Understanding the Trial With Idelalisib and Rituximab

Jeff Sharman, MD: Idelalisib is a PI3 kinase inhibitor. Therefore, it is differentiated from the BTK inhibitors or the BCL2 inhibitors. Idelalisib inhibits PI3 kinase, which is one of the proximal signaling molecules in the B-cell receptor signaling pathway. In that particular study, idelalisib clearly outperformed rituximab. It was a combination ofidelalisib and rituximab versus rituximab alone.

The combination clearly outperformed rituximab monotherapy, so in this particular patient, having them started on rituximab monotherapy might be one place where I would differ from prior management. Had that patient been in my practice at the time, I probably would have gone straight to the combination of idelalisib and rituximab.

The progression-free survival was about a year and a half. Overall survival in this very difficult treatment population was, of course, longer than that. Recall that these patients all had multiple prior cytotoxic regimens, so whether or not they’re representative of current patients who are relapsed refractory is less clear.

My own personal experience with this combination is that it can serve a useful purpose in selected, carefully monitored patients. It’s important when starting a patient on a PI3 inhibitor to monitor liver function tests quite closely. The label provides very specific recommendations for the timing to do that because liver function test abnormalities occur primarily within the first 3 months. Once they occur, it’s important to interrupt idelalisib and allow the patient to recover. Once they’ve recovered, it’s very rare for those liver function tests to become abnormal again, so it appears to be a one-and-done phenomenon.

However, diarrhea is another consideration, and grade 3 diarrhea in this trial was reported around 16%. It’s important to know that even grade 2 diarrhea can be quite symptomatic for patients. The appropriate intervention is actually to suspend therapy, and it’s important to do so early if the patient has diarrhea. You need to train a patient to stop idelalisib if they experience diarrhea, even if they haven’t been in to be seen, because if there’s a delay and they continue their idelalisib until they’re waiting to be seen, that can become quite serious. We also monitor for atypical infections, such as cytomegaly virus or PCP. In many cases, if we can, we try to utilize PCP prophylaxis.

Finally, we’re asked to describe the ongoing challenges in treating relapsed/refractory CLL, and discuss future directions and unmet needs in relapsed refractory CLL.

We are definitely seeing more patients who are experiencing progression after novel agents, so perhaps progression after BTK or BCL2. What good options remain for those patients? I think that recognizing idelalisib-rituximab as a useful combination can be quite helpful amongst these patients, potentially even utilizing that prior to rituximab-venetoclax in some situations where medical comorbidities may make venetoclax more challenging.

I think it will be interesting to see if the noncovalent inhibitors can move forward and restore efficacy of targeting BTK, even amongst patients with prior BTK inhibitor resistance. We’ll be excited to see how cellular therapies evolve in this space, including chimeric antigen receptor T-cell therapy, which is going to be great for those patients young and robust enough to get it. But, again, this older population may be excluded from such strategies.

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