TP53 and IGHV Status Retain Utility as Prognostic Markers in CLL

Historical prognostic markers for chemoimmunotherapy have largely lost their clinically relevance in the context of targeted therapies for patients with chronic lymphocytic leukemia (CLL); however, IGHV and TP53 mutational status remain important predictive markers of response, now for novel treatments, according to a debate that took place during the 2021 SOHO Annual Meeting.^1,2

Although several markers of CLL activity and growth, notably IGHV and TP53 mutational status, are predictive of outcomes with fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR), the advent of targeted therapy has largely replaced chemoimmunotherapy as a treatment option for patients with CLL. Therefore, some debate exists regarding the current utility of these markers in patients receiving continuous therapy with BTK inhibitors or time-limited therapy with venetoclax (Venclexta).

During the debate, Inhye Ahn, MD, of Dana-Farber Cancer Institute, spoke in favor of using old prognostic markers in CLL, whereas Steven Coutre, MD, a professor of medicine at Stanford University, argued against using old prognostic markers.

Following both presentations, 89% of audience members voted in favor of using old prognostic markers in CLL management, according to a virtual poll.

Moreover, both presenters concluded that although the prognostic vs predictive value of IGHV and TP53 mutational status remains uncertain, all patients with CLL in clinical practice or enrolled on clinical trials should undergo fluorescence in situ hybridization (FISH) testing, TP53 mutational analysis, and IGHV mutational analysis. These conclusions are corroborated by the current International Workshop on CLL (iwCLL) guidelines for the diagnosis, indications for treatment, response assessment, and supportive management of CLL.³

IGHV Mutations

Somatic hypermutation of IGHV is a stable marker in CLL, with unmutated IGHV predicting for an unfavorable response to chemoimmunotherapy. However, in the context of targeted agents, no difference in progression-free survival (PFS) was observed between patients treated with ibrutinib (Imbruvica) with mutated IGHV or unmutated IGHV.⁴ Additionally, no difference in PFS was observed between IGHV mutational status in patients treated with venetoclax/obinutuzumab (Gazyva).⁵

However, 5-year follow-up data from the phase 3 MURANO trial (NCT02005471) demonstrated that patients with relapsed/refractory CLL who were treated with venetoclax plus rituximab and had mutated IGHV had twice as fast a doubling rate in CLL growth compared with patients with unmutated IGHV (P = .0057).⁶

“In the context of venetoclax therapy, IGHV mutations may, in fact, become a useful marker,” Ahn said. “More data are needed to determine if IGHV mutation status has prognostic value in light of fixed-duration therapy and whether this would eventually translate into a difference in outcome, especially survival,” Ahn said.

Coutre echoed this sentiment, stating that, “IGHV mutation status may be predictive of response duration with time-limited therapy. We are starting to see separation between [patients with] mutated and unmutated [IGHV with fixed-duration treatment] in distinction to continuous BTK [treatment] where mutational status doesn’t seem to make a difference and both groups of patients continue to benefit equally as they stay on therapy.”

TP53 Aberrations

TP53 aberrations are defined as 17p deletions by hierarchical FISH or TP53 mutations by sequencing plus FISH. The presence of TP53 aberrations confers a more aggressive disease state and an unfavorable response to chemoimmunotherapy.

“TP53 aberrations have been the strongest negative predictor of survival in CLL. These patients do very poorly with chemoimmunotherapy,” Ahn said.

Inferior PFS has been observed with ibrutinib (Imbruvica) treatment in patients with TP53-mutated CLL vs TP53 wild-type CLL. Findings from the phase 3 RESONATE trial (NCT01578707) showed that at a median follow-up of 6 years, the median PFS with ibrutinib was 41 months in patients with TP53-mutated CLL vs 57 months in patients with TP53 wild-type CLL (HR, 1.7; 95% CI, 1.2-2.6).⁷

“With continuous BTK inhibitor therapy, we seem to get the greatest benefit in [patients with TP53 wild-type CLL]. With the time-limited therapy, we don’t seem to get as long of a benefit, but it may play an important role when choosing initial therapy for this group of patients,” Coutre said.

Future Directions in CLL

Currently, the standard of care for patients with asymptomatic disease is active surveillance, irrespective of risk.² The phase 3 EVOLVE CLL/SLL trial (NCT04269902) is currently recruiting patients with newly diagnosed, high-risk, asymptomatic CLL or small lymphocytic lymphoma to evaluate the utility of early vs delayed treatment with venetoclax/obinutuzumab.⁸

“Does early intervention change the natural history of the disease? It’s a very important question to many of our patients,” Coutre said.

Overall survival will serve as the primary end point of the study, with safety, overall response rate, duration of response, PFS, PFS2, time to next treatment, minimal residual disease (MRD), and quality of life serving as key secondary end points. Translational end points will include MRD and resistance.

In addition to treatment decisions, biomarkers are needed to predict for the risk of immune failure from infection in patients with lower-risk CLL, Ahn explained.¹

“As the treatment landscape of CLL is rapidly evolving, the research around developing a better prognostic marker should evolve as well. Such efforts would include developing a flexible prognostic platform that allows integration of data collected before, during, and after therapy,” Ahn concluded.

References

1. Ahn I. Old prognostic markers still have a role in CLL management. Presented at: 2021 SOHO Annual Meeting; September 8-11, 2021; virtual. Session V.
2. Coutre S. Chronic lymphocytic leukemia 2021: old prognostic markers have no role in CLL management. Presented at: 2021 SOHO Annual Meeting; September 8-11, 2021; virtual. Session V.
3. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi:10.1182/blood-2017-09-806398
4. O’Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131(17):1910-1919. doi:10.1182/blood-2017-10-810044
5. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200. doi:10.1016/S1470-2045(20)30443-5
6. Kater AP, Kipps TJ, Eichhorst B, et al. Five-year analysis of Murano study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia (R/R CLL) patients (pts) following fixed-duration venetoclax-rituximab (VenR) therapy (tx). Blood. 2020;136(suppl 1):19-21. doi:10.1182/blood-2020-136109
7. Munir T, Brown JR, O’Brien S, et al. Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94(12):1353-1363. doi:10.1002/ajh.25638
8. Testing the effects of early treatment with venetoclax and obinutuzumab versus delayed treatment with venetoclax and obinutuzumab for newly diagnosed patients with high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma who do not have symptoms, the EVOLVE CLL/SLL study. ClinicalTrials.gov. Updated September 9, 2021. Accessed September 9, 2021. https://clinicaltrials.gov/ct2/show/NCT04269902