Factors in Risk Stratifying Patients With CLL

William G. Wierda, MD, PhD:Risk stratification is an important feature, particularly when you’re considering starting patients on treatment. We have these prognostic factors, and they risk-stratify patients in terms of outcomes, and they’re useful to have a discussion with patients on what to expect from their disease and how closely we should be monitoring the patient. In terms of those features that are important for directing treatment, there are a few. I mentioned one of them. FISH [fluorescence in situ hybridization] is an important feature. FISH shows us chromosome abnormalities, and we change or alter treatment based on the presence of chromosome abnormalities, particularly 17p deletion. So that’s really one of the first things I look at when I’m assessing a patient and determining what is the best treatment for them.

The other thing, as I mentioned, that goes along with 17p deletion isTP53and mutation status inTP53. So it’s an important feature to know about a patient who’s starting on treatment. Those 2 features, 17p deletion andTP53mutation, would direct a patient to ibrutinib-based therapy. We know that with loss of 17p deletion, those patients are not sensitive to chemotherapy or chemoimmunotherapy. And so that would be a poor option for patients who have a 17p deletion. Whereas ibrutinib is very effective, and there are other drugs that are also effective for patients who have a 17p deletion.

The other important feature to assess and to consider in thinking about first-line therapy is patients’ age and if patients are younger and fit and able to tolerate chemoimmunotherapy versus patients who are older who are not able to tolerate chemoimmunotherapy. In terms of the older group, we usually use 65 as the cutoff. Those patients who are older are less able to tolerate chemotherapy. And we’ve had recent data that have been reported at ASH [the American Society of Hematology Annual Meeting & Exposition] in 2018, which have further driven our treatment choices, particularly for the older group of patients, for whom chemoimmunotherapy is probably not an ideal choice. Those patients tolerate chemoimmunotherapy not as well as the younger and fit patients. They tend to have more toxicity. They can get a remission. Their remissions will last variable periods of time, and they’ll be relapsing and needing salvage therapy.

So treatment for patients over 65 is based on a clinical trial that was presented at ASH 2018, which reported the results of a trial called the iLLUMINATE trial, in which patients were randomized to treatment with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab. That trial showed improvement in progression-free survival for patients who received ibrutinib-based therapy. And so that trial, recently reported, really sets the standard treatment for patients over 65 as a nonchemotherapy-based treatment, ibrutinib-based treatment. That trial evaluated ibrutinib with a CD20 antibody. We can discuss the importance of CD20 antibodies in ibrutinib-based therapy as well.

The other feature to evaluate that’s particularly relevant for patients who are younger than 65, patients who perhaps can tolerate the more intensive chemoimmunotherapy, is their immunoglobulin heavy-chain variable-gene sequence analysis and making a determination of whether or not they have a mutated or unmutated immunoglobulin gene. Now this patient is 78, so the most appropriate treatment for this patient is an ibrutinib-based treatment. But if the patient was, say, 58, then I would want to know what their immunoglobulin heavy-chain variable-gene sequence was and whether they were mutated or unmutated. If they have a mutated immunoglobulin gene, those patents should be considered for chemoimmunotherapy treatment still because we know that most of those patients will achieve a complete remission with FCR-based treatment, FCR being fludarabine, cyclophosphamide, and rituximab. More than 70% of those patients should achieve a complete remission, and in more than 50%—approximately 55% in our University of Texas MD Anderson Cancer Center experience—of those patients will have more than 10 years of progression-free survival. And they may be cured from their disease with FCR-based treatment.

We don’t see that same effect with other chemoimmunotherapy regimens, like bendamustine and rituximab, for that patient population. So if we’re talking about chemoimmunotherapy in the frontline setting, we’re talking about it now for patients who are younger than 65 and patients who have a mutated immunoglobulin gene. For the patients who are younger than 65 and have an unmutated immunoglobulin gene, we know if they get chemoimmunotherapy, their disease will come back. They’ll need re-treatment.

And there was a trial that was reported at ASH that’s referred to as the ECOG [Eastern Cooperative Oncology Group] E1912 trial. That trial evaluated ibrutinib plus rituximab versus FCR in the frontline setting for younger, fit patients. And that trial not only showed an improvement in progression-free survival for patients who received ibrutinib-based therapy, but there was an overall survival advantage for ibrutinib plus rituximab over FCR. So for the younger, fit patients, including those younger than 65 who have an unmutated variable gene, the recommendation now is for ibrutinib-based therapy.

Transcript edited for clarity.

An Elderly Woman With CLL

• A 78-year—old female presented with symptoms of fatigue and loss of appetite for the past six months
• PMH: recurrent bronchitis during past 12 months, treated with antibiotics
• PE: vital signs WNL, right cervical lymphadenopathy, spleen palpable 5 cm below costal margin, otherwise well-appearing
• Laboratory findings:
  • WBC, 53,000; 76% lymphocytes
  • Hb; 10.4 g/dL
  • Platelets; 150 X 10⁹/L
  • ANC; 180/mm³
• Flow cytometry; CD5+, CD19+, CD23+
• Cytogenetics, FISH: trisomy 12; IgVH mutated
• β2M, 3.6 mg/L
• BM biopsy; diffuse infiltration by CLL
• Diagnosis; chronic lymphocytic leukemia
• The patient was treated with ibrutinib and achieved a complete response to therapy after 4 months