Conference Coverage

Consider treatment, testing when CLL symptoms emerge



Asymptomatic chronic lymphocytic leukemia (CLL) patients should be observed, but consider therapy when symptoms develop, said Paul M. Barr, MD.

Dr. Paul M. Barr of the University of Rochester Medical Center Courtesy Matt Wittmeyer/University of Rochester Medical Center

Dr. Paul M. Barr

He described a patient who had been observed for 7 years when he began to complain of increasing fatigue and lost work time. A complete blood count (CBC) showed thrombocytopenia.

The recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines state that assessments before treatment in this type of patient should include history and physical, evaluation of infectious disease status, and routine laboratory testing – including CBC and differential, chemistry, serum immunoglobulin, and direct antiglobulin test.

“Bone marrow biopsies and [computed tomography] scans are listed as ‘not necessarily required,’ ” Dr. Barr, medical director of the Clinical Trials Office for Wilmot Cancer Institute at the University of Rochester (N.Y.) said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

He added that he opts for CT scans prior to therapy “to understand the patient’s disease burden and potentially to compare to later” and that bone marrow biopsy is “still very reasonable” for understanding the source of a patient’s cytopenias.

“Is it marrow failure or [immune thrombocytopenia]? Could the patient have [myelodysplastic syndrome]? All important considerations,” he said.

Positron emission tomography (PET) scans, however, are only considered when there is concern about transformation, he noted.

Predictive tests that should be conducted before initiating therapy, and that could help in guiding therapy decisions, include TP53 mutation testing and immunoglobulin heavy chain variable region gene (IGHV) mutational status testing (although this doesn’t need to be repeated if it was done at diagnosis because mutational status doesn’t change). Another helpful test is molecular cytogenetics using fluorescence in situ hybridization (FISH) for del(13q), del(17p), and trisomy 12 in peripheral blood lymphocytes. This should be repeated even it was done at diagnosis because patients can acquire additional molecular aberrations over time, Dr. Barr said.

Among the data that justify this advice for predictive testing are studies showing the curative potential of fludarabine/cyclophosphamide/rituximab (FCR) in mutated IGHV CLL, the progression-free survival (PFS) benefits of ibrutinib for patients with del(17p), and the activity of idelalisib in relapsed/refractory CLL patients, including those with TP53 dysfunction.

“The IGHV mutation status is useful to know what to expect from chemoimmunotherapy over time,” Dr. Barr said, explaining that several analyses demonstrate that patients with mutated IGHV genes (patients with low-risk disease) respond exceptionally well to chemoimmunotherapy, especially FCR.

In fact, studies, including a 2016 study by Philip A. Thompson and his colleagues and another by Kirsten Fischer and her colleagues, show that nearly 60% of patients with IGHV mutation remain in remission 10 years after FCR treatment, he said. However, the same is not necessarily true for bendamustine/rituximab (BR); the CLL10 study showed a significantly greater PFS with FCR, compared with that seen with BR.

Unmutated patients in that study had lower PFS, but the outcomes were still better with FCR than with BR, he said.

Studies of novel agents, including ibrutinib and idelalisib, suggest they may have particular benefit in higher-risk patients.

Ibrutinib was shown in a phase 2 study to be of benefit regardless of IGHV status, and this was replicated in the first-line RESONATE 2 study, which compared ibrutinib with chlorambucil and showed it had better PFS than that seen in unmutated patients treated with FCR in other studies, said Dr. Barr, the first author on that study.

“So you can see how the treatment paradigms are starting to evolve. It does look like ... comparing across trials, that ibrutinib leads to better remission durations, compared to chemoimmunotherapy, so far,” he said.

Ibrutinib has also been shown to be of benefit for patients with del(17p). A single-arm phase 2 study showed 79% PFS in relapsed, high-risk patients, which is much better than has been seen with chemoimmunotherapy, he noted.

“Venetoclax is also a very good option for this patient population in the relapse setting,” he said, adding that the PFS with venetoclax has been shown to be very similar to that with ibrutinib.

Similarly, idelalisib has been shown to provide comparable benefit in relapsed/refractory CLL patients, with and without del(17p)/TP53 mutation, he said.

Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.

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