CLL Case Review: IgHV-Unmutated Therapy Options - Episode 1
Matthew S. Davids, MD, MMSc:This patient is a 74-year-old gentleman who presented to his primary care physician with about 3 months of weight loss and fatigue. The patient had not previously had any significant diagnoses, just some mild hypertension and was generally healthy prior to this.
On physical examination the patient had a mildly elevated blood pressure, about 130s over 80s. But what was most notable was some palpable splenomegaly with a spleen about 7 cm below the costal margin, as well as some bulky lymphadenopathy on exam.
The laboratories were notable for a markedly elevated white blood cell count of 100,000, with the majority of the cells being lymphocyte cells. The patient was not anemic with a hemoglobin of around 15, and the platelet count was just modestly low, at around 125,000. There was no neutropenia and the LDH [lactate dehydrogenase] test was normal.
Peripheral blood flow cytometry was sent, which was consistent with chronic lymphocytic leukemia [CLL]. And therefore, a panel of prognostic marker tests were sent.
Beta-2 microglobulin, which was elevated at 4.3, and additional prognostic markers that were sent include the FISH [fluorescence in situ hybridization] cytogenetics, which came back as normal, as well as theIgHVmutation status, which was unmutated.TP53sequencing was also performed and was wild-type, meaning there was no aberration inTP53. So overall in assessing this patient, I would say he has a good performance status with an ECOG [Eastern Cooperative Oncology Group] PS [performance status] of 1.
From the staging perspective we typically use the Rai system, which I’ll note is a clinical staging system. So we don’t need CT [computed tomography] scans to make the staging for this patient. We can say that based on the palpable splenomegaly that this patient has Rai stage II disease, which we do consider to be one of the earlier stages of CLL. And yet sometimes patients with Rai stage II disease will require treatment.
The first thing we look at when we’re trying to evaluate the prognosis for a patient with CLL is generally the FISH test. This looks at the chromosomal aberration inside the CLL cells. And based on the pattern we can predict how the patients may do over time. The biggest branch point with FISH testing is the status of chromosome 17. Those patients who have deletion 17p CLL have a more aggressive disease course. Traditionally they have not responded well to chemoimmunotherapy-based regimens, and the overall survival of those patients has unfortunately been shorter.
Patients who don’t have deletion 17p have a more varied prognosis, and that depends upon a number of other factors, including the specific FISH abnormalities. This patient here has normal FISH, which is generally a more favorable abnormality. Patients can also have chromosome 13 deletion, or trisomy 12, which also tend to be in the favorable group. And then patients with deletion 11q historically have had a more intermediate prognosis.
I would say increasingly that theIgHVmutation status has become one of our most important tests in terms of helping us determine the optimal initial therapy for patients with CLL.IgHVstatus can either be mutated or unmutated. It’s about a 50/50 split in terms of patients at diagnosis.
Patients with unmutatedIgHVtend to have more steady progression of their CLL and require treatment sooner after diagnosis. Historically, although they respond well initially to chemoimmunotherapy regimens, they tend to have less durable responses to that type of treatment approach. So increasingly that’s directing us toward using more of the novel agents for patients with the unmutatedIgHV.
The other key test that we think is helpful in patients with CLL, particularly those are being considered for treatment, is sequencing theTP53gene. The reason for this is that there are patients who have an intact chromosome 17 where the FISH test looks normal. But on sequencing studies they have aTP53somatic mutation. And these patients often will have a more aggressive disease course similar to deletion 17p, and are typically patients for whom we would not be recommending chemoimmunotherapy.
Transcript edited for clarity.
Case:A 74-Year-Old Male WithIgVH-Unmutated CLL