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Assistant Professor of Medicine
Division of Hematologic Malignancies & Cellular Therapy
Department of Medicine
Attending Physician, Hematologic Malignancies
Duke University Health System
Durham, North Carolina
Danielle M. Brander, MD, has disclosed that she has received consulting fees from AbbVie, ArQule, AstraZeneca, Genentech, Pharmacyclics, Pfizer, Teva, TG Therapeutics, and Verastem and funds for research support paid to her institution from AbbVie; ArQule; Ascentage; AstraZeneca; BeiGene; DTRM; Genentech; Juno Therapeutics, a Bristol-Myers Squibb company; MEI Pharma; Pharmacyclics; TG Therapeutics; Tolero; and Verastem.
Contemporary treatment of chronic lymphocytic leukemia (CLL) involves multiple therapeutic options including various targeted agents (BTK, BCL-2, and PI3K inhibitors either as monotherapy or in combination with anti-CD20 monoclonal antibodies) or chemoimmunotherapy (CIT) regimens. The selection of an appropriate therapeutic regimen differs for individual patients based on both disease-specific and patient-specific factors. When evaluating frontline treatment choices, testing for genetic mutations can be critical to ensuring optimal outcomes. However, estimates from the real-world, prospective, observational informCLL registry place prognostic testing rates for previously untreated patients with CLL at 36% having FISH testing and 12% being tested for TP53 or IGHV mutational status. In practice, this means that patients with high-risk disease who may benefit from treatment with targeted agents could be inappropriately receiving CIT. To prevent this, we must equip ourselves with the baseline prognostic knowledge that ensures optimal decision-making and patient outcomes. Here, I’ll briefly highlight current key prognostic markers and how they inform the management of treatment-naive patients with CLL in practice today.
Let’s first discuss TP53 aberrations—either a deletion in chromosome 17p (del[17p]), which eliminates the gene encoding tumor-suppressor protein p53, or TP53 point mutations themselves. Patients may have just one of these aberrations or a mixture across alleles so it is important to test for both.
Historically, in the era of CIT, those with even a single TP53 aberration experienced significantly inferior survival compared with patients with wild-type TP53. For instance, patients with an isolated del(17p) typically required treatment within 1 year of diagnosis but responded poorly to standard regimens such as fludarabine plus cyclophosphamide and rituximab (FCR). A combinatorial effect was observed wherein harboring a TP53 mutation in addition to del(17p) drove survival rates down even further. Data from the Munich Leukemia Laboratory found that, among such doubly aberrant patients, median OS was halved—32 months instead of the 64 months observed among those with del(17p) alone.
Fortunately, with the advent of BTK inhibitors ibrutinib and acalabrutinib, metrics such as PFS have been significantly extended for these high-risk patients. Use of venetoclax plus obinutuzumab has also been shown to improve outcomes vs CIT, but it remains an open-ended question in high-risk patients whether this fixed-duration regimen should be discontinued at the standard 12 months of administration or continue beyond 12 months.
IGHV Mutational Status
Whereas TP53 aberrations occur in a minority of untreated patients with CLL (~ 10%), the presence of unmutated IGHV at diagnosis is quite common (~ 60%).
The adverse implications of unmutated IGHV have been demonstrated across studies including in one where patients treated with FCR who achieved undetectable measurable residual disease were still highly likely to relapse if IGHV unmutated. Only 16% of these patients had a long remission compared with 80% of the IGHV-mutated patients with a deep response. Moreover, median OS was cut by nearly a decade among patients with an unfavorable IGHV status. Clearly, considering the disease biology of IGHV is important when prescribing CIT.
The good news is that, in follow-up studies of frontline ibrutinib (eg, RESONATE-2 in older patients with CLL), any difference in PFS between mutated and unmutated IGHV patients disappeared. Similarly, in the CLL14 trial that evaluated venetoclax plus obinutuzumab, all patients treated with this regimen—either IGHV mutated or unmutated—had a more favorable PFS vs IGHV-unmutated patients receiving CIT. Of note, their PFS was similar to IGHV-mutated patients receiving CIT.
In summary, the optimal management of our patients with CLL still requires testing of the key markers that I have discussed here and we should endeavor to strive for universal testing of our patients with CLL.
Have current recommendations for prognostic testing been readily and universally adopted at your institution? Join the conversation by answering the poll question or leaving a comment. I also invite you to view an on-demand Webcast where I discuss CLL management in more depth with my colleagues, Drs. Jeff Sharman and Nicole Lamanna.