Treatment Options for CLL

Matthew S. Davids, MD, MMSc:So, when I think about initial treatment for CLL, the most important factor is the functional status ofTP53. In other words, if a patient has a deletion 17p that can deleteTP53or if they have a mutation that makesTP53nonfunctional, those patients do not typically respond well to chemoimmunotherapy-based regimens, which can be helpful for most patients with CLL. So, even though this is a small subset of patients, in the range of about 10% of CLL patients at initial diagnosis, it’s very important to send the FISH testing to identify the small subgroup of patients who are not going to respond well to the traditional treatments.

If this patient were found to have deletion 17p or aTP53mutation, then ibrutinib would be the treatment of choice as frontline therapy. And I would say there’s very little controversy about that because right now, that’s the best-approved option for patients with that particular subtype of CLL. The only challenging situation might be a patient who has severe cardiac issues or bleeding risks, and there, alternative therapies could be considered, but typically not chemoimmunotherapy.

So, if the patient does not haveTP53dysfunction—and this would be about 90% of patients—then there’s a bigger range of options for a patient like this. And we start to think about other factors, including theIGHVmutation status, the age of the patient, and what their comorbidities are.

For a patient like this in their mid-70s, with some other medical comorbidities but not terribly sick, I think we have a pretty good range of options. You may be familiar with the FCR regimen, or fludarabine/cyclophosphamide/rituximab. This is the gold standard, most powerful regimen we have for younger CLL patients. Typically, we think of that in patients under the age of 65. So, for a patient like this in their mid-70ss with other medical issues, I would not recommend FCR.

That leaves us with a couple of different chemotherapy-based options, and one of which is bendamustine with rituximab (BR). This is also a very active combination, like FCR, but it does tend to be better tolerated, particularly for these older and frailer patients. So, for this patient, I think BR would be a very reasonable chemoimmunotherapy choice. We also have a regimen that’s comprised of chlorambucil, the older alkylating oral agent, given in combination with CD20 antibodies, and that could either be obinutuzumab, the newer CD20 type 2 antibody, or ofatumumab, the older type 1 antibody. And either of those would also be quite reasonable to use and would be generally well tolerated.

Ibrutinib is also an evolving treatment option for patients outside of theTP53dysfunction setting. We now have some data from the randomized RESONATE-2 study suggesting that at least compared to chlorambucil, ibrutinib has a significant advantage in terms of progression-free and overall survival.

So, I think ibrutinib is a reasonable option to consider for this patient. However, I will say that there are ongoing studies comparing ibrutinib to bendamustine/rituximab and ibrutinib/rituximab. This is the Alliance study that’s ongoing, and we don’t know the results of that trial yet. So, it’s hard to know whether ibrutinib or a bendamustine-based regimen may be optimal for this patient. One thing that can help guide us there is theIGHVmutation status. If patients have unmutatedIGHV, they typically have less durable benefit to chemoimmunotherapy, and that might tip the balance more toward an ibrutinib-based regimen for frontline therapy.

Transcript edited for clarity.

• A 76-year-old male presented with symptoms of low-grade fever, (101.1^oF) chills, and weight loss. The patient feels severely fatigued and required extensive rest. He was recently hospitalized for pneumonia.
• PMH: Hypertension controlled on candesartan, diabetes managed with metformin
• PE: Pallor and is weak-appearing, vital signs WNL, enlarged mobile lymph nodes bilaterally (~2.0 cm), anterior cervical chain, no hepatosplenomegaly
• PS, ECOG 2
• Laboratory findings:
  • WBC; 18.5 X 10⁹/L, 65% lymphocytes
  • Lymphocytes; 86.2 X 10⁹/L
  • Hb; 12.2 g/dL
  • Platelets; 305 X 10⁹/L
  • ANC; 120/mm³
• Flow cytometry; CD5+, CD19+, CD23+, CD38-low,
• Cytogenetics, IgVH mutation status, unknown
• β2M, 2.6 mg/L
• BM biopsy; 50% lymphocytes
• Diagnosis; chronic lymphocytic leukemia
• The patient was treated with ibrutinib and achieved a complete response to therapy after 2 months