Second-Line Treatment in Chronic Lymphocytic Leukemia

Jeff Sharman, MD: After first-line treatment, what is the trigger to start second-line therapy in CLL? Again, the same indications that we talked about for first-line therapy are true in second-line therapy: rapid progression of lymphocyte count, symptomatic bulky lymph nodes, emergence of bone marrow dysfunction. Those are true in both the front-line and relapsed refractory setting.

When you’re considering treatment for patients with therapy in the relapsed setting, that’s going to be strongly influenced by what they received in the first-line setting. For a patient such as this with the deletion of 17p, you don’t have a whole lot of options. They would include venetoclax in combination with rituximab, similar to the MURANO study, or idelalisib and rituximab. Because this patient has significant chronic kidney disease, the risk of tumor lysis is quite high.

Furthermore, we know that if there’s a sweet spot for PI3 kinase inhibitors, it tends to be in that older population with significant medical comorbidities. I think this is a great patient for whom to consider idelalisib-rituximab. It wouldn’t be wrong to pick rituximab with venetoclax; however, it would need to be very carefully monitored for risk of tumor lysis, likely even admitting that patient to the hospital for the first several dose levels. With some 79-year-old patients, that’s a difficult proposition to make, so I think in this particular case starting idelalisib-rituximab would be very reasonable.

We’re asked to comment on the patient’s status at the current time. Does his risk status matter? The answer is yes. We’re probably going to get about a year and a half median progression-free survival for idelalisib-rituximab. The question will be what to do next.

In a 79-year-old, perhaps other medical comorbidities may limit survival beyond that, but this is a patient where if the next therapy is going to be venetoclax-based treatment, I don’t want that patient to develop bulky adenopathy before transitioning to that therapy because the risk of tumor lysis may be too great.

Regarding next treatment options, there are clinical trials in this space looking at BTK inhibitors that may work even after a prior BTK inhibitor has stopped working. LOXO305 is one potential option, and ARQ 531 is another BTK inhibitor that could work in this space. If the patient is able to travel for a clinical trial, that might be an option.

Transcript edited for clarity.

Case: A 79-Year-Old Man With Relapsed Chronic Lymphocytic Leukemia

Initial presentation

• A 79-year-old man presented to a new medical oncologist for the first time complaining of vague intermitted abdominal pain, and progressive fatigue
• PMH:
  • Hypertension, medically controlled
  • MI, 8 years ago, on 81 mg aspirin
  • CLL, diagnosed 7 years ago
  • After a period of watchful waiting he began treatment with ibrutinib 420 mg PO qDay; symptoms improved and achieved stable disease, resolution of lymphadenopathy
  • After 5 years of disease control on ibrutinib he complained of increasing fatigue and decreased appetite, on physical exam there was return of palpable lymphadenopathy; spleen was palpable ~4 cm below costal margin
  • He was started on rituximab
  • Currently after 6 months on rituximab monotherapy he presents to the clinic
• PE: palpable bilateral cervical and right-sided inguinal lymphadenopathy
  
  

Clinical workup

• Labs: WBC 55,000, lymphocyte 82%, ANC 3100/mm3, Hb 9.4 g/dL, plt 90 x 109/L, LDH 220 U/L, Beta-2-microglobulin 3.9 mg/L; creatinine clearance 31 mL/min
• FC CD 5+, CD19+, CD20+ monoclonal B-cell population
• FISH: CLL probe set tested, deletion 17p
• IgHV mutational status: unmutated
• Rai stage IV; ECOG PS 1
• Treatment of idelalisib 150 mg PO BID was added to rituximab