Clinical Management of Relapsed CLL - Episode 2

CLL Prognosis and Treatment Options

January 12, 2018

Danielle Brander, MD:17p deletions in patients who have not been treated are not very common. About less than 10% of patients at the time of their diagnosis or at the time of their first treatment will have a 17p deletion detected. However, we know from multiple studies that this incidence increases by line of therapy. That is, for patients who have had treatment before and especially for patients who are refractory to chemotherapy, especially fludarabine. And the incidence of finding 17p deletion orTP53mutations goes up substantially to almost 40% or 50% of patients. Again, that’s why it’s important not only to be thinking about testing for FISH at first diagnosis, but also for patients who have relapsed disease. If they didn’t have the deletion at the start of first treatment, check for it when they relapsed because it might change your focus in how recommend management for the patient.

Deletion of 17p, historically, has been the strongest prognostic marker because patients had a shorter time to treatment, a shorter time to first treatment, a shorter duration of response to therapy, and, historically, also a shortened overall survival. The reason I mention “historically” is a lot of the studies that looked at progression-free survival and overall survival were in the era of chemoimmunotherapy. Now, in the era of some of the novel targeted drugs such as ibrutinib or venetoclax, we’re seeing a substantial improvement to patient’s duration of response to their first treatment, as well as their survival.

TheIgHVmutation status is a very important prognostic marker for patients with CLL. In the frontline setting, or prior to patients receiving first-line treatment, which is considered the higher risk situation, about half the patients have a mutatedIgHV. The unmutatedIgHVpredicts that patients are much more likely to require treatments, have a shorter time to that first treatment, and have a shorter response to therapy no matter the response they achieve to that frontline chemotherapy. That is even for patients who achieve a complete response at the end of their chemotherapy. If they have an unmutatedIgHV, they have a shorter duration of response to that treatment.

Though I mentioned that about half the patients at diagnosis or before first treatment have unmutatedIgHVand half have mutated, this actually varies by the FISH status. That is, for patients with the higher-risk deletion, or the high-risk deletion 17p, many of those patients, the overwhelming majority, are expected to have an unmutatedIgHV. These prognostic markers tend to group together.

For patients with deletion of 17p orTP53mutations, we don’t recommend chemotherapy-based regimens. And, again, the reason for that is we expect attenuated response and a shortened response to that type of drug. And there’s also concern that exposure to chemotherapy for patients withTP53dysfunction could lead to clonal evolution. Therefore, our frontline treatment options for patients with deletion of 17p really focus on the non-chemotherapy approaches. That involves currently now-approved ibrutinib frontline or other approaches such as high-dosed steroids and rituximab. So, combining the immunotherapy but avoiding chemotherapy.

This patient was enrolled on a clinical trial and treated with ibrutinib 420 mg daily, which is the standard starting dose for a CLL patient. The rationale for using ibrutinib is that it works by mechanisms independent of having an intactTP53function. That is, for patients with deletion 17p orTP53mutations, we’re concerned that standard chemotherapy when achieved the responses we want or the duration of response. Therefore, the rationale for choosing ibrutinib is that, especially for older patients, we know that in the first-line treatment, frontline treatment, it’s generally well tolerated, and it achieves particularly good responses in areas of bulky disease, such as the lymph nodes or spleen, which was her primary area where she was having symptoms.

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