Relapsed Chronic Lymphocytic Leukemia - Episode 1

Risk Stratification for CLL Settings & Typical Prognoses

January 8, 2019

Ian W. Flinn, MD, PhD:The patient is a 71-year-old man who presented to his primary care physician with increasing fatigue and lethargy. On physical examination, he was found to have diffused adenopathy in his cervical nodes and his axilla. He also was found to have a leukocytosis with a white count of nearly 150,000, which was predominantly lymphocytes. This led to flow cytometry on his peripheral blood, which showed that he had a classic immunophenotype for CLL [chronic lymphocytic leukemia]. He was CD20 positive, CD19 positive, CD5 positive, and CD23 positive.

FISH [fluorescence in situ hybridization] testing revealed that he had a trisomy 12 but no other aberrations. The patient then went to bone marrow testing, which confirmed the diagnosis of CLL that was made in the peripheral blood, and there was diffused involvement as marrow, with more than 80% of involvement of the marrow.

So the patient was symptomatic. He had anemia. His hemoglobin was 11.1. Platelet count was above 100,000; it was approximately 130,000. And so the patient was started on ibrutinib,, but line therapy, for his CLL. He did quite well. He went into remission; that was within 5, months. But, unfortunately, 3 years later, the patient progressed on ibrutinib, with a rising lymphocyte count. His lymphocytes went up to greater than 200,000 on the ibrutinib, at which time he was stopped and we evaluated his; he had the same genetic aberrations. He still had a trisomy 12 and did not pick up any other findings on his FISH testing.

Risk stratification for patients with CLL is based on FISH testing and looking at patients’ mutational status of the immunoglobulin heavy chain. There are other tests that can be done, such as next-generation sequencing. I think the primary elements are FISH and mutational status. FISH looks at the major chromosomal changes. We know that in more than 80% or 85% of patients, we can find a FISH abnormality in patient’s peripheral blood. There are some FISH abnormalities that actually have a good prognosis. For instance, patients who have a 13q deletion. That, by itself, this is a good prognostic factor.

Whereas patients who have a 17p deletion, which affects p53 or 11q deletion, which affectsATM, these patients unfortunately have a worsened prognosis than patients who have no abnormalities. This patient has trisomy 12, which was sort of intermediate in prognosis.

Now we also look at mutational status of the immunoglobulin heavy chain. This is really getting at where the transformation for a malignant cell occurred from a normal to a leukemic cell, in the normal ontogeny of lymphocyte growth. So patients who have an unmutated immunoglobulin heavy chain, they have a worse prognosis than patients who have a mutated immunoglobulin chain.

Now one thing I’d like to point out is that a lot of our understanding of prognosis with these factors occurred in the chemoimmunotherapy age. And so some of the things that we think of as having a very, very bad prognosis are improved with some of the new more targeted therapies, such as patients with a 17p deletion. And while they’re still worse than if you didn’t have these abnormalities, they’re not as bad as they were in the past.

This patient, at the onset, we thought had a fairly intermediate prognosis. He did not have bad FISH testing, but he did have an unmutated immunoglobulin heavy chain. Now this patient progressed a little bit on the early side. I guess I’m a little bit disappointed by the ibrutinib refractoriness here very early on. And we tend to think that patients who become refractory to ibrutinib, that they’re going to have a more aggressive outlook on their disease.

In my practice, we are now using next-generation sequencing for patients … both in the frontline and relapsed setting in CLL. I think this is an additional test that potentially could have been done, but it’s not universally done. It does allow us to know whether there are abnormalities, such as p53 abnormalities orATMabnormalities, that we are not picking up by FISH. Of course, FISH testing looks for missing parts of the chromosome, but you can have an attack chromosome where the gene is mutated and not operating correctly. And I think that would be one thing to have ordered.

Transcript edited for clarity.

A 71-Year-Old Man With CLL

  • A 71-year—old man presented with symptoms of persistent fatigue and weight loss
  • PMH: Left axillary lymph node, 1.5 cm X 1.5 cm
  • PE: Left axillary lymph node, 1.5 cm X 1.5 cm
  • Laboratory findings:
    • WBC, 133,000; 85% lymphocytes (ALC, 68,000 cells/mL)
    • Hb; 11.4 g/dL
    • Platelets; 111 X 109/L
    • ANC; 174/mm3
  • Molecular testing:
    • Flow cytometry; CD19++, CD5+, CD20+, CD23++, CD38+
    • IgVHmutated
    • FISH, +12
  • β2M, 3.0 mg/L
  • Diagnosis; chronic lymphocytic leukemia
  • BM biopsy; CLL in 88% of cells
  • The patient was treated with ibrutinib and achieved a complete remission within 5 months
  • 13 months later, the patient reported extreme fatigue; now with 3.0 X 3.0-cm lymph node
  • Laboratory findings:
    • Repeat FISH: remained +12
    • WBC, 225 X 109/L
    • HB, 9.6 g/dL
    • Platelets, 103 X 109/L