Choosing Treatment for Relapsed CLL

Danielle Brander, MD:When considering second-line therapy for patients, I take into account multiple factors: the patient’s age and their functional status, their end organ function, what their goals of therapy are, and what their profile of prognostic markers looks like. Again, for patients who haven’t hadTP53dysfunction found in either deletion 17p orTP53mutation, testing for this is critically important as that will take you down a different route of considering options.

However, in general, in the second-line setting, patients who had chemotherapy as a first treatment are likely to have a much shorter duration of response if chemotherapy is used in the second-line setting. And this is increasingly why we’re using the novel targeted agents in the second-line setting over repeating chemotherapy, unless patients have a specific reason for the chemotherapy again or if they had a longer duration of response to chemoimmunotherapy as a first treatment.

For this patient who has a known deletion 17p—because she’s overall functional, wants a goal of treatment to keep her in a good quality of life for as long as possible, and she has sufficient organ function—I consider treatments that I think are going to get her the best response and the best duration of response. For her, ibrutinib was not tolerated and she progressed very quickly. Because she had a high burden of disease in the bone marrow as well, I considered venetoclax, as this is approved for patients with relapsed refractory CLL with the deletion of 17p in order to achieve a deep response, such as a complete response that hopefully will last her for many years.

BCL-2 has long been recognized as an important antiapoptotic protein. That is, it pushes cells away from the normal process of programmed cell death. When you target BCL-2, you take away that antiapoptosis and restore the normal process of cell death. Therefore, when venetoclax targets this protein, which is especially important in keeping the CLL cells in the antiapoptotic side, you push them more to the state of cell death.

Venetoclax has been studied in several phase I, II clinical trials for patients with previously treated or relapsed refractory CLL. In one of those studies, venetoclax was additionally combined with rituximab, and for those 49 patients, over half the patients achieved a deep complete response to their therapy, which was especially impressive given many of them had had several lines of prior treatment.

Transcript edited for clarity.

Case: An Older Patient with Relapsed CLL

March 2015

• A 70-year-old female reported symptoms of weight loss, fatigue, and pain in the upper left portion of her abdomen
• PE showed moderate axillary lymphadenopathy and splenomegaly, spleen palpated 7 cm below the costal margin
• Otherwise, the patient is overall well-appearing and continues to exercise
• Laboratory results:
  • WBC, 48,000; 73% lymphocytes
  • Hb, 10 g/dL (1 year ago Hb, 12 m/dL)
  • Platelets, 125,000/mm³(1 year ago platelets, 165,000/mm³)
  • ANC 1,800/mm³(WNL)
  • LDH, 250 U/L
  • Beta-2-microglobulin, 4.2 µg/L
• Cytogenetics by FISH showed 17p deletion in 56%
• IgVH unmutated
• Bone marrow biopsy; diffuse infiltration by CLL
• The patient was enrolled in a clinical trial and was treated with ibrutinib 420 mg daily
• After 18 months, she achieved complete remission of her disease and resolution of her symptoms

November 2017

• The patient developed had developed atrial fibrillation and despite cardiology interventions could not restart ibrutinib
• During routine follow up, the patient reported increasing fatigue
• PE: cervical lymphadenopathy, ~4 cm; spleen, palpable 8 cm below the costal margin
• Normal kidney function
• Laboratory results:
  • ALC; 112,000 cells/mL
  • Hb; 10.8 g/dL
  • Platelets; 105,000 cells/mm³
• The patient was started on venetoclax