Critical Reviews in Oncology / Hematology 201 (2024) 104428

Available online 3 July 2024

1040-8428/© 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Safety profile of first-line targeted therapies in elderly and/or comorbid

chronic lymphocytic leukaemia patients (unfit subpopulation). A

systematic review and network meta-analysis

Anita Stozek-Tutro ˙ a,*

, Monika Reczek b

, Paweł Kawalec c

a Jagiellonian University Medical College, Doctoral School of Medical and Health Sciences, Cracow, Poland b HTA Consulting, Cracow, Poland c Jagiellonian University Medical College Institute of Public Health, Cracow, Poland

ARTICLE INFO

Keywords:

Chronic lymphocytic leukaemia

Targeted therapies

Systematic review

Network meta-analysis

ABSTRACT

This systematic literature review (CRD42023393903) and a Bayesian network meta-analysis (NMA) aimed to

assess the relative safety profile of first-line targeted therapies (acalabrutinib, ibrutinib, obinutuzumab, ofatumumab, pirtobrutinib, ublituximab, umbralisib, venetoclax, zanubrutinib) in chronic lymphocytic leukaemia

(CLL) patients with advanced age and/or comorbidities. The NMA revealed that zanubrutinib was the safest

treatment option in terms of the overall safety profile (e.g., serious adverse events [AEs] grade 1–5), followed by

venetoclax-obinutuzumab, which showed an advantage in terms of AEs grade 1–5. The use of Bruton’s tyrosine

kinase inhibitor (BTKi) monotherapy was more favourable in terms of the risk of haematological AEs, but

chemoimmunotherapy showed advantages in terms of cardiovascular, gastrointestinal, and infectious AEs. The

risk of secondary cancers was similar between treatments. In conclusion, targeted therapies are associated with

variable and clinically relevant AEs. The therapies appear to be safer when used as monotherapy rather than in

combination with immunological agents in naïve CLL patients with advanced age and/or comorbidities.

1. Introduction

Chronic lymphocytic leukaemia (CLL), a B-cell leukaemia, is the

most common leukaemia in Western countries with an annual incidence

rate reaching 3.79/100,000 in Europe and 4.40/100,000 in the United

States (Hallek, 2019; National Cancer Institute, 2023; Sant et al., 2010).

CLL is twice as common in men as in women, and primarily affects

elderly individuals. The diagnosis is usually made between the age of 65

and 74 years, with a median of 69 years (National Cancer Institute,

2023).

Due to the significant biological and genetic diversity of CLL, the

clinical presentation is highly variable (Eichhorst et al., 2021; Hallek,

2019; Hus et al., 2021). So far, numerous prognostic factors of CLL have

been identified (Hallek, 2019; Yun et al., 2020). However, apart from

the well-known cytogenetic biomarkers (e.g. deletions of the short arm

of chromosome 17 [del17p], mutations in the TP53 gene [mTP53], lack

of mutations of the gene encoding the variable region of the immunoglobulin heavy chain [umIGHV]), the main unfavourable indicators are

advanced age and the presence of comorbidities (Eichhorst et al., 2021;

Shadman, 2023; Yun et al., 2020). For years, patients in this subpopulation of CLL did not have access to effective therapeutic options. Due to

their advanced age and comorbidities, they were unable to receive the

highly toxic fludarabine-based therapy (so called “unfit” population)

(Eichhorst et al., 2021; NCCN Clinical Practice Guidelines in Oncology,

2023; Shadman, 2023). The progress that has been made in recent years

in the understanding of the biology of CLL has contributed to the

introduction of new drugs for the treatment of this subpopulation (Karr

and Roeker, 2023). These new drugs, also called targeted therapies,

include, for example, new monoclonal antibodies (ofatumumab (OFA),

obinutuzumab (OBI)), BTK inhibitors (first generation: ibrutinib (IBR),

second generation: acalabrutinib (ACA), zanubrutinib (ZAN)), 3-kinase

phosphatidylinositol inhibitor (idelalisib), and BCL-2 inhibitor (venetoclax, VEN). Targeted therapies are characterised by a different

mechanism of action, which affects not only the duration of therapy but

also the efficacy and safety profile (Eichhorst et al., 2021; NCCN Clinical

Practice Guidelines in Oncology, 2023).

* Correspondence to: Jagiellonian University Medical College, Doctoral School of Medical and Health Sciences, street: Łazarza 16, room 217, Cracow 31-530,

Poland.

E-mail addresses: anita.stozek-tutro@doctoral.uj.edu.pl (A. Stozek-Tutro), ˙ m.reczek@hta.pl (M. Reczek), pawel.kawalec@uj.edu.pl (P. Kawalec).

Contents lists available at ScienceDirect

Critical Reviews in Oncology / Hematology

journal homepage: www.elsevier.com/locate/critrevonc

https://doi.org/10.1016/j.critrevonc.2024.104428

Critical Reviews in Oncology / Hematology 201 (2024) 104428

2

The treatment of the naïve unfit CLL subpopulation began to change

in the early 2000s with the introduction of therapeutic regimens

combining anti-CD20 antibodies (e.g., obinutuzumab) with chlorambucil (CLB). While these regimens showed general good efficacy, they

were not perfect. For example, their limited efficacy was reported

among patients with cytogenetic abnormalities, such as del17p. A significant advancement in the treatment of naïve unfit CLL patients was

the approval of drugs such as IBR in 2016 and VEN in combination with

OBI in 2020 (Frustaci et al., 2023; Karr and Roeker, 2023; Monica et al.,

2018). In this case, the clinical efficacy was found to be unaffected by

specific cytogenetic abnormalities, including the previously mentioned

del17p. Although both therapies had an acceptable safety profile, they

differed significantly with respect to certain types of adverse events

(AEs) (EMA, 2024a, 2023a). Treatment with IBR was associated with an

increased risk of cardiac AEs, particularly an increased risk of atrial

fibrillation. An increased risk of bleeding events was also reported

(Leong et al., 2016; Wiczer et al., 2017). On the other hand, therapy with

VEN and OBI was associated with an increased risk of severe neutropenia, infections, and tumour lysis syndrome (TLS) (EMA, 2024a). In

the following years, second-generation BTKIs (ACA, ZAN) were introduced into CLL therapy, along with subsequent therapeutic doublets

(after VEN+OBI) such as IBR+OBI or IBR+VEN (EMA, 2024b, 2024a,

2023b, 2023a). Each of these regimens has a different safety profile

(NCCN Clinical Practice Guidelines in Oncology, 2023). In addition,

other therapeutic doublets, and even triplets, of targeted therapies are

currently in clinical trials (Eichhorst et al., 2023). Given the significant

recent advances in therapeutic options for this population, as well as the

potential challenges in selecting the most suitable therapy for these

patients, we decided to focus on the unfit population in this study.

The effectiveness of targeted therapies has been confirmed in randomised clinical trials (Eichhorst et al., 2021; Karr and Roeker, 2023;

NCCN Clinical Practice Guidelines in Oncology, 2023). However, due to

the limited availability of studies directly comparing the efficacy and

safety of individual options, several systematic reviews with network

meta-analysis (NMA) have also been conducted in recent years (Carida `

et al., 2022; Chanan-Khan et al., 2022; Molica et al., 2023; Pearson et al.,

2022; Rizzuto et al., 2023). Nevertheless, the published systematic reviews with NMA have certain limitations. For example, some of them

were conducted to evaluate only selected therapeutic options (Carida `

et al., 2022; Chanan-Khan 2022, Molica 2023, Rizzuto 2023), while

others included also subpopulation eligible for fludarabine-based therapy, what may have affected the obtained results and conclusions

(Carida ` et al., 2022; Rizzuto 2023). Furthermore, some of them were

published only as conference proceedings (Chanan-Khan 2022, Pearson

2022, Carid`

a et al., 2022) or as a list to the Editor (Molica 2023).

However, the most important limitation of the above systematic reviews

is the fact that they primarily focus on the assessment of efficacy,

completely omitting the assessment of the safety profile (Chanan-Khan

2022) or analysing only a few selected endpoints regarding this area

(Carida ` et al., 2022; Molica 2023, Rizzuto 2023, Pearson 2022) (Carida `

et al., 2022; Chanan-Khan et al., 2022; Molica et al., 2023; Pearson et al.,

2022; Rizzuto et al., 2023). Considering the specificity of the unfit

subpopulation, it seems necessary to expand on the knowledge about the

relative safety profile of all new therapeutic options, including newly

approved ones such as ZAN and IBR+VEN combination therapy.

This study aimed to address this knowledge gap by conducting a

systematic review and network meta-analysis of existing literature

regarding the safety profile of novel therapeutic options (targeted

therapies) used in patients with naïve CLL with advanced age and/or

comorbidities (unfit subpopulation).

2. Materials and methods

This study was conducted in line with the Preferred Reporting Items

for Systematic Review and Meta-Analyses (PRISMA) (Page et al., 2021)

guidelines and had a prespecified protocol registered on PROSPERO

(Registration no CRD42023393903).

2.1. Data selection (systematic literature review)

A systematic review of the literature was performed to identify

randomised clinical trials (RCTs) involving patients with naïve CLL with

advanced age and/or comorbidities, who received first-line treatment

using targeted therapies (ACA, IBR, OBI, OFA, pirtobrutinib, ublituximab, umbralisib, VEN, ZAN) in monotherapy or combination therapy.

Detailed inclusion and exclusion criteria are presented in Table 1.

A literature search involving the main medical databases: MEDLINE,

EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL), were conducted on May 23, 2023. Additional data sources were

also searched, including the websites of selected government agencies

(European Medicine Agency [EMA]), clinical trial registries (clinicaltrial.gov, EU Clinical Trial Register), and websites of societies and

scientific conferences in the field of haemato-oncology and oncology

(American Society of Clinical Oncology [ASCO], American Society of

Hematology [ASH], European Hematology Association [EHA], and

others). Moreover, the references of the included studies were analysed

to identify relevant publications, not indexed in the databases listed

above. Hand searching on the Internet and contact with the authors of

selected clinical trials were employed. The last search of additional data

sources was performed on July 1, 2023. No time limits were applied to

any of the above-mentioned sources, except for the websites of societies

and organizations, where searches were limited to approximately the

last 12 months (2022–2023) due to potential delays in indexing conference materials in the main medical databases.

The search strategy in the main medical databases was developed

using keywords grouped into three domains representing population

(CLL), interventions/comparator (targeted therapies), and type of clinical trial (RCT), combined with appropriate Boolean operators. Searches

were not restricted to endpoint keywords, resulting in a high-sensitivity

search strategy that covered all safety outcomes. The detailed search

strategy and search results are presented in the supplementary materials

(Tables S1-4 Suppl. Mat.). The selection of abstracts and full-text publications was carried out by two reviewers (AST, MR) working independently. Any discrepancies in the process of study qualification for

analysis were resolved by consensus.

2.2. Data extraction & synthesis (network meta-analysis)

Data extraction, including study methodology, baseline characteristics

of patients, and results of the analysed endpoints from included studies,

was performed by one reviewer (AST) according to standardised forms.

First, data were extracted from full-text publications and then from other

materials. The extracted data were validated by a second reviewer (MR).

Any disagreements were resolved by consensus. A revised Cochrane risk

of bias tool for randomised trials (RoB2) was used to assess the risk of bias

in the studies included in the analysis (Sterne et al., 2019). The visualisation of RoB2 results was developed using the robvis tool (Creative

Commons Attribution-NonCommercial-NoDerivatives 4.0 International

License, 2023).

The NMA was performed using a Bayesian framework according to

National Institute for Health and Care Excellence (NICE) guidelines

(Dias et al., 2011), and the Markov chain Monte Carlo method was

implemented in WinBUGS with vague prior distributions for model parameters (Lunn et al., 2000). Both fixed-effects and random-effects

models were used. The selection of the model was made depending on

the heterogeneity of the studies and the value of the Deviance Information Criterion (DIC), considering the complexity of the model and the

adequacy of the fitting to data. In this approach, the model for which a

lower value of the DIC parameter was obtained was preferred. However,

when a lower DIC value indicated a model, whose results were

A. Stozek-Tutro ˙ et al.

Critical Reviews in Oncology / Hematology 201 (2024) 104428

3

inconsistent with the results of the direct comparison (and the DIC value

for the fixed and random models did not differ by more than 5), the

opposite model was selected. Three chains were run for each analysis

with 50,000 burn-in iterations for both models (fixed and random),

followed by 100,000 iterations. The results of the NMA are presented as

odds ratios (ORs) with 95 % credible intervals (CrI). If the associated

95 % CrI included a value of 1.0, then the ORs were considered as not

statistically significant. Statistical summaries were presented in tables

and appropriate forest plots.

For each analysed endpoint, the overall cumulative ranking of each

therapeutic option was estimated using the surface under the cumulative

ranking curves (SUCRA). SUCRA takes values from 0 % to 100 %. The

higher the SUCRA value, the more preferred the therapeutic option is in

terms of the analysed endpoint.

Details related to network geometry for individual endpoints, input

and output data for the NMA, are presented in the supplementary material. The figures presenting the NMA results were prepared using

Adobe Illustrator.

3. Results

3.1. Search results

The literature search conducted in medical databases and registers

identified 6664 publications. After removing duplicates, 3662 publications were screened, and consequently 3002 publications were excluded

based on titles and abstracts. After analysing 276 full-text publications,

another 218 publications were excluded. Ultimately, literature review

identified 10 RCTs ((ALLIANCE (Woyach et al., 2018), CLL11 (ClinicalTrials.gov, 2018a, 2018b, 2018c; EMA, 2014a; EU Clinical Trials

Register, 2018; Goede et al., 2014), CLL14 (Al-Sawaf et al., 2019;

Al-Sawaf et al., 2021; ClinicalTrials.gov, 2023a; EMA, 2020a; EU Clinical Trials Register, 2019a; Fischer et al., 2019a; Fischer et al., 2019c;

Fischer et al., 2019b), COMPLEMENT1 (ClinicalTrials.gov, 2019a;

EMA, 2014b; EU Clinical Trials Register, 2019b; Hillmen et al., 2015,

2013), ELEVATE-TN (AstraZeneca, 2019; ClinicalTrials.gov, 2023b;

EMA, 2020b; Munir et al., 2020; Sharman et al., 2020, 2019), GLOW

(ClinicalTrials.gov, 2022; EMA, 2022a; Kater et al., 2022; Munir et al.,

2021; Munir et al., 2022b), ILLUMINATE (Burtt et al., 2019; ClinicalTrials.gov, 2019b; EMA, 2019b; EU Clinical Trials Register, 2020;

Moreno et al., 2019), MABLE (ClinicalTrials.gov, 2015; EU Clinical

Trials Register, 2016a; Leblond et al., 2012; Michallet et al., 2018,

2016), RESONATE-2 (Aronson, 2016; Burger et al., 2016; Burger et al.,

2016a, 2016b; Burger et al., 2015; ClinicalTrials.gov, 2017; Coutre

et al., 2018; EMA, 2016c; EU Clinical Trials Register, 2016b; Hillmen

et al., 2016; Tedeschi et al., 2015), SEQUOIA (EMA, 2022d; Ghia et al.,

2022; Kahl et al., 2022; Munir et al., 2022a; NA, 2022; Tam et al., 2022,

2021)) reported in 59 publications (Table S6-8, Supp. Mat.). No studies

have been found for targeted therapies such as pirtobrutinib or

umbralisib and ublituximab. The selection process of clinical trials is

presented in the PRISMA diagram (Fig. 1). The list of excluded studies is

provided in Table S5 of the Suppl. Mat.

3.2. The characteristics of studies

All studies included in this systematic review were multicenter,

phase 3, and open label and provided evidence for IBR (5 RCTs), ACA (2

RCTs), ZAN (1 RCT), VEN (2 RCTs), OBI (5 RCTs), and OFA (1 RCT) in

approved monotherapy or in combination therapy. Four studies used

CLB and OBI combination therapy (CLB+OBI) as a comparator (CLL14,

ELEVATE-TN, GLOW, ILLUMINATE), but some minor differences in the

dosing of this regimen were noted between studies. For example, in

CLL14, unlike in other studies, after completing 6 cycles of CLB+OBI

therapy, patients additionally received 6 cycles of CLB monotherapy.

Cross-over was allowed in seven studies in the case of progression, while

it was inadmissible in two (CLL14, COMPLEMENT1), and one study

Table 1

Systematic review – inclusion and exclusion criteria.

PICOS Inclusion criteria Exclusion criteria

Population • Adult patients with untreated

chronic lymphocytic

leukaemia (CLL) for whom

fludarabine-based therapy

was inappropriate due to

advanced age and/or presence

of comorbidities (unfit subpopulation of CLL)

• Paediatric patients with

untreated chronic

lymphocytic leukaemia

• Adult patients with

untreated chronic

lymphocytic leukaemia

not requiring therapy

Intervention • Acalabrutinib

• Acalabrutinib +

Obinutuzumab

• Ibrutinib

• Ibrutinib + obinutuzumab

• Ibrutinib + rituximab

• Ibrutinib + venetoclax

• Obinutuzumab +

chlorambucil

• Ofatumumab + chlorambucil

• Pirtobrutinib

• Umbralisib + ublituximab

• Venetoclax + obinutuzumab

• Zanubrutinib

N/A

Comparator • Acalabrutinib

• Acalabrutinib +

Obinutuzumab

• Ibrutinib

• Ibrutinib + obinutuzumab

• Ibrutinib + rituximab

• Ibrutinib + venetoclax

• Obinutuzumab +

chlorambucil

• Ofatumumab + chlorambucil

• Pirtobrutinib

• Umbralisib + ublituximab

• Venetoclax + obinutuzumab

• Zanubrutinib

Additional comparators used for

the developing of the network:

• Chlorambucil

• Chlorambucil + rituximab

• Bendamustine + rituximab

N/A

Outcomes • AEs leading to treatment

discontinuation

• AE grade 1–5

• AE grade 3–5

• SAE grade 1–5

• SAE grade 3–5

• Anaemia grade 1–5

• Anaemia grade 3–5

• Thrombocytopenia grade 1–5

• Thrombocytopenia grade 3–5

• Neutropenia grade 1–5

• Neutropenia grade 3–5

• Febrile neutropenia grade 1–5

• Febrile neutropenia grade 3–5

• Diarrhea grade 3–5

• Infection grade 3–5

• Pneumonia grade 1–5

• Pneumonia grade 1–5

• Hypertension grade 1–5

• Atrial fibrillation grade 3–5

• Secondary cancer

N/A

Study design &

additional

criteria

• RCTs published as full text

publication (study report or

conference proceedings such

as abstract, poster or slide

deck were included only if

they constituted

supplementary materials for a

full-text publication)

• Language: English

• Observational studies

• Systematic and nonsystematic reviews

• Studies published only as

a study report or

conference proceedings

(abstract, poster or slide

deck)

• Language: other than

English

AE – adverse event, CLL – chronic lymphocytic leukaemia, SAE – serious adverse

event, N/A – not applicable

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(MABLE) did not provide information about cross-over. In all studies,

the efficacy of therapy was assessed as the primary endpoint, while

safety outcomes were determined as secondary endpoints.

Four studies were completed (CLL11, ILLUMINATE, MABLE, RESONATE2) and one study (COMPLEMENT-1) was terminated because most

patients (62 %) received next-line treatment after progression, including

new highly effective therapies that could confound the interpretation of

the results. The remaining five studies are still ongoing. The median

follow-up period in the included trials varied, however in this study only

data for a similar duration of follow-up periods were used

(18.4–38 months).

All clinical trials involved patients with naïve CLL requiring therapy

with advanced age and/or with comorbidities (unfit subpopulation of

CLL – patients ineligible for fludarabine). The MABLE study was the sole

exception, including not only naïve CLL patients but also those with

relapsed/refractory CLL. In this study, data for the safety profile were

presented jointly for naïve and previously treated patients. The sample

size of each study ranged from 211 to 1328, giving a total number of

4171 patients. In all studies, participants were primarily patients with

very good and good performance status (ECOG 0–1), with a small

(≤12 %) percentage of patients with ECOG ≥2 status. Three studies

involved patients without del17p (GLOW, RESONATE2, SEQUOIA),

while in the remaining clinical trials, the percentage of patients with

del17p did not exceed 15 %. The percentage of patients with the presence of umIGHV was similar between studies and ranged from 44 %

(RESONATE2) to 63 % (ELEVATE-TN). Additional data regarding the

methodology and characteristics of clinical trials are presented in the

tables (Table S6-8 in Suppl. Mat.).

Risk-of-bias assessment revealed some concerns in 8 studies, while

two (ALLIANCE, MABLE) were found to be of high risk of systematic bias

(Table S9 in Suppl. Mat.). The main concern for all studies was the lack

of blinding. In the case of the ALLIANCE and MABLE studies, additional

issues related to a high potential of systematic bias were identified.

These included inadequate presentation of patient flow in the ALIANCE

study and the lack of analysis of safety outcomes in subgroups by

treatment line in the MABLE study (likely indicating selective

reporting).

3.3. Safety profile of targeted therapies

3.3.1. General AEs

Data on the overall safety profile of targeted therapies were reported

in 9 studies for AEs grade 1–5 and grade ≥3, 10 studies for serious AEs

(SAEs) grade 1–5, 3 studies for SAEs grade ≥3, and in 6 studies for AEs

leading to treatment discontinuation; details are presented in the supplementary materials.

The results of the NMA showed that IBR+VEN therapy was associated with the highest risk of AEs leading to treatment discontinuation

compared with other (evaluated) targeted therapies, i.e., ZAN (OR

[95 % CrI] = 16.5 [2.73; 153.68]), ACA (12.56 [2.58, 102.7]), CLB+OBI

(6.93 [1.69, 51.72]), ACA+OBI (9.62 [2.02, 78.15]), and VEN+OBI

(6.67 [1.46, 52.55]), while no significant differences were found between the remaining targeted therapies. ZAN had the highest probability

of being the safest therapeutic option in this area (SUCRA: 86 %)

(Figure S1, Table S10-11 Suppl. Mat).

Similarly, IBR+VEN had a higher risk of occurrence of any AE

compared with ZAN (19.59 [1.24, 703.01]), ACA (47.21 [3.6, 1825]),

CLB+OBI (8.38 [1.19, 211.2]), CLB+OFA (12.04 [1.28, 330.8]), ACA+OBI (35.94 [2.64, 1381.2), and VEN+OBI (178.9 [9.62, 13793.1]).

However, no significant differences were revealed between IBR+VEN

and IBR or IBR+OBI. At the same time, VEN+OBI reduced the risk of any

AEs compared with IBR (0.04 [0.00, 0.48]), CLB+OBI (0.06 [0.00,

0.34]), CLB+OFA (0.08 [0.00, 0.65]), IBR+VEN (0.01 [0.00, 0.10]), and

IBR+OBI (0.01 [0.00, 0.28]), ranking as the safest option (SUCRA:

96 %) (Figure S2, Table S12-13 Suppl. Mat). The NMA results revealed

that grade ≥3 AEs were generally significantly more frequent in groups

Fig. 1. PRISMA – flow diagram.

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treated with combined therapies such as VEN+OBI, ACA+OBI,

IBR+OBI, and IBR+VEN than in monotherapy groups, especially those

on second-generation BTK inhibitors like ZAN or ACA. ZAN ranked the

highest among the evaluated targeted therapies (SUCRA: 98 %) (Fig. 2).

The analysis showed that the SAEs grade 1–5 were significantly less

frequent in the case of ZAN therapy as compared with other targeted

therapies, such as IBR (0.35 [0.20, 0.59]), ACA (0.38 [0.17, 0.85]),

IBR+OBI (0.25 [0.11, 0.57]), IBR+rituximab (RTX) (0.39 [0.22, 0.67]),

IBR+VEN (0.28 [0.12, 0.66]), and ACA+OBI (0.28 [0.13, 0.62]), but

there were no significant differences between ZAN and CLB+OBI,

CLB+OFA or VEN+OBI. Similar results were obtained for the CLB+OBI

combination therapy, although with no significant difference compared

with IBR+RTX. ZAN achieved the highest rank in the SUCRA ranking

(SUCRA: 95 %) (Fig. 3). Moreover, based on limited data, our analysis

indicated that CLB+OBI has a significantly lower risk of grade ≥3 SAEs

than other therapeutic options (ACA, ACA+OBI, IBR+OBI, IBR+VEN),

ranking as the safest therapy (SUCRA: 99 %). ZAN was not evaluated in

this aspect due to data constraints (Figure S5, Table S18-19 Suppl. Mat.).

3.3.2. Haematological AEs

The most frequently reported haematological AEs for targeted therapies were anaemia (10 trials for grade ≥3 and 9 trials for grade 1–5),

thrombocytopenia (9 trials for grade 1–5 and ≥3), neutropenia (9 trials

for grade 1–5 and ≥3), and febrile neutropenia (5 trials for grade 1–5

and 9 trials for grade ≥3).

The results of the NMA indicate that the anaemia grade 1–5 was

significantly less frequent in the case of ZAN therapy than for other

treatment options, such as CLB+OBI (0.35 [0.12, 0.98]) and ACA (0.28

[0.08, 0.96]). We did not detect significant differences between any

other individual regimens containing targeted therapies (Figure S6,

Table S20-21 Suppl. Mat.). Moreover, there were also no significant

differences between assessed targeted therapies in terms of anaemia

grade ≥3 (Figure S7, Table S22-23 Suppl. Mat.). For both endpoints,

ZAN achieved the highest SUCRA value (SUCRA: 92 % and 86 %)

(Fig. 4).

According to the results of the NMA, thrombocytopenia grade 1–5 was

reported significantly less frequently in the case of monotherapy with BTK

inhibitors, especially with ZAN therapy. ZAN showed an advantage over

ACA (0.19 [0.05, 0.69]), ACA+OBI (0.10 [0.03, 0.34]), VEN+OBI (0.08

[0.02, 0.27]), IBR+OBI (0.05 [0.01, 0.18]), and IBR+VEN (0.25 [0.06,

0.96]). In turn, among the combined therapies, IBR+VEN had the most

favourable profile, showing an advantage over VEN+OBI and IBR+OBI

(detailed values are presented in the supplementary materials). Additionally, the advantage of CLB+OFA over CLB+OBI, ACA+OBI,

Fig. 2. Results of NMA – AEs grade 3–5.

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Critical Reviews in Oncology / Hematology 201 (2024) 104428

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VEN+OBI, and IBR+OBI, as well as the advantage of IBR+VEN over

VEN+OBI and IBR+OBI were also noted (Figure S8, Table S24-25 Suppl.

Mat.). Similar results were obtained for grade ≥3 thrombocytopenia

(Figure S9, Table S26-27 Suppl. Mat). For both endpoints, ZAN achieved

the highest SUCRA rank (SUCRA: 98 % and 93 %).

The risk of neutropenia grade 1–5 and grade ≥3 was significantly

lower in the case of monotherapy with BTK inhibitors, especially ZAN

and ACA. Both options presented an advantage over CLB+OBI (0.12

[0.06, 0.24], 0.14 [0.08, 0.25]), CLB+OFA (0.21 [0.08, 0.55], 0.26

[0.10, 0.63]), ACA+OBI (0.21 [0.09, 0.49], 0.26 [0.14, 0.45])), VEN+OBI (0.12 [0.05, 0.26], 0.14 [0.07, 0.27]), IBR+OBI (0.27 [0.11,

0.66], 0.33 [0.15, 0.70]), and IBR+VEN (0.23 [0.09, 0.58], 0.28 [0.13,

0.61]). Moreover, the use of combination therapies such as ACA+OBI,

IBR+OBI, and IBR+VEN was associated with a lower risk of neutropenia

grade 1–5 compared with VEN+OBI (Figure S10, Table S28-29 Suppl.

Mat). Similarly, the use of ACA+OBI and IBR+VEN was associated with

a lower risk of neutropenia grade ≥3 compared with VEN+OBI

(Figure S11, Table S30-31 Suppl. Mat). Monotherapies ZAN and ACA

were ranked highest (neutropenia grade 1–5, SUCRA: 98 % and 92 %;

neutropenia grade ≥3, SUCRA: 96 % and 91 %).

The results of the NMA indicate that the rate of febrile neutropenia

grade 1–5 and grade ≥3 was significantly lower in the ACA group than in

the CLB+OBI group (0.17 [0.02, 0.74], 0.17 [0.02, 0.73]). Moreover,

the advantage of ACA and ACA+OBI over VEN+OBI therapy was noted

regarding neutropenia grade 1–5 and grade ≥3. There were no significant differences in this respect in the remaining comparisons for targeted therapies. For both endpoints, ACA achieved the highest score in

the SUCRA ranking (SUCRA: 89 % and 89 %) (Figure S12-13, Table S32-

35 Suppl. Mat.).

3.3.3. Cardiovascular AEs

As part of the cardiovascular risk assessment, we were able to analyse

the risk of atrial fibrillation and hypertension grade 1–5, which were

reported only in 4 trials. Our results showed that CLB+OBI reduced the

risk of hypertension grade 1–5 compared with ACA+OBI (0.21 [0.04,

0.69]), IBR+OBI (0.21 [0.07, 0.57]), and IBR+VEN (0.32 [0.10, 0.87]),

at the same time no significant differences were found between

CLB+OBI and VEN+OBI or ACA. The NMA also revealed no significant

differences in the remaining comparisons of targeted therapies.

CLB+OBI achieved the highest SUCRA rank (SUCRA: 93 %) (Figure S14,

Table S36-37 Suppl. Mat.).

Similar results were obtained in the analysis for atrial fibrillation

grade 1–5, where CLB+OBI presented significantly better results than

IBR+OBI (0.01 [0.00, 0.17]) and IBR+VEN (0.1 [0.01, 0.39]), with no

Fig. 3. Results of NMA – SAEs grade 1–5.

A. Stozek-Tutro ˙ et al.

Critical Reviews in Oncology / Hematology 201 (2024) 104428

7

notable differences compared with VEN+OBI. There were no other

differences between individual targeted therapies, except for the comparison of VEN+OBI versus IBR+OBI, in which the advantage of VEN+OBI was found (0.02 [0.00, 0.30]). CLB+OBI ranked highest in the

SUCRA analysis (SUCRA: 92 %) (Figure S15, Table S38-39 Suppl. Mat.).

3.3.4. Gastrointestinal AEs

The most frequently reported AE related to the gastrointestinal system was grade 1–5 diarrhoea, for which data were available in 9 clinical

trials. The NMA revealed that among the assessed therapeutic options,

CLB+OBI and ZAN had the most favourable safety profile. CLB+OBI

reduced the risk of diarrhoea compared with IBR (0.22 [0.09, 0.56]),

ACA (0.51 [0.31, 0.82]), ACA+OBI (0.43 [0.26, 0.68]), VEN+OBI (0.45

[0.28, 0.73]), IBR+OBI (0.22 [0.11, 0.45]), and IBR+VEN (0.13 [0.06,

0.26]), while therapy with ZAN showed a lower risk of diarrhoea

compared with IBR (0.28 [0.08, 0.97]), IBR+OBI (0.28 [0.08, 0.97]),

and IBR+VEN (0.17 [0.05, 0.56]), without differences between other

targeted therapies included in the comparison. CLB+OBI and ZAN

therapies achieved the highest scores in the SUCRA ranking (SUCRA:

81 % and 66 %, respectively) (Figure S16, Table S40-41 Suppl. Mat.).

3.3.5. Infections

Among infection-related AEs, data enabling NMA were available for

grade ≥3 infections, which were reported in 6 trials, and cases of grade

1–5 and ≥3 pneumonia, which are the most common type of infections

reported in included trials (7 trials). For grade ≥3 infections, the use of

CLB+OBI was associated with a significantly lower risk than the use of

IBR (0.23 [0.09, 0.63]), IBR+RTX (0.23 [0.08, 0.73]) or ACA+OBI (0.34

[0.17, 0.64]). This was also the case of CLB+OFA, which showed

advantage over the same therapeutic options as CLB+OBI. No significant

differences were found in relation to the remaining comparisons. Both

combination therapies, CLB+OBI and CLB+OFA ranked highest in the

SUCRA analysis (SUCRA: 87 % and 87 %, respectively) (Figure S17,

Table S42-43, Suppl. Mat.).

Moreover, NMA results showed CLB+OBI and CLB+OFA to present a

more favourable safety profile over ACA+OBI in terms of pneumonia

grade 1–5 (0.24 [0.08, 0.63], 0.14 [0.02, 0.73]). No significant differences in the remaining comparisons of targeted therapies were observed.

In relation to grade 1–5 pneumonia, the highest SUCRA value was

recorded for CLB+OFA (SUCRA: 85 %), while for pneumonia grade ≥3,

CLB+OBI was ranked highest (SUCRA: 73 %) (Figure S18-19, Table S44-

47, Suppl. Mat.).

3.3.6. Secondary cancers

Data on the incidence of secondary cancers grade 1–5 were available

in seven studies. The NMA results indicate no significant differences

between the assessed regimens containing targeted therapies. However,

among them, IBR+VEN obtained the highest SUCRA value (SUCRA:

82 %), an indication of being the safest therapy (Figure S20, Table S48-

49 Suppl. Mat.).

Fig. 4. Results of NMA – Anaemia grade 3–5.

A. Stozek-Tutro ˙ et al.

Critical Reviews in Oncology / Hematology 201 (2024) 104428

8

4. Discussion

This is, to the best of our knowledge, the first high-quality systematic

review and NMA to comprehensively evaluate the safety profile of targeted therapies in naïve CLL patients with advanced age and/or

comorbidities. The results of our systematic review with NMA showed

that each of the evaluated therapeutic options containing targeted

therapies exhibits a distinct safety profile. In everyday clinical practice,

this means that the first-line therapy selection should be based not only

on efficacy results but also on differences in safety profiles. A better

understanding of the differences in the safety profile of targeted therapies allows clinicians to optimise the treatment process and personalise

therapy.

Our study suggests that the therapeutic options that are likely to have

the most favourable safety profile are second-generation BTK inhibitors

(ZAN, ACA), followed by VEN+OBI and CLB+OBI. The advantage of

second-generation inhibitors, especially ZAN, was visible both in terms of

the overall safety profile (AE grade ≥3 and SAE grades 1–5) as well as in

terms of haematological AEs (anaemia, neutropenia, and thrombocytopenia). In turn, the advantage of VEN+OBI and CLB+OBI compared with

the other targeted therapies was marked with AEs describing the overall

safety profile such as AE grade 1–5 or SAE grade ≥3, respectively. These

results are indicative of both their mechanism of action and their timelimited usage. For instance, CLB+OBI was approved for 6-month therapy and VEN+OBI was approved as a 12-month course. This represents an

advantage over BTK inhibitor therapies, which are administered continuously until progression or unacceptable toxicity occurs.

According to current clinical practice guidelines (e.g., NCCN,

ESMO), the choice of the first-line therapy in CLL should be based on the

patient’s clinical characteristics and preferences. Regarding the clinical

characteristics, the most important factors include genetic profile,

advanced age, the presence of comorbidities, currently used therapies,

and potential AEs (Eichhorst et al., 2021; NCCN Clinical Practice

Guidelines in Oncology, 2023). Based on the above recommendations

from clinical practice guidelines and the results of this NMA, it should be

emphasised that the selection of the safest therapy should be based on

the individual assessment of potential tolerability issues. For example,

patients with advanced age and numerous comorbidities should receive

monotherapy (e.g., second-generation BTKi) rather than combination

therapy (e.g., BTKi+BCL-2) to avoid intolerance and additional complications such as drug-drug interactions. The results of the NMA

showed that ZAN was associated with the lowest risk of AEs leading to

treatment discontinuation compared with the other targeted therapies

assessed, while IBR+VEN had the highest risk in this area. In patients

with swallowing problems due to advanced age, time-limited treatment

(e.g., VEN+OBI or CLB+OBI) should be considered first to reduce the

potential risk of non-compliance, which in turn determines the efficacy

of the overall therapy. Similarly, patients with gastrointestinal problems

should receive time-limited treatment (e.g., CLB+OBI) rather than

long-term therapy with BTKi (except ZAN) to reduce gastrointestinal

AEs resulting from chronic oral therapy. A similar approach should be

used when selecting therapy in immunocompromised patients. According to our results, the best choice for these patients would be to use

CLB+OBI or CLB+OFA, depending on their market availability. Both

therapies had the lowest risk of infections, including pneumonia.

One of the first targeted therapies introduced in the treatment of CLL

was IBR – a first-generation BTKi. The drug is highly effective for naïve

CLL patients; however, it has imperfect target specificity, which is

associated with tolerability issues and AEs, in particular an increased

risk of cardiac AEs such as atrial fibrillation (Frustaci et al., 2023; Karr

and Roeker, 2023). Data from clinical trials and epidemiological studies

estimated the rate of IBR-related atrial fibrillation to be as high as 10 %

(Leong et al., 2016; Wiczer et al., 2017). This AE can lead to treatment

discontinuation, which is associated with a poor prognosis (Iskierka-Jazd˙ zewska ˙ et al., 2019). Unfortunately, we were not able to fully assess

this aspect of safety because only 4 studies reported data for targeted

therapies. However, based on our results, it is reasonable to recommend

avoiding IBR-based therapies in patients with cardiovascular disease.

Instead, other therapies should be chosen, especially from a different

therapeutic group, such as VEN+OBI or CLB+OBI. In addition, the use of

second-generation BTKi may also be considered in the selection of

optimal therapy, as they are designed to overcome the limitations of IBR

(EMA, 2024b, 2023b). However, this approach needs to be confirmed in

future studies, as we were not able to perform appropriate calculations.

Nevertheless, cardiac safety monitoring of patients is necessary whenever a BTKi is used.

Recent epidemiological data indicate that patients with CLL have a

higher risk of developing other cancers compared with the general

population (Kumar et al., 2019). While some therapeutic options have

been confirmed to have an impact on the development of secondary

cancers (e.g. FC ± RTX), the impact of targeted therapies on the carcinogenesis process remains unclear (Chatzikonstantinou et al., 2023). In

our study, we analysed the relative odds of secondary cancer, although,

the results of the NMA revealed no significant differences between the

regimens. It is necessary to conduct further research in this area to verify

the role and impact of targeted therapies. Moreover, taking into account

the NMA results, we suggest an individualised approach to monitoring

this safety aspect, especially when long-term CLL treatments are used,

for example, BTKi.

Despite the aforementioned advantages, our study also has some

limitations that should be considered when interpreting the results.

First, the main limitation of the NMA is the heterogeneity of the included

studies in terms of the length of the follow-up. Most of the studies

included in the NMA are still ongoing, which means that new data from

them are successively published. However, to ensure consistency and a

high reliability of our analysis, we only used data from the most similar

duration of follow-ups. Second, the RoB2 assessment revealed that two

of the 10 included studies (MABLE, ALLIANCE) had a high risk of the

systematic bias, that could potentially affect the results of the NMA.

However, as these studies were necessary to establish a network connecting different regimens of targeted therapies, we decided not to

exclude them. The fact that consistent results were obtained in both

indirect and direct analyses supports the reliability of the NMA results

and suggests that the high risk of bias in a few studies did not significantly affect the overall results. Third, as previously mentioned, the

MABLE study included both previously untreated and treated patients

with CLL. Despite contacting the authors of the MABLE study, we were

unable to obtain safety data according to lines of treatment. However, it

seems that this limitation should not impact the results of the NMA

significantly – the majority of included patients were treatment naïve

(~70 %), also previous treatment regimens had probably limited influence on the short-term safety observations, especially since the distribution of treatment-experienced patients across study arms was

balanced. It is also worth mentioning that the MABLE study have been

previously used in the published NMAs by other researchers, for

example, Pearson et al., who assessed the relative effectiveness of targeted therapies (Pearson et al., 2022). Fourth, the safety endpoints

analysed in this systematic literature review with NMA were originally

designated as secondary outcomes in individual clinical trials. Therefore, the impact of the potential insufficient statistical power to

demonstrate differences in the safety profile between individual targeted therapy regimens, and consequently, the impact on the obtained

NMA results cannot be excluded. Fifth, some of the analysed endpoints

were not reported in all studies, which means that we were unable to

perform a relative assessment of the safety profile for all targeted therapies simultaneously in a given area, e.g., SAEs grade ≥3 were reported

in only four trials.

Additionally, despite the wide range of endpoints assessed in this

systematic review with NMA, we were unable to evaluate haemorrhagic

and bleeding events, usually described as associated with BTK inhibitors

therapy. A feasibility assessment of the NMA conducted prior to this

analysis indicated that clinical trials differed in the reporting of this type

A. Stozek-Tutro ˙ et al.

Critical Reviews in Oncology / Hematology 201 (2024) 104428

9

of events, making it impossible to establish an appropriate network of

connections necessary for the NMA. In addition, the results of the

feasibility assessment indicated that performing the NMA to assess the

relative risk of TLS (often, but not exclusively, linked to VEN-based

treatments) was also not feasible due to the very small number of

events reported in the individual trials included in our study. Moreover,

an analysis in subpopulations identified based on cytogenetic abnormalities, e.g., with del17p or umIGHV, was unfeasible due to insufficient

data. Future studies are needed to determine the impact of these abnormalities on the safety profile of targeted therapies used in the first

line of CLL treatment.

In summary, this systematic review with NMA was designed and

conducted in accordance with applicable standards for this type of study

and based on the best available scientific evidence. The limitations

described above seem to have little impact on the obtained results and

conclusions. We believe that the results of this study will fill in the

current gap in knowledge about the relative safety profile of targeted

therapies and will support decision-making processes regarding the

optimal therapy for naïve CLL patients with advanced age and/or

comorbidities.

5. Conclusions

Therapeutic regimens based on targeted therapies are associated

with their characteristic and clinically relevant AEs, and there are differences in the occurrence and severity of those AEs. Targeted therapies

appear to be safer when used as monotherapy rather than in combination with immunological agents in CLL patients of advanced age and/or

with comorbidities. However, ZAN seems to be the option with the most

favourable safety profile in this subpopulation. Further studies are

needed, including head-to-head RCTs or studies based on real-world

data, to confirm these findings.

Founding source

The open access publication fee has been supported on the source of

funding from the \"Initiative of Excellence - Research University\" Strategic Programme provided by Jagiellonian University in Krakow.

CRediT authorship contribution statement

Anita Stozek-Tutro: ˙ Conceptualization, Methodology, Investigation, Formal analysis, Visualization, Writing – original draft, Writing –

review & editing. Monika Reczek: Investigation, Formal analysis,

Validation, Visualization. Paweł Kawalec: Conceptualization, Writing –

review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial

interests or personal relationships that could have appeared to influence

the work reported in this paper.

Acknowledgements

None

Supplementary material

Supplementary data to this article can be found in separate

document.

Appendix A. Supporting information

Supplementary data associated with this article can be found in the

online version at doi:10.1016/j.critrevonc.2024.104428.

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Anita Stozek-Tutro ˙ , Ph.D. student at Jagiellonian University Medical College, Doctoral

School of Medical and Health Sciences, with extensive experience in hematooncology /

oncology trials synthesis, systematic reviews and indirect treatment comparisons (network

meta-analyses) for scientific and pharmaceutical market access purposes.

Monika Reczek, Pharmacy Master’s graduate with postgraduate studies in Biostatistics in

medical research. She is a seasoned practitioner in the field of Market Access, specializing

in evidence synthesis for Health Technology Assessment.

Paweł Kawalec, Health scientist in clinical pharmacology and Evidence-based Medicine

expert; Head of Department of Nutrition and Drug Research, Institute of Public Health,

Jagiellonian University Medical College. His research focuses on the clinical effectiveness

assessment of pharmacotherapies in oncology as well as inflammatory diseases but also

with some expertise in pharmacoeconomics and Health Technology Assessment

A. Stozek-Tutro ˙ et al.