Long-Term Management of Patients with P53 Aberrations

Thomas Kipps, MD, PhD

With the emergence of point mutations, including TP53 aberrations in chronic lymphocytic leukemia (CLL), the need for approaches to address mutations or deletions of chromosome 17p becomes of paramount importance. Thomas Kipps, MD, PhD, distinguished professor of medicine and Evelyn and Edwin Tasch Chair in Cancer Research, UC San Diego Moores Cancer Center, will address the challenges and emerging approaches in CLL in a plenary session on September 29, 2022, during the Annual Meeting of the Society of Hematologic Oncology (SOHO 2022).

CLL, a malignant, clonal, proliferative disorder of mature CD5-positive B lymphocytes, remains an incurable disease. It is characterized by clinical heterogeneity ranging from an indolent, multiyear course to rapidly progressive disease. An estimated 21,000 new cases and 4500 deaths occur annually in the United States, making CLL the most prevalent chronic leukemia in clinical practice. However, great progress has been made, leading to more individualized treatment approaches and prolonged overall survival.

Acquired TP53 aberrations in patients with CLL have long been known to decrease survival length. Point mutations or deletions of chromosome 17p lead to a loss of apoptotic response to DNA damage. The extent of mutations can increase over time and is prognostic at each stage of the disease.

Because of resistance to chemotherapy, patients with TP53 defects should be treated with targeted therapy with an inhibitor in the B-cell receptor pathway, such as a Bruton tyrosine kinase inhibitor (BTKi) or B-cell lymphoma 2 inhibitor (BCL2i). Newer agents, including the BCL2i venetoclax (Venclexta) and the BTKis ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), have revolutionized the treatment of CLL.¹ Both types of therapy are effective and can be given orally for prolonged periods of time, but which regimen to use as a front-line treatment is still under debate.^2,3

Although BTKis are highly effective, persistent, deep remissions are rare, necessitating continuous therapy for long-term disease control (as per RESONATE [NCT01578707] and RESONATE-2 [NCT01722487] trial data). Venetoclax, especially when given in combination with anti-CD20 monoclonal antibody therapy, has a high probability of eradicating measurable residual disease and can be given for a limited period of time (24 months of treatment with rituximab [Rituxan] or 12 months of treatment with obinutuzumab [Gazyva]).^3,4

However, despite a positive impact on the length of survival, the negative prognostic importance of TP53 mutations persists. The introduction of next-generation sequencing with increased sensitivity and the ability to detect variant allele frequencies (VAFs) down to 1% has led to an ongoing discussion regarding the relevant threshold for the initiation of further therapy. A commonly used threshold is 10% VAFs, but findings from a recent study demonstrated that even low-burden VAF is associated with decreased overall survival.5 The clinical impact of persistent TP53 mutations was similar in patients with low burden VAF of less than 1%, between 1% and 5%, or between 5% and 10%.⁶

The 5-year follow-up report on the phase 3 MURANO study [NCT02005471]

emphasized the importance of following TP53 status.4The trial compared venetoclax/rituximab for up to 24 months with 6 cycles of bendamustine/rituximab (BR) in patients with relapsed or refractory CLL (R/R CLL). Undetectable minimal residual disease (uMRD) was reported for 82.5% of patients in the venetoclax/rituximab arm, compared with 23.1% receiving BR, and was maintained in 64% of 130 patients randomly assigned to venetoclax. The high rate of uMRD was independent of TP53 aberrations or IGVH mutations and correlated with longer progression-free survival; only 2 of 83 patients (2.4%) had progression of disease after a median follow-up of 9.9 months.⁴

According to recently published data, the phase 2 multicenter study (IMPROVE, NCT04754035) was designed to discontinue treatment in patients with R/R CLL who reached an undetectable MRD level of less than 10-4 (uMRD4) with venetoclax monotherapy or after the addition of ibrutinib.⁷ Patients with uMRD4 after 11 cycles discontinued venetoclax; those who were MRD positive had ibrutinib added to their regimen and continued both drugs for an additional 12 cycles or until they achieved uMRD4, had disease progression, or experienced toxicities. After the end of cycle 24, patients who were MRD positive continued receiving ibrutinib. Seventeen patients (45%) achieved uMRD4 on day 1 of cycle 12 and discontinued venetoclax. Nineteen (55%) patients who were MRD positive had ibrutinib added, and after a median of 7 months (range, 3-10) of combined treatment, 16 (84%) achieved uMRD4 and were thus able to stop both drugs. After a median follow-up of 36.5 months, 7 of 32 patients (22%) continued with undetectable MRD, and 10 patients progressed.7 Evidence from this study emphasized the value of monitoring very low levels of detectable disease, giving patients the option of additional therapy.

Kipps, referring to data from another recent study,⁸ emphasized: “We need to learn more about the biology of CLL cells from patients who fail to clear detectable MRD after prolonged therapy with venetoclax. Studies are in progress that could provide for improved therapeutic approaches for patients at high risk for developing resistance to current targeted therapies.”

Challenges With BTK Inhibitors

Some patients treated with ibrutinib develop atrial fibrillation.9 Newer agents in that drug class, acalabrutinib (FDA approved in 2019) and zanubrutinib (currently used off-label but expected to be approved soon), appear to have the same efficacy with lower cardiovascular toxicities.^10,11 Additional BTKis are being studied, including the non–covalently binding BTK is pirtobrutinib and nemtabrutinib. BTKis are often given as single drugs until unacceptable toxicity or disease progression occur, but the duration can be shortened when combined with venetoclax and/or anti-CD20 antibodies once remission with uMDR is observed.

Two PI3K inhibitors, idelalisib (Zydelig) and duvelisib (Copiktra), are also highly effective in relapsed CLL, but are associated with autoimmune reactions, potentially leading to hepatitis, enteritis/colitis, or pneumonitis.¹² Allogeneic hematopoietic stem cell transplantation, chimeric antigen receptor T cells, and bispecific monoclonal antibodies are currently under investigation.

New therapies continue to be developed and several clinical trials are evaluating new combinations, giving patients with relapsed or refractory disease, most of them with TP53 aberrations, additional options.

References

1. Hallek M, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. Am J Hematol. 2021;96(12):1679-1705. doi:10.1002/ajh.26367

2. Brem EA, O’Brien S. Is a BTKi or BCL2i preferable for first “novel” therapy in CLL? The case for BTKis. Blood Adv. 2022;6(4):1361-1364. doi:10.1182/bloodadvances.2019001204

3. Seymour JF. Is BTKi or BCL2i preferable as first novel therapy in patients with CLL? The case for BCL2i. Blood Adv. 2022;6(4):1365-1370. doi:10.1182/bloodadvances.2019001205

4. Seymour JF, Kipps TJ, Eichhorst BF, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140(8):839-850. doi:10.1182/blood.2021015014

5. Malcikova J, Pavlova S, Kunt Vonkova B, et al. Low-burden TP53 mutations in CLL: clinical impact and clonal evolution within the context of different treatment options. Blood. 2021;138(25):2670-2685. doi:10.1182/blood.202000953

6. Lazarian G, Cymbalista F, Baran-Marszak F. Impact of low-burden TP53 mutations in the management of CLL. Front Oncol. 2022;12:841630. doi:10.3389/fonc.2022.841630

7. Scarfo L, Heltai S, Albi E, et al. Minimal residual disease-driven treatment intensification with sequential addition of ibrutinib to venetoclax in R/R CLL. Blood. Published online August 3, 2022. doi:10.1182/blood.2022016901

8. Ghia EM, Rassenti LZ, Choi MY, et al. High expression level of ROR1 and ROR1-signaling associates with venetoclax resistance in chronic lymphocytic leukemia. Leukemia. 2022;36(6):1609-1618. doi:10.1038/s41375-022-01543-y

9. Ganatra S, Sharma A, Shah S, et al. Ibrutinib-associated atrial fibrillation. JACC Clin Electrophysiol. 2018;4(12):1491-1500. doi:10.1016/j.jacep.2018.06.004

10. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210

11. Hillmen P, Brown JR, Eichhorst BF, et al. ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Future Oncol. 2020;16(10):517-523. doi:10.2217/fon-2019-0844

12. Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132(23):2446-2455. doi:10.1182/blood-2018-05-850461