arm of the trial.
We looked at 211 patients, which were randomized one-to-one to receive either arm. An independent review committee confirmed progressive disease in all patients. Patents who had been randomized to the chlorambucil/obinutuzumab arm were allowed to receive ibrutinib, single-agent ibrutinib, upon progression. The primary endpoint of the trial was progression-free survival and this abstract was primarily looking at the minimal residual disease response, assessed with our next generation sequencing. Then we looked at the concordance in the bone marrow and the peripheral blood, and then we also updated the progression-free survival data for this update.
We found, in terms of progression-free survival, that with a median follow-up of 34.1 months, the 30 months estimated PFS was 80.5% in the ibrutinib/venetoclax arm and 35.8% in the chlorambucil/obinutuzumab arm. The hazard ratio was significant at 0.216 with a p-value <0.001.
The overall survival data was also updated and the hazard ratio is 0.76, in favor of ibrutinib/venetoclax, although the numbers are really too small to claim a difference. There were 11 deaths in the ibrutinib/venetoclax arm as compared with 16 in the chlorambucil/obinutuzumab arm. In terms of the MRD results, with next generation sequencing, we found that nearly 52% of the patients were MRD negative in the bone marrow and 55% in peripheral blood in the ibrutinib/venetoclax arm. But when we looked deeper with the next generation sequencing, we found that nearly two-fifths of the patients were achieving very deep remission in the ibrutinib venetoclax arm. All the pre-specified groups were benefiting from the ibrutinib venetoclax arm of the study.
But the other intriguing finding was that the main patients who were getting undetectable MRD with unmutated IGHV, which are high-risk patients as compared to the mutated IGHV patients. So that’s good news for that subset of patients. I think that is a very important finding that these patients are benefiting the most from this combination of therapy.
PW: How can you explain that biologically?
Dr. Munir: I think these are two very different drugs. Ibrutinib primarily works in the microenvironment, in the bone marrow as well as the nodes, as well as the spleen, and moves the CLL cells out in the peripheral blood. But a lot of the unmutated IGHV cancer cells need very little stimulation to proliferate and ibrutinib is very good at blocking those proliferation signals, whereas venetoclax is very good at killing cells, so it is a pro-apoptotic drug.
I think the synergistic mechanism of these drugs working into compartments is most probably the reason we are seeing very deep rates of MRD negativity within the unmutated IGHV patients, whereas where the proliferation is not very high in mutated IGHV patients, the ibrutinib most probably has not got the similar impact and that’s why we see slightly lower rates. But again, the mutated IGHV patients, as we know, from all studies have benefited from ibrutinib as well. But it is an intriguing finding and I think we need to do more research to find out why this subset is benefiting the most.
PW: Could you compare and contrast with the CAPTIVATE study?
Dr. Munir: I think CAPTIVATE used the same principle, but after a year of therapy, there was a division in the two cohorts. One was a fixed duration cohort and then there was an MRD driven cohort. Both trials are primarily looking at this combination of drugs, and actually, the data for unmutated IGHV is pretty similar in the fit population, as well as the unfit population. Their data is pretty concordant.
The tolerability is very good for both studies. I think the main issue in the elderly population is some cardiac toxicity that we see with ibrutinib, and there were some patients initially who did not tolerate ibrutinib very well in the initial part of the study, but for the majority of the patients, this combination is very potent and it’s very well tolerated.
In both cases, once the ibrutinib, once you finish the combination, whether you go onto the placebo arm or ibrutinib arm of the CAPTIVATE study, the progression-free survival was in excess of 90%, 12 months after stopping therapy. So it looks like the durability of the response appears to be very good with this combination, at least with 1 year of follow-up that we are seeing in both trials.
So we’re seeing very similar data, very similar kinds of responses. There’s no major difference that we are seeing. I think the tolerability of the combination will be dependent on the individual side effects of the individual drugs we are using in this combination.
PW: What are the next steps?
Dr. Munir: We have shown that the MRD is durable at 1 year post follow-up, and we want to see the durability later on as well, that that response continues, and whether the MRD is an important marker to look at the progression-free survival or not. At 1 year follow-up, it doesn’t appear to be but it might change over time.
We are going to collect more data to see the sustainability of the response with this combination. And if say in a year’s time or 2 years, unmutated IGHV patients are most probably still in remission and have not progressed, then it looks like that this is a very good combination for this subset of patients.
References
- Munir T. et al. First Prospective Data on Minimal Residual Disease (MRD) Outcomes after Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O) for First-Line Treatment of CLL in Elderly or Unfit Patients: The Glow Study. 2021 American Society of Hematology Annual Meeting. December 2021, Abstract 70.
