Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and BCL2 inhibitor venetoclax have been very successful as individual therapies for treating chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Still, on their own, they rarely lead to the eradication of measurable (a.k.a. minimal) residual disease (MRD). Therefore, researchers are very interested in whether they can combine these therapies with improving patient outcomes and achieving better remissions while also limiting the time patients have to spend on treatment.
At the American Society of Hematology (ASH) 2021, our own Dr. Brian Koffman interviewed Dr. Talha Munir, a hematologist at St. James’s University Hospital in Leeds, United Kingdom. They discussed the latest results from the GLOW study, a phase 3 clinical trial which compared fixed-duration ibrutinib + venetoclax with chemoimmunotherapy (chlorambucil + obinutuzumab) as a first-line treatment.
- The GLOW study was primarily for patients with untreated CLL and other concurrent diseases or conditions.
- Patients received either:
- Experimental: Ibrutinib + venetoclax for 12 cycles (~1 year)
- Standard of care: chlorambucil + obinutuzumab
- Previously presented results from this study had shown that ibrutinib + venetoclax provided better progression-free survival than chlorambucil + obinutuzumab.
- Researchers also tested for measurable residual disease (MRD) in the blood and bone marrow using next-generation sequencing, which can detect 1 CLL cell in 100,000 cells.
- In the ibrutinib + venetoclax group, 2 out of 5 patients (40.6%) had undetectable measurable residual disease (uMRD) in their bone marrow.
- Only 1 in 13 patients (7.6%) in the chemoimmunotherapy group reached uMRD.
- MRD results were very similar between the bone marrow and the peripheral blood, suggesting that measuring MRD in the blood may be sufficient rather than taking repeated bone marrow samples.
- With ibrutinib + venetoclax treatment, uMRD at three months was sustained at 12 months after the end of treatment.
- Interestingly, over 90% of patients treated with ibrutinib + venetoclax were progression-free 12 months after the end of treatment, irrespective of whether they still had detectable MRD.
- In contrast, patients in the chlorambucil + obinutuzumab arm with detectable MRD relapsed more quickly than those with uMRD.
Since the GLOW trial was designed, it has become quite clear that targeted therapies like ibrutinib and venetoclax are much more effective than chemoimmunotherapy, so it is not surprising that the combination of ibrutinib + venetoclax beat chlorambucil + obinutuzumab as a first-line treatment. These results complement those of the phase II CLARITY study, which looked at fixed-duration ibrutinib + venetoclax for treating relapsed/refractory CLL and achieved similar rates of uMRD. Interestingly, the ongoing phase 3 GAIA (CLL13) study has data suggesting that while the triple combination of ibrutinib + venetoclax + obinutuzumab is very effective at producing high rates of uMRD, it may not provide any significant benefit over combination venetoclax + obinutuzumab. In summary, all of these studies show that fixed-duration ibrutinib + venetoclax is an effective therapy. However, while it is better than chemoimmunotherapy, the jury is still out on whether it is better than other targeted therapy combinations.
Please enjoy this interview with Dr. Munir from the ASH meeting, which was held in December 2021 in Atlanta, GA.
You can read the actual abstract here: 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
Take care of yourself first.
Ann Liu, PhD