Selecting Treatment for Relapsed/Refractory CLL
The third patient was a 75-year old retired school teacher with comorbid hypertension and reflux disease. This patient’s CLL was diagnosed 5 years ago and treatment with ibrutinib was initiated 3 years ago for active del(17p) disease and was well tolerated without the need for dose adjustment. At the time of the review, the patient’s absolute lymphocyte count (ALC) was increasing and a 2 cm palpable cervical lymph node was detected. Other disease characteristics include TP53-mutated, IGHV-unmutated (0%), and BTK-mutated. The authors noted that the patient was becoming refractory to ibrutinib, and given the rising ALC while on ibrutinib and mutation in BTK (C481S), a new regimen was needed.
In this case, the authors options were limited because of the patient and disease characteristics. CIT is contraindicated due to mutated TP53 and switching to an alternative irreversible BTKi is also contraindicated due to presence of BTK mutation. An alternative inhibitor of the B cell receptor signaling pathway such as PI3-kinase is also not an option as it will probably prove ineffective. But BCL2i-based therapy with venetoclax has demonstrated durable responses in patients who develop BTKi-refractory CLL, and the authors felt that this was the best option for this patient. Continuous venetoclax monotherapy was initially approved for relapsed/refractory del(17p) CLL, and even though it has not been formally demonstrated in a randomized clinical trial, the authors felt that adding a CD20 monoclonal antibody (mAb) may improve the efficacy of venetoclax therapy, so rituximab was added to the regimen.
Median progression-free survival for relapsed/refractory del(17p) CLL is 24 months with venetoclax monotherapy but the addition of rituximab could improve that outcome. As this patients has very high disease, an allogeneic stem cell transplant (allo-SCT) should be considered as an option over the long term. Other options may include participation in a CD19-chimeric antigen receptor-T cell therapy clinical trial, reversible BTKi, or other novel strategies.
“Further progress in treatment for CLL will come with developing treatments that achieve a higher proportion of patients with uMRD remission with shorter fixed-duration treatment,” the authors wrote.
Commenting on the paper, Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at Mount Sinai in New York, New York, noted that venetoclax is considered a standard therapy for CLL. “We have the lucky problem of having many therapies to treat this disease,” he said. “Amazing progress has been made in the past 5 years.”
Even before the advent of all these new treatments, patients with CLL generally did pretty well. “Most patients lived for 10 or 20 years,” he said, “But then we also had high-risk patients who used to die within 2 years, before these new treatments were available. The high-risk patients were an unmet need.”
Many patients with CLL will now be able to stay in remission for years. “With venetoclax, it sometimes gives such a deep molecular remission, that they can stop taking it after 1 year,” Dr Brody explained.
“That sounds very appealing. But on the flip side, the BTK inhibitors been around a little longer and we have more ‘tried and true’ experience of how long remissions last, and they may be easier to take.”
Both options can be characterized as gentle when compared with other cancer therapies, and especially to chemotherapy. “We can use chemotherapy in these patients as well,” Dr Body added. “It works pretty well but most patients prefer the targeted therapies.
Wierda WG, Tambaro FP. How I manage CLL with venetoclax-based treatments [published online February 19, 2020]. Blood. doi: 10.1182/blood.2019002841
This article originally appeared on Hematology Advisor