Optimizing Targeted Therapy in IgVH-Unmutated CLL - Episode 1

Approaching a Case of IgVH-Unmutated CLL

William Wierda, MD, PhD:The case is a 58-year-old female who is incidentally noted to have an elevated lymphocyte count. A diagnosis of chronic lymphocytic leukemia was made based on the typical markers that we look for and assess for that diagnosis. The markers that we look for are CD5, CD19, and CD23. The presence of all of those on the surface of the cells and restriction regarding the light chain, either kappa or lambda, make the diagnosis of CLL. She was asymptomatic at the time she was diagnosed. She was noted also to have an elevated white blood cell count and to not have any significant anemia or thrombocytopenia. Because she was asymptomatic and had relatively normal blood counts, she had no initial indications for treatment and was monitored.

This patient did also have a bone marrow biopsy, which isn’t essential for the diagnosis of CLL. We’re doing fewer bone marrow biopsies these days. Bone marrow biopsies are more helpful these days in terms of response assessment and particularly are done on clinical trials where we’re clarifying whether patients are in complete remission or in partial remission. In terms of other features that were assessed, those features don’t necessarily need to be characterized upon initial diagnosis because we don’t change management based on those results. Another feature assessment is the FISH test. This patient had FISH done when they were initially assessed and were noted to have a 17p deletion and trisomy 12. The 17p deletion is a high-risk feature, and that’s something that gets our attention. It’s something that we use to determine how to manage patients and how to follow them in the clinic. It’s not necessarily useful in terms of determining when to start treatment. It isn’t an essential test to do when patients are newly diagnosed, but certainly FISH needs to be done if you have a patient who needs treatment.

The other feature is her mutation status. She had her immunoglobulin heavy chainVgene mutation status assessed, and she was noted to have an unmutatedVgene, which is also a higher-risk feature. Those patients may be managed differently, depending on what treatment we’re talking about. Like FISH, which isn’t an essential test to do in patients who are diagnosed, but it is very helpful when you’re determining treatment and how to manage patients. Beta-2-microglobulin was evaluated in this patient. That’s been an easy test to do that’s prognostic. A higher beta-2-microglobulin is generally correlated with a more active disease and has been correlated with shorter time to first treatment.

Overall, this patient, although when initially presented, did not have any indication for treatment, did have some high-risk features, and would be a patient I would monitor relatively closely to determine whether she needs to be treated. She should not be treated initially based just on the fact that she has a 17p deletion. We know from our own data, about a third of patients with 17p deletion don’t have active progressive disease and don’t need treatment for sometimes several years. You may be doing a disservice to this patient by treating early just based on the 17p deletion.

She’s a young patient, which is unusual. Usually patients who have CLL diagnosed are over 70, and they don’t need treatment usually until sometime after their diagnosis. They don’t usually need initial treatment, so most patients will have some period of observation. This patient had a period of observation of about 2 years and then had indications of active progressive disease by virtue of developed fatigue and night sweats. Those were the indications for treatment for this patient. The other test that wasn’t done on this patient that we would be interested in obtaining is theTP53mutation status, which is also prognostic. It’s very common for patients who have a 17p deletion to also have a mutatedTP53, and so we like to know that information. There are also patients who don’t have 17p who do haveTP53mutation. Those patients would be managed differently, so that is an important test to obtain if you have access to that test.

Patients who have a 17p deletion or mutatedTP53lack p53 function, and the importance of that is that they don’t do well with chemotherapy. Chemotherapy doesn’t work for those patients, so we have other treatments that have been identified that are clearly active in managing those patients, one of which is a BTK inhibitor. Particularly in this case, the treatment that this patient got was ibrutinib. That’s really the only drug right now that’s available in untreated patients who have 17p as their first treatment. The other drugs that are active to treat patients with 17p deletion, while they’re approved, are for previously treated patients. One of them is venetoclax, which we’ll talk about. The other is idelalisib. For this patient with a 17p deletion, having that feature, the standard treatment and best treatment for that patient is ibrutinib or a BTK inhibitor. That patient would not be appropriate for treatment with chemotherapy or chemoimmunotherapy.

Transcript edited for clarity.

A 58-Year Old Female with IgVH-Unmutetd CLL

  • A 58-year-old female with incidentally noted lymphocytosis on routine
  • PMH: hypercholesterolemia managed on simvistatin, mild osteoarthritis
  • PE: 1.0-cm cervical node, no palpable spleen or liver
  • PS, ECOG 0
  • Laboratory findings:
    • WBC; 45 X 109/L, 85% lymphocytes
    • Lymphocytes; 86.2 X 109/L
    • Hb; 13.9 g/dL
    • Platelets; 274 X 109/L
    • ANC; 1,950/mm3
    • LDH 160 U/L
  • Flow cytometry; CD5+, CD19+, CD20+(dim), CD23+, slg+ (dim), ZAP70+
  • Cytogenetics by FISH; del(17p), trisomy 12, IgVH unmutated
  • β2M, 3.6 mg/L
  • BM biopsy; 70% lymphocytes, diffuse pattern
  • Diagnosis; chronic lymphocytic leukemia
  • Observed for over 2 years, then developed progressive sever fatigue and night sweats
  • The patient was treated with ibrutinib and achieved a complete response to therapy after 2 months