TP53-aberrated CLL: is BTK inhibitor monotherapy enough?

In this issue of Blood Advances, Tam et al¹ report on the outcome of patients with chronic lymphocytic leukemia (CLL) and TP53 aberrations, such as del(17p) and/or TP53 mutation, after zanubrutinib treatment. The frontline (n = 132) and later-line treatment (n = 94) results, based on the company-sponsored SEQUOIA (treatment-naïve, phase 3, bendamustine-rituximab as comparator), ALPINE (relapsed/refractory, phase 3, ibrutinib as comparator), and AU-003 (phase 1/2) studies, are presented. Targeted treatment has become the mainstay of treatment for CLL, initially for patients with TP53 aberrations and subsequently for patients with all CLL molecular phenotypes.² Therefore, reevaluating the significance of prognostic markers and reporting outcomes for subgroups of patients who received these targeted treatments is warranted.

Previous work has demonstrated that independent risk factors, including (1) TP53 aberrations, (2) previous treatment for CLL, (3) elevated β2-microglobulin, and (4) elevated lactate dehydrogenase can predict progression-free survival (PFS) and overall survival (OS) on ibrutinib treatment.³ In the case of >1 TP53 aberration, such as del(17p) combined with TP53 mutation(s) or multiple TP53 mutations, the prognosis for patients on ibrutinib is also inferior.^4,5 In line with these previous reports, Tam et al¹ demonstrated inferior outcomes for patients with TP53-aberrated CLL when compared with patients with TP53 wildtype CLL in the frontline setting (5-year PFS, 70.7% vs 76.5%; and 5-year OS, 82.4% vs 86.9%) and in the relapsed/refractory setting (3-year PFS, 59.3% vs 69.8%; and 3-year OS, 73.6% vs 85.2%). Furthermore, for patients with TP53 aberration(s) who were treated in the frontline setting (median follow-up, 64.8 months), 19.7% experienced adverse events that led to treatment discontinuation and 7.1% experienced fatal adverse events. For patients treated in the later-line setting (median follow-up, 39 months), 23% experienced adverse events that led to discontinuation and 17.6% experienced fatal adverse events.

When evaluating the 3 different marketed Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib,⁶ and zanubrutinib) as monotherapy for the treatment of TP53-aberrated CLL in the frontline and later-line setting, it is clear that there are some differences in the toxicity profile and maybe differences in efficacy. However, the following questions remain. First, is BTK inhibitor monotherapy sufficient for patients with TP53 aberrated CLL? And second, what is the treatment alternative for patients with TP53 aberrated CLL?

To answer the first question, the longest follow-up from a clinical trial that evaluated BTK inhibitor monotherapy for the treatment of CLL with TP53 aberrations in the frontline setting was reported from the National Institutes of Health (NIH) experience with ibrutinib.⁷ The NIH reported a 10-years PFS and OS of 38.6% and 69.7%, respectively, with 17.9% of patients remaining on treatment at 10 years. However, outside of the clinical trial setting, 65.2% of patients discontinued ibrutinib within the first 2 years of treatment (mixture of TP53 aberrated/wildtype, frontline, and later-line treated patients),⁸ indicating that adherence to BTK inhibitor monotherapy and the efficacy of this approach is markedly lower outside clinical trials. Hence, BTK inhibitor monotherapy seems insufficient for frontline and later-line treatment of most patients with TP53-aberrated CLL.

The second question is more challenging. Which treatment should be offered for the treatment of TP53-aberrated CLL? For frontline, TP53-aberrated CLL, 2 phase 2, single-arm trials evaluated time-defined triplet treatment with ibrutinib/acalabrutinib-venetoclax-obinutuzumab.^9,10 The studies reported (1) a 3-year PFS of 79.9% and an OS of 92.6% for the ibrutinib-based triplet and (2) a 4-year PFS of 70% and an OS of 88% for the acalabrutinib-based combination. The ibrutinib-based trial also demonstrated that no PFS events occurred among patients with a sole TP53 mutation nor among patients with immunoglobulin heavy-chain variable region (IGHV)-mutated CLL, emphasizing the impact of multihit TP53 aberrations and the interactions between IGHV mutational status and TP53 aberrations. Therefore, despite good results with the triplet combination, the triplet regimens did not provide a clear path toward time-defined treatment for the majority of patients who face frontline treatment of TP53-aberrated CLL and who have IGHV-unmutated status and/or multihit TP53 aberrations. Testing of minimal residual disease (MRD)–guided de-escalation and treatment intensification in high-risk CLL is thus warranted in this setting.

Two investigator-initiated trials explored this approach for the later-line treatment of CLL (including 24% to 37.5% of patients with TP53 aberrations), namely CLL2-BZAG (zanubrutinib, venetoclax, obinutuzumab, MRD guided for 13-31 months duration) and VISION/HO141 (ibrutinib, venetoclax, randomization between ibrutinib maintenance or MRD-guided observation with the option for reinitiation).^11,12 At 18 months, a 96% PFS and 96.8% OS were achieved in the CLL2-BZAG trial. A 4-year PFS of 81% and an OS of 88% was achieved in the VISION/HO141 trial without a statistically significant differences between patients allocated to MRD-guided observation or those allocated to ibrutinib maintenance. No differences in PFS or the achievement of undetectable MRD were observed between TP53 aberrated and TP53 wildtype CLL. In addition, using an MRD-guided approach to determine the duration of treatment led to a reduction in the risk of adverse events, in particular lower risks of infection, hypertension, bleeding, and atrial fibrillation in the patients randomized to MRD-guided observation.¹¹

In summary, the current evidence suggests the following:

• 1.For patients with single-hit, TP53-aberrated CLL, IGHV-mutated status, and no previous CLL treatment, BTK inhibitor monotherapy or time-defined triplet combination should be adequate (see figure). However, it is important to note that most patients with TP53-aberrated CLL represent multihit TP53 aberrations, including ∼80% of del(17p), IGHV-unmutated CLL, and later-line CLL treatment.
• 2.Therefore, for most patients with TP53-aberrated CLL, the current treatment options are insufficient. To develop an optimal treatment approach for these patients requires collaborations among the clinical, research, and pharmaceutical communities to develop and test MRD-guided options for de-escalation, intensification, and reinitiation of treatment. Such clinical trials could be based on doublet treatment combinations with stepwise intensification for patients who do not achieve optimal initial response and MRD-guided reinitiation for patients with subsequent molecular progression. Combinations with bispecific antibodies and chimeric antigen receptor T cells should also be tested in clinical trials for this patient population.

Management of TP53 aberrated CLL. Among patients with TP53-aberrated CLL, including those with del(17p) and/or TP53 mutations, patients in the frontline setting with no previous CLL treatment, only a single-hit TP53 aberration (either del(17p) alone or 1 TP53 mutation), and IGHV-mutated status should be adequately treated with BTK inhibitor monotherapy (or a time-defined triplet combination of BTK inhibitor, BCL2 inhibitor, and CD20 monoclonal antibody). For the remaining patients with TP53-aberrated CLL (multihit TP53 aberrations, IGHV-unmutated status, and/or later-line treatment), more elaborate MRD-guided combination regimens are warranted.

More than a decade after BTK inhibitor monotherapy initiated the paradigm shift for targeted treatment of CLL, it is clear that one size does not fit all. The findings highlighted by Tam et al¹ suggest that treatment approaches for these patients need to combine molecular phenotyping, MRD-guided therapy, and assessment of frailty (life expectancy and comorbidities) to provide truly personalized therapy for patients with CLL.

Conflict-of-interest disclosure: C.U.N. reports research funding and consultancy fees from AbbVie, AstraZeneca, Janssen, BeiGene, Genmab, Octapharma, Takeda, MSD, Lilly, CSL Behring, Galapagos, Synamics, and Novo Nordisk Foundation.