Case 4: A Young, Fit Patient With MRD-Positive CLL After Immunochemotherapy

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

William Wierda, MD, PhD:Welcome back. We’re going to finish up with case number 4, which Dr. Bagg is going to present for us.

Adam Bagg, MD:This last case is of a 53-year-old woman who has an elevated white cell count. This was detected incidentally, presumably at the time of a routine physical examination. This is not an uncommon presentation of chronic lymphocytic leukemia. She was noted to be hypertensive and has a small left lymph node in the left axilla, and laboratory findings show a marked absolute lymphocytosis with hemoglobin and platelet counts and an LDH that is within normal limits. Flow cytometry shows an immunophenotype (as one would expect in chronic lymphocytic leukemia) with coexpression of CD25 and CD23 by, presumably, monoclonal B cells. The cells are also noted to be CD38-positive, which historically has been considered to be a poor prognosticator. Immunoglobulin gene heavy-chain region sequencing shows that this region is mutated. This CLL has transited through the germinal center. Results of the FISH test show trisomy 12. The bone marrow shows 86% involvement. At first, the patient was monitored. Then she became symptomatic.

Repeat FISH testing, which is important, remains to show a trisomy 12. The white cell count has increased to 250,000, and both the hemoglobin and platelet counts have now dropped. The lymph node that was 1 by 1 cm is now enlarged to that of 4 by 3 cm.

She was treated with FCR. She achieved a complete remission after 6 cycles but remains to be MRD—positive.

William Wierda, MD, PhD:So, this is a 53-year-old woman with relatively good prognostic features. Maybe you can comment on the diagnostic work-up and the prognostic features of this patient?

Adam Bagg, MD:As I alluded to when I was presenting this case, the expression of CD38 is considered to be a poor prognostic variable, from an immunophenotypic point of view. Whether that affects therapy—I’ll leave that up to you to discuss. Mutation of the immunoglobulin heavy-chain gene indicates that this CLL cell has transited the germinal center. Typically, this is associated with a good prognosis. Her FISH status reveals a trisomy 12. Historically, trisomy 12 has been the most frequent abnormality detected in patients with CLL by cytogenetics. Importantly, notable by its absence is conventional karyotypic analysis by cytogenetics, which could be prognostic. Trisomy 12, detected by FISH, is considered, in most instances, to be neutral, prognostically. However, there may be some clinical associations with it. That’s all the information that we have. We do not have targeted mutational analysis, which I think is important, nowadays, in all patients with CLL. In particular, it is useful to look atTP53mutations but also to look at a handful of other genes, such asNOTCH1,SF3B1,ATM, and a few others.

William Wierda, MD, PhD:Can you comment on CD200? Sometimes we get CD200 on our phenotyping reports. What’s the relevance of CD200?

Adam Bagg, MD:CD200 is a relatively new marker that can help facilitate the diagnosis of chronic lymphocytic leukemia. CD200 is reported to be expressed fairly exclusively on CLL, compared with its mimics—in particular, mantle cell lymphoma in the leukemic phase. There are, however, recent reports of CD200 being expressed on indolent mantle cell lymphomas—those that lackSOX11expression, for example. So, one needs to be careful. Nevertheless, it is a useful marker for diagnosing chronic lymphocytic leukemia.

In addition to the expression of CD200 in indolent mantle cell lymphomas, hairy cell leukemia (which should not be in the morphologic and immunophenotypic differential diagnosis of CLL) can also express CD200. CD200, together with other novel markers, likeLEF1, used by immunohistochemistry, is an example of newer tools that we have available to distinguish CLL from its potential mimics. It’s important to note that CD5 and CD23 expression are usually useful, but you should also look at the intensity of a variety of other immunophenotypic markers by flow cytometry—CD20, immunoglobulin, CD22, and CD79b, compared with all other small B-cell neoplasms that can spill over into the blood.

Transcript edited for clarity.