Combinatorial Novel Agent Therapy

In a phase 2 trial of ibrutinib plus venetoclax, 88% of patients had a complete response at 12 months, and 61% had undetectable minimal residual disease. Although long-term trials are still needed, a BTK inhibitor in combination with a BCL2 antagonist is appealing due to the shorter treatment duration and potential for improved survivorship. Data from an anticipated randomized trial are forthcoming.

Toxicity and Resistance

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At the start of treatment with BTK inhibitors, some patients develop lymphocytosis, causing their white blood cell count to increase by a factor of 2 or more. This side effect may persist for more than 12 months, although typically resolves during the first months of therapy.7 The most frequent negative side effects of BTK inhibitors include diarrhea, myalgia, arthralgia, bruising, and bleeding. A minority of patients develop atrial fibrillation (ibrutinib, 6.5% at 16.6 months; acalabrutinib, 5% at 16.1 months).

During initial trials of the BCL2 antagonist, some patients developed severe tumor lysis syndrome. Due to these observations, venetoclax is administered at a low dose with a slow ramp-up period and includes strict monitoring to avoid tumor lysis syndrome among recipients.

Secondary resistance to BTK inhibitors, which occurs early in the first year of therapy, may be caused by Richter transformation. Such resistance is often linked to mutations in BTK, causing a point mutation (C481S) at the binding site, a mutation in PLCG2, which codes for phospholipase C gamma 2, or a mutation in both genes.

In general, patients are more likely to be ineligible for molecular targeted therapies due to unacceptable adverse reactions rather than due to resistance to therapy.


The CLL therapeutic landscape has changed drastically in recent years because of improved understanding of the disease from basic research into cell signaling pathways and the CLL microenvironment. “Rather than just relying on anti-proliferative or DNA damaging activity of classical chemotherapy, which damages both cancer cells and many other cells in the body, we are now able to better target the disease itself,” Dr Burger said. The challenge going forward for CLL treatment is to reduce drug exposure and toxic effects of the molecular-targeted therapies.

Disclosure: The author declared affiliations with industry. Please refer to the original article for a full list of disclosures.


  1. Burger JA. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020;383(5):460-473. doi:10.1056/NEJMra1908213.
  2. Byrd JC, Furman RvR, Coutre SvE, et al. Targeting BTK with ibrutinib in relapsed chronicv lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42. doi:10.1056/NEJMoa1215637
  3. O’Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131(17):1910-1919. doi:10.1182/blood-2017-10-810044
  4. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388
  5. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x
  6. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (Pts) with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134:31. doi:10.1182/blood-2019-128404
  7. Woyach JA, Smucker K, Smith LL, et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood. 2014;123(12):1810-1817. doi:10.1182/blood-2013-09-527853

This article originally appeared on Hematology Advisor