Optimizing Targeted Therapy in IgVH-Unmutated CLL - Episode 2

Stratifying Patients With CLL by Stage and Risk Status

William Wierda, MD, PhD: There are 2 staging systems that are used. One is the Rai staging system, and the other is the Binet staging system. In the United States, the standard staging system is the Rai staging system, and the Europeans use the Binet staging system. They are very similar and are based on the same features. The Rai staging system has been simplified into 3 risk categories: low risk, intermediate risk, and high risk. Patients who have low-risk disease have only a lymphocytosis, which is only an elevated absolute lymphocyte count. The intermediate-risk patients are those patients who have enlarged lymph nodes and/or enlarged liver or spleen. The high-risk patients are patients who have cytopenias by virtue of having the disease; the cutoffs that we use are hemoglobin of less than 11 or a platelet count of less than 100,000. Either of those 2 features would put patients into a high-risk category or stage 3 or 4 disease by the Rai staging system.

When patients need treatment and you’re assessing them, trying to determine which treatment is the most appropriate treatment for a patient, a feature that we think about is age. “Does the patient belong into the older-age category, or are they younger and more fit and able to tolerate the more intensive treatments?” Patients who are older don’t tolerate the chemoimmunotherapies that we’ve been using for several years. Those are reserved for the younger patients who can tolerate the chemotherapy. We spoke about 17p deletion, which is clearly an important feature to assess before you choose treatment for a particular patient. As I also mentioned,TP53mutation status is an important feature to know. They sort of go hand in hand. We need to know theTP53mutation status and the 17p deletion status.

The other feature that we use is the immunoglobulin heavy chain variable gene sequence analysis for older patients. It’s not as useful as for younger patients these days. For younger patients who can tolerate chemoimmunotherapy, the best treatment is based on theirIgVHmutation status. We know we can get patients who have an unmutatedVgene in remission with chemotherapy, but virtually all of them will relapse, and their remission duration is relatively short. Those are the patients we prefer to manage with a small molecule inhibitor like ibrutinib because treatments are changing so quickly. We feel like there will be something better coming along for those patients, and we would like to spare them exposure to chemotherapy and the risks that come with chemotherapy, like MDS and AML, in preference to a small molecule inhibitor. In that case, we will have an option to manage them probably more effectively at a later date.

The patients who are younger and have a mutatedVgene are the patients who do exceptionally well with chemotherapy or chemoimmunotherapy, particularly FCR. For a patient who doesn’t have a 17p deletion and who has a mutatedVgene, the standard treatment and recommendation would be for an FCR-based treatment—fludarabine, cyclophosphamide, and rituximab. Treatment with FCR for that patient population achieves complete remission in most of those patients—over 70% of them. There is a large proportion of them—55% or so—who will be progression-free for longer than 10 years. And there’s discussion about the possibility that some or many of those patients are cured.

The features that are important for the younger patients are 17p, of course, and mutation status. FCR is the choice for patients who have a mutatedVgene. For patients with an unmutatedVgene, the preference is for a small molecule inhibitor because it leaves other options open later and doesn’t expose patients to the higher risk of getting myelodysplastic syndrome or AML.

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