Case 1: An Elderly Patient With Newly Diagnosed High-Risk CLL

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

William Wierda, MD, PhD:Thank you for joining us today for thisTargeted Oncology^™Virtual Tumor Board,which is focused on chronic lymphocytic leukemia. Novel small molecule targeted therapies and chemoimmunotherapy regimens for CLL have drastically improved outcomes, but they have also increased the complexity of treating symptomatic patients. In addition, there remains to be a substantial unmet need for many patients with relapsed or refractory CLL. In today’sTargeted Oncology^™Virtual Tumor Board presentation, my colleagues and I will look at 4 clinical cases. We will discuss the individualized approach to treatment for each of these patients and will review the data considered in our decision making.

I’m William Wierda, professor of medicine at the University of Texas MD Anderson Cancer Center in Houston, Texas. Today, I am joined by Dr. Adam Bagg, professor of pathology and laboratory medicine at the University of Pennsylvania Perelman School of Medicine, in Philadelphia; medical oncologist Dr. Matt Davids, assistant professor of medicine at Harvard Medical School in Boston; and Dr. Nitin Jain, associate professor of medicine, also from MD Anderson Cancer Center. So, let’s get started with the first case.

The first case is a 75-year-old female with reported symptoms of weight loss and fullness in her left upper quadrant. Her past medical history is significant for hypertension and hypercholesterolemia, both of which are medically controlled. Her physical exam shows moderate axillary lymphadenopathy. Her spleen is palpable at 4 cm below her left costal margin. Otherwise, she’s well appearing and continues with her daily activities.

Her laboratory findings are significant for an elevated white blood count at 48,000; 73% are lymphocytes, her hemoglobin is 9.1, platelets are 125, the absolute neutrophil count is 1800, her LDH is 250, and her beta2 microglobulin is 4.2. A flow cytometry shows a monoclonal population of cells that are also expressing CD5, CD19, and CD23. FISH is done, and results show deletion 11q. A molecular analysis shows an unmutated immunoglobulin heavy-chain variable gene, and sequencing ofTP53shows wild-typeTP53. A bone marrow biopsy shows diffuse infiltration by CLL.

This is a previously untreated patient. She is diagnosed with chronic lymphocytic leukemia. She has Rai stage III disease, with a hemoglobin of 9.1 and some disease features that have some implications in a prognosis for this patient. So, why don’t we start with you, Dr. Bagg. May you comment on the diagnostic workup and the molecular findings for this patient?

Adam Bagg, MD:Thanks very much, Dr. Wierda. Obviously, the flow cytometry is important in the characterization and diagnosis of CLL. Although it is not likely to be an issue in this case, it’s important to be aware of the percentage of cells with the clonal immunophenotype. In some cases, the total number of clonal B cells may actually fall below 5x10⁹/L, which, by definition, is not CLL. Of course, in this patient, who has a very elevated absolute neutrophil count—73% lymphocytes and 48,000 white cells— that’s unlikely to be an issue.

Another important point, from a diagnostic point of view, is that although we all know that the co-expression of CD5 and CD19, together with CD23, is fairly pathognomonic of chronic lymphocytic leukemia, it’s sometimes useful to look at other immunophenotypic markers, such as CD20, CD22, CD79B, and surface immunoglobulin—all of which are decreased in intensity in CLL—to build a portrait of the diagnosis of chronic lymphocytic leukemia.

FISH panels, nowadays, usually look at 5 or 6 abnormalities. In this individual, deletion of 11q, presumably 11q22.3, was detected. In most studies, this is believed to be an adverse prognosticator, presumably targeting theATMgene. With regard to additional molecular studies, the distinction of whether the B cell has or has not transited the germinal sensor, with the indication of the immunoglobulin heavy-chain variable region being mutated or unmutated, is an important prognostic factor. In this patient, the immunoglobulin heavy-chain variable region is unmutated, which is a poorer prognostic factor.

The only gene that seems to have been investigated in this patient isTP53, which was reported to be wild-type, or negative. A caution to the interpretation of aTP53mutation analysis, for the practitioner, is to know which exons have been evaluated. Some laboratories will do a more widespread exonic analysis, looking, for example, at exons 2 through 11. Others may have a more restrictive analysis, looking at exons 4 through 10, which may miss some mutations. So, it’s worth looking at the fine prints in a mutational analysis to be sure that there has been reasonable coverage of the gene of interest.

Finally, the bone marrow biopsy notes that the infiltration in the marrow is diffuse. Historically, before the advent of genetic-based prognostication, diffuse infiltration was considered to be an adverse variable as compared with those with a nodular infiltration.

Transcript edited for clarity.