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Review

Chronic Lymphocytic Leukemia: Prognostic Factors in the Era of Novel Drugs

by
Antonio Urso
1,†,
Enrica Antonia Martino
2,†,
Antonio Cuneo
1,
Massimo Gentile
2,3,‡ and
Gian Matteo Rigolin
1,*,‡
1
Hematology Unit, St Anna University Hospital, 44124 Ferrara, Italy
2
Hematology Unit, Azienda Ospedaliera Annunziata, 87100 Cosenza, Italy
3
Department of Pharmacy, Health and Nutritional Science, University of Calabria, 87036 Rende, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
These authors also contributed equally to this work.
Cancers 2024, 16(15), 2732; https://doi.org/10.3390/cancers16152732
Submission received: 7 June 2024 / Revised: 29 July 2024 / Accepted: 29 July 2024 / Published: 31 July 2024
(This article belongs to the Section Cancer Drug Development)
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Abstract

:

Simple Summary

The treatment of chronic lymphocytic leukemia (CLL) has dramatically changed following the availability of new drugs with targeted mechanisms of action. Traditional and new prognostic factors are being investigated to individualize and guide these new treatments. In this review, we discuss the clinical relevance of genomic factors including immunoglobulin heavy chain variable (IGHV) mutational status, TP53 abnormalities, complex karyotype, and prognostic scores in relation to new targeted agents.

Abstract

Novel drugs have profoundly changed the outcomes in chronic lymphocytic leukemia (CLL) patients, and the traditional prognostic factors that were identified in the era of chemoimmunotherapy need to be validated in the context of these new targeted therapies. Currently, the most important prognostic genetic biomarkers are the immunoglobulin heavy chain variable (IGHV) mutational status, genetic aberrations including del(17p)/TP53 abnormalities, and the complex karyotype. In this review, we discuss the prognostic role of these genomic markers in relation to novel treatments. Moreover, we present and discuss new scoring systems that were elaborated and validated in the era of new drugs. In routine clinical practice, the application of an extensive genomic work-up with validated prognostic markers could improve the identification of “very high-risk” CLL patients who could benefit from novel, more effective targeted treatments.

1. Introduction

Chronic lymphocytic leukemia (CLL) is a low-grade lymphoproliferative neoplasm characterized by the accumulation of clonal B-cells expressing CD5, CD19, CD20(dim), and CD23 in the lymphoid organs and blood [1]. CLL represents the most prevalent type of hematological neoplasm in Western countries, and it is characterized by a relative clinical heterogeneity, varying from an indolent to an aggressive course with shorter progression-free survival (PFS) and overall survival (OS) [2]. This clinical variability reflects CLL’s biological and molecular diversity. Thus, there has been a need to develop tools aiding clinicians in better prognostic assessment. The Rai and Binet systems, pivotal in CLL’s prognostic history, remain standard staging systems. Both systems assess lymphocytosis, lymphadenopathy, hepatomegaly, or splenomegaly, and anemia or thrombocytopenia. The Rai system classifies patients into low-, intermediate-, and high-risk subgroups, each associated with distinct survival outcomes. These range from a median OS exceeding 10 years for low-risk cases to a median OS as short as 1.5 years for high-risk patients [3]. In contrast, the Binet system categorizes patients into three subgroups (A, B, and C), with group C having the worst prognosis. Both staging systems allow for the stratification of CLL patients into three risk groups (low, intermediate, and high), each of which are characterized by different survival (150, 101, and 19 months, respectively) [4].
In the era of chemoimmunotherapy, the advent of prognostic biomarkers has made the Rai and Binet staging systems overly simplistic for stratifying CLL patients. Currently, the crucial prognostic biomarkers routinely employed in clinical practice include the immunoglobulin heavy chain variable (IGHV) mutational status, cytogenetic aberrations such as the deletion of 17p (del(17p) and 11q (del11q), complex karyotype, and mutations of the TP53, NOTCH1, ATM, and BIRC3 genes [5,6,7,8,9,10,11,12].
The unmutated status of IGHV is associated with a higher rate of disease progression, shorter time to first treatment, and decreased OS. On the contrary, a mutated status is indicative of a more indolent course [5].
In the era of chemoimmunotherapy, mutations in TP53, a gene encoding for a tumor suppressor protein located on the short arm of chromosome 17, either alone or in combination with del(17p), have been linked to an unfavorable prognosis as demonstrated by a shorter time to next treatment and decreased or lack of response to treatment with Fludarabine–Cyclophosphamide–Rituximab (FCR) and Bendamustine–Rituximab [6,7]. The ATM gene, essential for cell cycle checkpoint activation and DNA damage response, is affected in del(11q) and present in 15–20% of CLL cases at diagnosis [8]. Often associated with unmutated IGHV status and bulky disease, del(11q), combined with TP53 alterations, leads to highly adverse outcomes in CLL patients, promoting a clonal advantage in vitro and in vivo [9]. Treatment-naive CLL patients with del(11q) can achieve sustained remission with FCR [10]. Additionally, a complex karyotype is defined as the occurrence of three or more chromosomal abnormalities in one clone [11], while high cytogenetic complexity is characterized by the presence of five or more chromosomal abnormalities [11]. A complex karyotype occurs in up to 15% of patients and is frequently associated with unmutated IGHV status. It serves as a stronger predictor than del(17p) of an inferior outcome in relapsed/refractory CLL patients, even in the era of new small molecules [12].
Although less common in clinical practice, the detection of mutations in NOTCH1, ATM, and BIRC3 genes appears very valuable in assessing CLL patient prognosis in the era of chemoimmunotherapy, as BIRC3 mutations confer a 10-year survival rate of 29% [13], while NOTCH1 and ATM mutations have been associated with adverse prognostic effects [14].
Regarding the significance of biochemical abnormalities as a prognostic indicator, serum β2-microglobulin (β2M) has been routinely considered a feasible biomarker, where elevated levels (>2.0 mg/L) correlate with a worse outcome [15]. Among cell surface markers, zeta chain-associated protein kinase 70 (ZAP-70), CD38, and CD49d expression are associated with earlier disease progression, shorter time to first treatment, and a sub optimal response to chemoimmunotherapy [16,17].
The CLL International Prognostic Index (CLL-IPI) was formulated by analyzing clinical, biological, and genetic parameters including age, clinical stage, TP53 status, IGHV status, and serum β2M, utilizing data from patients enrolled in eight randomized clinical trials in 2016. This index facilitated cases’ stratification into four distinct groups, each exhibiting different outcomes, thereby serving as a surrogate predictor of OS and time to first treatment in newly diagnosed CLL patients [18,19]. The drawback of this score lies in its lack of validation in the setting of relapsed/refractory CLL patients. Presently, the CLL treatment armamentarium has drastically improved with the availability of new small molecules in daily clinical practice, facilitating precision medicine. Bruton tyrosine kinase inhibitors (BTKi) and B-cell lymphoma 2 inhibitors (BCL2i) have demonstrated efficacy in improving PFS and OS with manageable adverse effects, even among CLL patients harboring negative biological prognostic factors. Moreover, these therapies have enhanced the depth of response, leading to improvements in treatment-free remission [20]. With the introduction of small molecules in clinical practice, it has become crucial to validate prognostic factors in the context of targeted drugs. Very recently, the German CLL study group reassessed the prognostic relevance of CLL-IPI in the era of targeted therapies, through an exploratory analysis of a pooled set of phase 2 and 3 clinical trials. Overall, the authors found that survival was improved with targeted therapies in comparison to chemoimmunotherapy and that CLL-IPI retained its prognostic role for PFS in the first-line treatment of patients; however, due to the short period of observation, a longer follow-up would be needed to assess the impact on OS. The authors also underscored that there is a need for the continuous evaluation of prognostic factors due to the ongoing evolving landscape of CLL treatment strategies also focusing on individual agents [21].
Additionally, new prognostic markers, such as the detection of measurable residual disease (MRD), could potentially be integrated into routine prognostic scores. Multi-parameter flow cytometry is currently the most used and standardized technique for MRD evaluation in CLL and, since 2018, the iwCLL guidelines have defined the threshold for undetectable MRD at 10−4 [1]. However, MRD status may have different clinical relevance, depending on which novel agent is used. Indeed, while undetectable MRD can frequently be achieved and has been associated with improved PFS in patients treated with Bcl-2 inhibitors, alone or in combination with anti-CD20 monoclonal antibody, only around 10% of patients treated with BTK inhibitors may obtain undetectable MRD, even though this does not preclude effective disease control and prolonged survival [22]. A better understanding of MRD dynamics, particularly in relation to new treatment combinations, could help to identify “very-high risk” CLL patients, who may benefit from more efficacious treatments [23].
In this review, we discuss the clinical outcomes of principal clinical trials with novel agents in relation to genomic factors including IGHV mutational status, TP53 abnormalities, and the complex karyotype, and to the new score systems that have been developed accordingly.

2. BTK Inhibitors (Covalent and Non-Covalent)

2.1. IGHV Mutational Status

The more aggressive course of patients with an unmutated IGHV configuration (U-CLL) [5,24] is accounted for by studies showing a cellular response to the antigenic engagement of B cell receptors, particularly within proliferation centers, in U-CLL and an anergic response to the antigenic stimulation in mutated cases (M-CLL) [25].
The prognostic and predictive role of the IGHV mutational status was confirmed in several trials using various chemo-immunotherapy regimens [26,27,28,29,30,31]. In patients treated with chemo-immunotherapy, the unmutated status of IGHV was associated with a higher rate of disease progression and worse outcomes [5,6,7]. However, in specific subsets of CLL patients, such as those using IGHV3-21, the clinical outcome appears to be independent of the IGHV mutational status, although these observations were mainly related to the chemo-immunotherapy era [32].
The advent of BTK inhibitors has counteracted the prognostic and predictive significance of this biomarker (Table 1). With the longest follow-up among trials with BTK inhibitors, the RESONATE-2 study still confirms the benefit of Ibrutinib in patients with unmutated IGHV status over Clhorambucil [33]. Similar results were observed in multiple randomized controlled trials comparing Ibrutinib ± anti CD20 monoclonal antibody against chemoimmunotherapy regimens in the frontline setting of both elderly and young CLL patients [22,34,35,36]. In high-risk U-CLL patients, similar results were reported in randomized controlled trials with second-generation BTKi (Acalabrutinib and Zanubrutinib versus chemo-immunotherapy) [37,38]. In the ELEVATE-TN trial [37,38], after a median follow-up of 74.5 months, in treatment-naive, unfit U-CLL patients, the median PFS was not reached in the Acalabrutinib-containing arm versus 22.2 months in the control arm of Chlorambucil–Obinutuzumab. Zanubrutinib is a BTK inhibitor, displaying higher potency and selectivity than Ibrutinib and Acalabrutinib, and with a more favorable safety profile. In the phase 3 SEQUOIA study, Zanubrutinib was demonstrated to be superior in terms of PFS in treatment-naive patients compared with Bendamustine–Rituximab [39]. Overall, patients with either mutated or unmutated IGHV in the experimental arm had significantly better PFS than patients in the chemo-immunotherapy group. Moreover, PFS was not influenced by IGHV mutational status in cases treated with BTK inhibitors. The benefit of BTK inhibitors in patients with IGHV borderline and/or harboring specific stereotyped BCR subsets (BCR subset #2) is currently under evaluation [40].
Pirtobrutinib is a selective, non-covalent, and reversible BTK inhibitor with activity towards both wild-type and C481-mutant BTK, commonly associated with resistance to covalent BTK inhibitors. In December 2023, the Food and Drug Administration approved Pirtobrutinib for the treatment of relapsed or refractory CLL patients who have received at least two lines of systemic therapy, including a BTK inhibitor and a Bcl-2 inhibitor, based on results from the phase 1/2 BRUIN trial [41,42]. Patients with U-CLL, representing the majority of cases, have an estimated median PFS of 18.7 months.
Table 1. Efficacy outcomes based on IGHV mutational status with BTK inhibitors.
Table 1. Efficacy outcomes based on IGHV mutational status with BTK inhibitors.
TrialSettingTreatmentAge
Median		No. of
Patients		U-CLL
N (%)		PFS %
M-CLL/U-CLL		OS %
M-CLL/U-CLL		Ref.
RESONATE-2TNIbr73 13658 (43)At 7 y 68/58NRBarr et al. [33]
Clb72 13360 (45)At 7 y 17/2NA
ECOG ACRIN E1912TNIbr + R58 354210 (75)At 5 y 83/75;At 5 y 97/95Shanafelt et al. [22]
FCR57 17571/115 (61.7)At 5 y 68/33At 5 y 92/84
Alliance A041202TNIbr71 18277/122 (65)At 2 y 84/79NAWoyach et al. [34]
Ibr + R71 18270/115 (61)AT 2 y 87/71NA
BR70 18371/123 (58)At 2 y 77/56NA
FLAIRTNIbr + R63 386194 (50)At 3 y 91.6/87.8NAHillmen et al. [35]
FCR62 385194 (50)At 3 y 90.5/74.2NA
iLLUMINATETNIbr + Obi70 11366/107 (62)At 4 y 89/67NAMoreno et al. [36]
Clb + Obi72 11657/107 (53)Median NA/15.2 mNA
ELEVATE-TNTNAca + Obi70 179103(57.5)At 4 y 89/86NASharman et al. [37,38]
Aca70 179119 (66.5)At 4 y 81/77NA
Clb + Obi71 177116 (65.5)At 4 y 62/4NA
SEQUOIATNZan70 241125/234 (53.4)At 2 y 83.4/88NATam et al. [39]
BR70 238121/131 (52.4)At 2 y 77.2/62.8NA
RESONATER/RIbr67 19598/134 (73)Median 48.4/49.7 mNAMunir et al. [42]
Ofa67 19684/133 (63)NANA
ELEVATE R/RR/RAca66 268220 (82.1)At 40.9 m 70.4/40.9NAByrd et al. [43]
Ibr65 265237 (89.4)At 40.9 m 53.6/48.1NA
ALPINER/RZan67 327239 (73.1)At 2 y 76/72NABrown et al. [44]
Ibr68 325239 (73.5)At 2 y: 74/60NA
BRUINR/RPirto67317168 (84)Median 19.4 mAt 24 m 73.2Mato et al. [41,42]
Abbreviations: BTK, Bruton Tyrosine Kinase; PFS, progression-free survival; OS, overall survival; Aca, Acalabrutinib; Zan, Zanubrutinib; Pirto, Pirtobrutinib; BR, Bendamustine–Rituximab; R, rituximab; FCR, Fludarabine–Cyclophosphamide–Rituximab; Ofa: Ofatumomab; Obi, Obinutuzumab; y, years; m, months; M-CLL: IGHV Mutated CLL; U-CLL, IGHV Unmutated CLL; NR: not reached; NA, not available.

2.2. TP53 Abnormalities

CLL patients harboring a TP53 disruption are those who probably benefited the most from the introduction of BTK inhibitors, given the poor outcome in the era of chemo-immunotherapy. Subgroup analyses of multiple randomized controlled trials comparing BTK inhibitors ± anti CD20 monoclonal antibodies to chemoimmunotherapy may question the predictive role of TP53 in the front-line treatment of patients with BTK inhibitors (Table 2). In the iLLLUMINATE trial, the Ibrutinib + Obinutuzumab treatment was associated with a significant PFS benefit in comparison to the control arm, with a PFS that was similar in patients with or without TP53 abnormalities [36]. Similar results were derived from the ALLIANCE trial [34] and in a pooled analysis across four studies (PCYC-1122e, RESONATE-2, iLLUMINATE, and ECOG-ACRIN E1912) [43].
The effectiveness of first-line Ibrutinib was also evaluated in a large series of 747 CLL patients with TP53 aberrations in a nationwide study, confirming that Ibrutinib is an effective first-line treatment for CLL patients with TP53 aberrations who are treated at both large academic centers and community practice hospitals [48]. Analogously, Acalabrutinib has demonstrated a survival benefit in high-risk cytogenetic subgroups, such as those with del(17p) and or mutated TP53, both in the ELEVATE-TN trial [37,38] and the ELEVATE-RR study, where PFS and OS were comparable across patients harboring high-risk cytogenetics such as del(17p), del(11q), complex karyotype, or advanced disease, regardless of the number of previous treatments [46]. Notably, in the ELEVATE-TN trial, no PFS advantage was observed in the TP53 mutant subgroup when obinutuzumab was added to acalabrutinib in comparison to acalabrutinib monotherapy [38].
By contrast, when BTK inhibitors are used in relapsed/refractory CLL patients, TP53 deficiency seems to maintain its negative predictive significance on PFS [45]. Such negative predictive value of TP53 disruption in relapsed/refractory settings was questioned by Zanubrutinib in a head-to-head randomized controlled trial with Ibrutinib, which showed a longer PFS in comparison to patients with a TP53 disruption who received Ibrutinib [47].
Finally, recent data suggest that Pirtobrutinib efficacy seems not to be influenced by TP53 disruption [41,42].

2.3. Cytogenetics

The introduction of novel agents in CLL treatment has questioned the predictive role of a complex karyotype. In the era of chemo-immunotherapy, a complex karyotype, defined as the presence of ≥3 chromosomal aberrations, was associated with a shorter time to first treatment, PFS, or OS [49]. Moreover, the presence of at least five cytogenetic abnormalities which defines a high-complex karyotype, is associated with a negative outcome, independently of TP53 status, while low or intermediate-complex karyotypes (three or four cytogenetic abnormalities) display a prognostic role only in the presence of TP53 disruption [11,50].
Nevertheless, in patients treated with BTK inhibitors, the complex karyotype should not be automatically considered as an adverse prognostic factor. In the front-line setting of patients treated with Ibrutinib, there are conflicting data. Indeed, while in the ALLIANCE trial, there was no significant impact on the PFS of the complex karyotype [34], while in the phase 2 GIMEMA LLC1114 trial, the complex karyotype was significantly associated with a shorter PFS in the multivariable analysis [51]. In a retrospective analysis including 456 TN and RR CLL patients treated with a single agent, Ibrutinib, or in combination with an anti-CD20 antibody, multivariable analysis showed that increasing karyotypic complexity was an independent predictor of shorter PFS (hazard ratio, 1.07; p < 0.0001) and OS (hazard ratio, 1.09; p < 0.0001) [12]. Finally, a phase 1/2 multicenter study evaluating Acalabrutinib in treatment-naive patients, with cases containing ≥3 chromosomal aberrations (n = 12), obtained an overall response rate of 100% and, after a median follow-up of 53 months, PFS and OS were superimposable in patients with or without complex karyotype [52].

2.4. Scoring Systems

Different prognostic models have been designed in order to better combine clinical and biological parameters (Table 3). A milestone in scoring systems in the era of Ibrutinib was represented by the four-factor prognostic model [53], which included 720 patients treated with the BTK inhibitor within phase II and III trials. Multivariable analysis and machine-learning algorithms identified four parameters, represented by TP53 aberration, prior treatment, β2M > 5 mg/L, and LDH > 250 U/L, which permitted the classification of patients into three different groups and that were demonstrated to be independently associated with an inferior PFS and OS. The model also maintained statistical significance for PFS and OS in the treatment-naive cohort. Moreover, the authors investigated the rates of BTK and/or PLCγ2 mutations, which classically confer resistance to Ibrutinib therapy, and found that the cumulative incidence of those mutations was increased in the high-risk group. Given the ease in translating the four-factor prognostic model into clinical practice, this model was also validated in the real-life setting. Indeed, the Italian multicenter working group on CLL (“Campus CLL dataset”) investigated the validity and reproducibility of the four-factor model in terms of PFS and OS, in a cohort of 586 patients treated with Ibrutinib outside of clinical studies as a first-line salvage therapy [54]. In this cohort, the presence of TP53 aberrations, a relapsed/refractory CLL status, and high LDH or β2-M levels were significantly associated with prognosis both in univariate and multivariate analysis. Moreover, the Italian group devised a survival risk score for Ibrutinib, termed SRSI, to predict OS in the setting of relapsed/refractory CLL patients treated with Ibrutinib outside of clinical trials. Again, the model included simple clinical variables such as LDH, β2-M levels, and hemoglobin, all of which were able to predict the outcome of patients treated with Ibrutinib [55,56].

3. BCL-2 Inhibitor (Venetoclax ± Anti CD20 Monoclonal Antibodies)

3.1. IGHV Mutational Status

Venetoclax is the only BCL2 inhibitor approved for the treatment of CLL.
In a pooled analysis of four phase 1 or 2 clinical trials (Table 4) that included relapsed CLL patients mostly treated with Venetoclax monotherapy [59], the IGHV mutational status did not correlate with response rates, although U-CLL patients experienced a shorter response duration. Recently, in the VENICE-1 phase 3B trial, in relapsed CLL patients treated with Venetoclax monotherapy, the IGHV mutational status did not impact on response rates, whereas U-CLL had a higher rate of undetectable MRD but an inferior PFS [60].
Venetoclax was also investigated in a head-to-head comparison with chemo-immunotherapy, both in frontline and relapsed/refractory settings (Table 4).
In relapsed/refractory CLL, the MURANO study [61] showed that after 5 years of follow-up, Venetoclax–Rituximab was superior to Bendamustine–Rituximab in terms of PFS in all the prespecified subgroups. U-CLL and M-CLL patients treated with Venetoclax–Rituximab exhibited similar response rates, including undetectable MRD at the end of treatment. After 5 years of follow-up, U-CLL patient had a higher rate of MRD conversion with subsequent progressive disease in comparison to M-CLL and a shorter median PFS in the Venetoclax–Rituximab arm [61]. Moreover, in multivariate analysis the mutated IGHV status was independently associated with a reduced risk of relapse [61]. The inferior PFS in U-CLL patients treated with Venetoclax–Rituximab could be justified by a faster CLL regrowth in U-CLL cases with undetectable MRD.
In the upfront CLL14 trial, Venetoclax–Obinutuzumab was superior to Chlorambucil–Obinutuzumab in most high-risk subgroups, including U-CLL [62]. PFS was longer in M-CLL than in the U-CLL counterpart in both treatment arms. In multivariate analysis, U-CLL predicted a worse PFS [63]. U-CLL and M-CLL obtained similar rates of undetectable MRD with Venetoclax–Obinutuzumab [62], while the MRD doubling time was not affected by the IGHV mutational status only in the Venetoclax–Obinutuzumab arm [64]. In the Venetoclax–Obinutuzumab-treated patients, OS was not influenced by the IGHV mutational status [65].
Table 4. Efficacy outcomes based on IGHV mutational status with Venetoclax.
Table 4. Efficacy outcomes based on IGHV mutational status with Venetoclax.
TrialSettingTreatmentAge
Median		No. of
Patients		No. of Pts with
U-CLL (%)		PFS
M-CLL/U-CLL		OS%
M-CLL/U-CLL		Ref.
CLL14TNVen + Obi72216121 (60.5)Median: NR/57.3 mAt 5 y 86.6/80.5Al-Sawaf et al. [62,63]
Clb + Obi71216123 (59.1)Median 54.5/26.9 mAt 5 y 87/70.8
MURANOR/RVen + R64.5194123 (68.3)Median NR/52.2 mAt 5 y 92.3/80.7Seymour et al. [61]
BR66195123 (68.3)Median 24.2/15.7 mAt 5 y 66.7/61.4
M12-175, M13-365, M13-982, M14-032R/RVen +/− R66436176 (76)NANARoberts et al. [59]
VENICE-1R/RVen68258111 (43)Median 31.8/28.3 mNAKater et al. [60]
Abbreviations: PFS, progression-free survival; OS, overall survival; NR: not reached; Ven, Venetoclax; Obi, Obinutuzumab; Clb, Chlorambucil; R, Rituximab; BR, Bendamustine-Rituximab; y, years; m, months; M-CLL, IGHV Mutated CLL; U-CLL, IGHV Unmutated CLL; NA, not available.

3.2. TP53 Abnormalities

TP53 abnormalities (del(17p) and/or TP53 mutations) have been associated with a reduced PFS in CLL patients treated with Venetoclax as a single agent, but they had no impact on response rates and rate of undetectable MRD [59,60] (Table 5).
The MURANO trial showed that, in comparison to Bendamustine–Rituximab, treatment with Venetoclax–Rituximab was associated to a PFS benefit in patients with del(17p) and/or TP53 mutations, although, in the Venetoclax–Rituximab arm, a better PFS was still observed in patients without del(17p) and/or TP53 mutation in comparison to those with TP53 abnormalities. Moreover, in the Venetoclax–Rituximab arm, the rate of undetectable MRD at the end of treatment seemed to be impaired by the presence of del(17p) as all these patients experienced progressive disease versus 22.2% of patients without del(17p) [61]. Furthermore, TP53 mutational status was identified as a covariate related to a faster MRD growth rate. Finally, in the Venetoclax–Rituximab arm, patients with del(17p) and/or TP53 mutation also had a significantly reduced 5-year OS [61].
The adverse prognostic significance of TP53 abnormalities was also confirmed in patients treated up front with a fixed duration Venetoclax–Obinutuzumab regimen. In the CLL14 trial, patients with TP53 abnormalities had a shorter PFS than those without TP53 abnormalities. Del(17p) (regardless of TP53 mutational status) and lymph node size ≥5 cm were the only variables significantly associated to a shorter PFS in multivariable analysis [62,63].

3.3. Cytogenetics

The predictive role of genomic complexity was evaluated in CLL patients treated with Venetoclax fixed-duration therapy. In the MURANO trial, high genomic complexity, as defined by the presence of five or more aberrations by array comparative genomic hybridization, was associated to higher rates of MRD positivity at the end of treatment [66] and of undetectable MRD conversion with subsequent progressive disease [61]. Moreover, in the Venetoclax–Rituximab arm, after a median follow-up of 5 years, genomic complexity negatively affected PFS but not OS [61].
In the frontline setting, the CLL14 trial showed that a complex karyotype with ≥3 chromosomal abnormalities maintained its adverse significance in the Chlorambucil–Obinutuzumab arm, whereas in the Venetoclax–Obinutuzumab arm, patients with and without a complex karyotype had similar outcomes for undetectable MRD, PFS, and OS [67].

3.4. Scoring Systems

To the best of our knowledge, there are no scoring systems specifically validated for Venetoclax-treated patients; therefore, this is an area of research that could be implemented in future studies. Nonetheless, in the aforementioned BALL score, 389 patients treated in the MURANO trial were selected and included as an external validation dataset [57].

4. Combinations of BTK and BCL2 Inhibitors

BTK inhibitors and Venetoclax have a synergistic mechanism of action in that BTK inhibitors have a preferential activity on dividing CLL cells in the lymph nodes, whereas Venetoclax exerts its activity preferentially on resting CLL cells, particularly in peripheral blood [68]. Different clinical trials combining BTK inhibitors and Venetoclax were therefore designed to improve outcome results.

4.1. IGHV Mutational Status

In the CAPTIVATE study, after 36 months of median follow-up, in the fixed-duration Ibrutinib–Venetoclax cohort, PFS rates for patients with U-CLL and M-CLL were similar (Table 6). Unexpectedly, U-CLL showed deeper MRD responses than M-CLL, with the best undetectable MRD rates in the bone marrow of 73% for U-CLL and 60% for M-CLL [69]. Of interest, similar results were also obtained in the MRD-guided cohort [70].
In the Ibrutinib–Venetoclax arm of the GLOW study, the 42-month PFS rate was longer in M-CLL than in U-CLL. Nevertheless, in a post hoc analysis, the undetectable MRD rate at the end of treatment was found to be higher and predictive of longer PFS only in U-CLL patients, while the M-CLL cases with detectable or undetectable MRD rates at the end of treatment had similar PFS. Based on these results, the evaluation of MRD seems to be more clinically relevant in U-CLL patients. Finally, in the Ibrutinib-Venetoclax cohort, the IGHV mutational status did not impact OS in both univariate and multivariate analysis [71].
In the recently published FLAIR phase 3 trial, after a median follow-up of 43.7 months, the Ibrutinib-Venetoclax arm showed a significant improvement in PFS and OS compared to FCR arm, but only in the U-CLL subgroup. No data are available on the impact of IGHV mutational status within the Ibrutinib-Venetoclax arm. Of interest, median time to undetectable MRD was shorter in patients with U-CLL versus those with M-CLL in both the peripheral blood and bone marrow [72].
The phase 3 GAIA/CLL13 trial reported a 36-month PFS rate that was slightly shorter in U-CLL treated with Obinutuzumab–Ibrutinib–Venetoclax than in M-CLL patients treated with the same regimen [73].

4.2. TP53 Abnormalities

A post hoc analysis of the CAPTIVATE trial showed that patients with TP53 aberrations (including both del17p and TP53 mutations) have the same rate of overall and complete responses, and undetectable MRD of patients without TP53 abnormalities, if treated with Ibrutinib–Venetoclax. With 36 months of follow-up, OS was not impaired by the TP53 status but, in the PFS analysis, the TP53 aberrations were associated to a slightly lower PFS rate (81% and 91% for patients with and without TP53 aberration, respectively) [69,70]. In the GLOW and CLL13 trials, patients with TP53 aberrations were excluded [71,73].

4.3. Cytogenetics

The phase 3 GAIA/CLL13 trial had identified the highly complex karyotype as defined by the presence of five or more karyotypic abnormalities, but not the complex karyotype with three or four chromosomal abnormalities, as an independent adverse prognosticator for PFS [74]. Of interest, the presence of translocations and, particularly, the unbalanced ones was also independently associated with an inferior PFS in the Venetoclax arms as previously observed in single-center series of patients mainly treated with chemo-immunotherapy [75]. CLL 13 data on the complex karyotype are of relevance because they were independent of TP53 disruptions, a factor frequently associated to complex karyotype [11].

4.4. Scoring Systems

To the best of our knowledge, there are no scoring systems specifically validated for combined BTK and BCL2 inhibitor treatments.

5. Future Directions: Conclusions

Novel drugs have profoundly changed the outcomes in CLL patients, and it appears evident from clinical trials and from data obtained in patients not included in clinical trials that, nowadays, chemoimmunotherapy has a very limited role in the treatment of CLL patients in both the frontline and relapsed refractory settings.
Targeted therapies have also been shown to improve outcomes in patients with “high-risk” genomic features including the IGHV unmutated status, TP53 dysregulation, and complex karyotype. However, conflicting data have been observed in clinical trials and real-life observations concerning the possibility of completely overcoming the negative prognostic impact of these high-risk genomic features with novel targeted agents.
The optimal first-line management of CLL patients and the most appropriate sequencing of targeted therapies or their combinations are still a matter of intense research. Actual guidelines and recommendations also suggest the individualization of treatment choices based on the clinical characteristics and preference of the patients.
In the era of novel targeted therapies, a better definition of prognostic and predictive factors will certainly help us to identify the most appropriate treatment in the different biological and clinical settings. This is of relevance as fixed-duration or continuous treatments are now available, and novel combinations of drugs with different but synergic mechanisms of action are being tested in prospective clinical trials [76].
Considering that MRD at the end of induction with a fixed-duration therapy was predictive of longer PFS and clinical benefit in most clinical trials, the European Medicine Agency (EMA) has accepted MRD as the surrogate endpoint for early licensure of new drug awaiting mature PFS data [77]. Because of that, MRD could represent an interesting surrogate clinical endpoint for outcome evaluation, as emerged from ongoing clinical trials (Table 7), and to guide individualized treatment decision, although its clinical utility in the different biological settings requires further research and standardized and reproducible methodologies [78] (Figure 1).
Additionally, mutations involving the BTK and PLCG2 [79,80] or BCL-2 [81,82] genes are emerging as relevant mechanisms for resistance and progression in patients treated with BTK and BCL2 inhibitors, respectively. The prognostic and predictive significance of these mutations is still a matter of intense research, and it is plausible that, in the future, the study of mutations could guide the choice and sequencing of treatments with novel agents [83].

Author Contributions

Conceptualization: A.C., M.G. and G.M.R.; literature search: A.U. and E.A.M.; writing the original draft manuscript: all the authors reviewed the manuscript for important intellectual content and contributed to the preparation of the final version. All authors have read and agreed to the published version of the manuscript.

Funding

Work supported by Fondo di Ateneo per la Ricerca (FAR) 2021–2023 University of Ferrara, Associazione Italiana contro le Leucemie-linfomi e mieloma (Sezione di Ferrara), and by Beat Leukemia Onlus (Milan, Italy).

Conflicts of Interest

G.M.R. received honoraria for participation in the speakers’ bureau and advisory board from Abbvie, Astra Zeneca, and Janssen. A.C. received honoraria for participation in the speakers’ bureau and advisory board from Abbvie, Astra Zeneca, Beigene, and Janssen Lilly; The other authors declare no conflicts of interest.

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Cancers 16 02732 g001
Figure 1. Recommendations and prognostic relevance for genomic biomarkers in CLL patients treated with targeted therapies.
Figure 1. Recommendations and prognostic relevance for genomic biomarkers in CLL patients treated with targeted therapies.
Cancers 16 02732 g001
Table 2. Efficacy outcomes based on TP53 status with BTK inhibitors.
Table 2. Efficacy outcomes based on TP53 status with BTK inhibitors.
TrialSettingTreatmentNo. of PtsMedian AgeNo. of Pts with TP53 Abnorms/Total Cases (%)PFS%OS%Ref.
Alliance A041202TNIbr18271 15/168 (9)At 2 y NENAWoyach et al. [34]
Ibr + R18271 20/168 (12)At 2 y NENA
BR18370 16/174 (9)At 2 y 7mNA
FLAIRTNIbr + R38663 2 (1)NANAHillmen et al. [35]
FCR38562 1 (<1)NANA
iLLUMINATETNIbr + Obi11370 13/112 (12)NENAMoreno et al. [36]
Clb + Obi11672 16/110 (15)Median 18 mNA
ELEVATE-TNTNAca + Obi17970 21 (11.7)At 1 y 95NASharman et al. [37,38]
Aca17970 19 (10.6)NANA
Clb + Obi17771 21 (11.9)At 1 y 19NA
NCT01500733TNIbr346334At 6 y 61At 6 y 79Ahn et al. [44]
SEQUOIATN
cohort C		Zan11170111/111 (100)At 2 y 88.9At 2 y 93.6Tam et al. [39]
RESONATER/RIbr19567 79/154 (51)18 m 66NAMunir et al. [45]
Ofa19667 68/149 (46)18 m 0NA
ELEVATE R/RR/RAca26866 100 (37.3)NANAByrd et al. [46]
Ibr26565 112 (42.3)NANA
ALPINER/RZan32767 30 (9.2)At 2 y 72.6NRBrown et al. [47]
Ibr32568 25 (7.7)At 2 y: 54.6NR
BRUINR/RPirto3176787/222 (39.2)Median 16.9 mNAMato et al. [41,42]
Abbreviations: BTK, Bruton Tyrosine Kinase; PFS, progression-free survival; OS, overall survival; NA, not available; NE, not evaluable; NR: not reached; Ibr, Ibrutinib; Clb, Chlorambucil; Aca, Acalabrutinib; Zan, Zanubrutinib; Pirto, Pirtobrutinib; BR, Bendamustine–Rituximab; R, Rituximab; FCR, Fludarabine–Cyclophosphamide–Rituximab; Ofa: Ofatumomab; Obi, Obinutuzumab; y, years; m, months.
Table 3. Scoring systems with novel agents in CLL.
Table 3. Scoring systems with novel agents in CLL.
Ref.Score SystemCLL TherapyNo. of
Patients		Status of DiseaseVariablesCategories
(Points)		OS Category
Soumerai et al. [57]BALL scoreIbrutinib
Idelalisib
Venetoclax		727
897
389		R/R
  • β2M (≥5 mg/L)
  • LDH > ULN
  • Hb (<110 g/L for women or <120 g/L for men)
  • time to initiation of last therapy (<24 months)

  • low (0–1)
  • int (2–3)
  • high (4)
  • low (0–1)
  • int (2–3)
  • high (4)
  • low (0–1)
  • int (2–3)
  • high (4)
2y OS
89.7%
79.5%
55.8%
82.6%
61.8%
49.5%
95.1%
84.6%
82.2%
Gentile et al. [55]SRSIIbrutinib541R/R
  • Hb (<110 g/L for women or <120 g/L for men)
  • β2M (≥5 mg/L)
  • LDH > ULN

  • Low (0)
  • Int (1–3)
  • High (4–5)
2y-OS
95.3%
81%
60.6%
Gentile et al. [56]SRSiR-idelalisib142R/R
  • Hb (<110 g/L for women or <120 g/L for men)
  • β2M (≥5 mg/L)
  • LDH > ULN

  • Low (0)
  • Int (1–3)
  • High (4–5)
2y-OS
88.6%
69.6%
54.3%
Ahn et al. [53]4-factor prognostic modelIbrutinib720R/R
  • TP53 aberration
  • prior treatment
  • β2M > 5 mg/L
  • LDH > 250 U/L

  • Low (0–1)
  • Int (2)
  • High (3–4)
3y-OS
93%
83%
63%
Morabito et al. [54]4-factor prognostic modelIbrutinib586R/R
  • TP53 aberration
  • prior treatment
  • β2M > 5 mg/L
  • LDH > 250 U/L

  • Low (0–1)
  • Int (2)
  • High (3–4)
3y-OS
89.7%
77.8%
60.3%
Molica et al. [58]CLL-3 modelIbrutinib338R/R
  • LDH values >UNL
  • Rai stage III/IV
  • early POD

  • Low (0)
  • Int (1)
  • High (2–3)
3-y OS
91%
84%
65%
Abbreviations: OS, overall survival; R/R. relapsed refractory; POD, progression of disease; UNL, upper normal limit.
Table 5. Efficacy outcomes based on TP53 status with BCL2i.
Table 5. Efficacy outcomes based on TP53 status with BCL2i.
TrialSettingTreatmentAge
Median		No. of PtsNo. of Pts with
TP53 D (%)		PFS%
TP53-ND/D		OS%
TP53-ND/D		Ref.
CLL14TNVen + Obi7221625 (12)At 5 y 65.8/40.6At 5 y 85.7/60Al-Sawaf et al. [62,63]
Clb + Obi7121624 (11)At 5 y 29.3/15.6At 5 y 54.2/80.7
MURANOR/RVen + R64.519453 (27)At 5 y 42.5/27.3At 5 y 88.7/70.2Seymour et al. [61]
BR6619555 (28)Median 19.6/13.4 mAt 5 y 61.8/60.7
M12-175, M13-365, M13-982, M14-032R/RVen +/− R66436243 (71)NANARoberts et al. [59]
VENICE-1R/RVen68258* 35 (14)* Median 30.5/19.4 mNAKater et al. [60]
Abbreviations: PFS, progression-free survival; OS, overall survival; D, disrupted; ND, not disrupted; NA, not available; Ven, Venetoclax; Obi, Obinutuzuab; Clb, chlorambucil; R, Rituximab; BR, Bendamustine-Rituximab; y, years; m, months; NA, not available. * refers to del(17p) only.
Table 6. Efficacy outcomes based on IGHV mutational status with BCL2 + BTK inhibitors.
Table 6. Efficacy outcomes based on IGHV mutational status with BCL2 + BTK inhibitors.
TrialSettingTreatmentNo. of
Patients		Age
Median		U-CLL
N (%)		PFS%
M-CLL/U-CLL		OS%
M-CLL/U-CLL		Ref.
CAPTIVATETNIbr-Ven19560119 (61)At 3 y 92/88At 3 y 100/98Allan et al. [69]
GLOWTNIbr-Ven1067167 (63.2)At 42 m 90.0/69.8NANiemann et al. [71]
Clb-Obi1057157 (54.3)At 42 m 43.1/15.0NA
FLAIRTNIbr-Ven26062123 (47.3)At 3 y 94.3/98.3At 3 y: 94.3/98.3Munir et al. [72]
FCR26362138 (52.5)At 3 y 88.6/71.2At 3 y; 88.6/71.2
CLL13TNIbr-Ven-Obi23160123 (53.2)At 3 y 96/86.6NAEichhorst et al. [73]
Ven + R23762134 (56.587/76.4NA
Ven + Obi22962130 (57)82.9/96.6NA
CIT22961131 (57.2)89.9/65.5NA
Abbreviations: PFS, progression-free survival; OS, overall survival; NA, not available; Ibr, ibrutinib; Ven, Venetoclax; Obi, obinutuzuab; Clb, chlorambucil; FCR, fludarabine–cyclophosphamide–rituximab; CIT, Chemoimmunotherapy; y, years; m, months.
Table 7. Ongoing clinical trials evaluating MRD as primary outcome.
Table 7. Ongoing clinical trials evaluating MRD as primary outcome.
TrialPhaseSettingTreatmentPrimary Endpoint
NCT037667632HR TNVenetoclaxMRD < 0.01% in BM at 12 months
NCT050690512RRBelimumab + Rituximab-VenetoclaxMRD negativity at the end of treatment
NCT059434961bTNTafasitamab + Acalabrutinib + ObinotuzumabMRD evaluation every 3 months up to 2 years
NCT051971923HR TNAcalabrutinib + Obinotuzumab-VenetoclaxMRD in BM and PB at the end of study
NCT049082282TNIbrutinib + ObinotuzumabMRD in BM at 30 days therapy initiation
NCT031288792TNIbrutinib + Venetoclax
Acalabrutinib + Venetoclax		MRD in BM after 12 cycles
Legend: HR, High Risk; TN, Treatment-naive; RR, Relapsed Refractory; MRD, Measurable Residual Disease; BM, Bone Marrow; PB, Peripheral Blood.
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Urso, A.; Martino, E.A.; Cuneo, A.; Gentile, M.; Rigolin, G.M. Chronic Lymphocytic Leukemia: Prognostic Factors in the Era of Novel Drugs. Cancers 2024, 16, 2732. https://doi.org/10.3390/cancers16152732

AMA Style

Urso A, Martino EA, Cuneo A, Gentile M, Rigolin GM. Chronic Lymphocytic Leukemia: Prognostic Factors in the Era of Novel Drugs. Cancers. 2024; 16(15):2732. https://doi.org/10.3390/cancers16152732

Chicago/Turabian Style

Urso, Antonio, Enrica Antonia Martino, Antonio Cuneo, Massimo Gentile, and Gian Matteo Rigolin. 2024. "Chronic Lymphocytic Leukemia: Prognostic Factors in the Era of Novel Drugs" Cancers 16, no. 15: 2732. https://doi.org/10.3390/cancers16152732

APA Style

Urso, A., Martino, E. A., Cuneo, A., Gentile, M., & Rigolin, G. M. (2024). Chronic Lymphocytic Leukemia: Prognostic Factors in the Era of Novel Drugs. Cancers, 16(15), 2732. https://doi.org/10.3390/cancers16152732

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