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2022-12-15T15:41:26.000Z

Educational theme | Targeted treatment for elderly patients with CLL

Dec 15, 2022
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Learning objective: After reading this article, learners will be able to recall the suitability of targeted agents for patients with CLL aged ≥80 years

Chronic lymphocytic leukemia (CLL) is a disease typically associated with older patient populations.1 The median patient age is 72 years, with ~20% of patients being aged ≥80 years. These patients often present with a range of comorbidities and organ dysfunctions and a high degree of frailty, which have been shown to negatively affect survival outcomes in the context of CLL.1

In recent years, targeted therapies such as Bruton's tyrosine kinase (BTK) inhibitors have transitioned into the standard of care treatment modality for this patient group, where they have displayed both favorable efficacy outcomes and safety profiles, displacing the more traditional chemoimmunotherapy treatment options.1 However, data on the use of targeted therapies in patients aged ≥80 years are sparse as this patient population has been underrepresented in clinical trials evaluating the use of these agents. For example, the median ages of patients in the iLLUMINATE (NCT02264574) and RESONATE (NCT01578707) trials were 73 and 71 years, respectively, while the MURANO (NCT02005471) and CLL14 (NCT02242942) trials had median patient ages of 65 and 72 years, respectively. Furthermore, the proportion of patients ≥80 years included in these trials is four-fold lower than in the general population of patients diagnosed with CLL.1

Our education theme series this quarter is centered on treatment considerations for older patients with lymphoma and CLL. Previous editions in the series have focused on treatment considerations for elderly patients with lymphoma and the management of aggressive B-cell lymphomas in older patients. This current article will address the suitability of targeted agents in older patients with CLL.

A recent publication by Simon et al.1 aimed to evaluate outcomes of patients with CLL aged ≥80 years treated with targeted agents by performing a pooled analysis of data from six German CLL Study Group (GCLLSG) clinical trials and evaluating data from the GCLLSG registry. Below, the Lymphoma Hub presents a summary of their findings.

Study design

Data were pooled from six GCLLSG trials: CLL14, CLL2‑BIO, CLL2‑BIG, CLL2‑BAG, CLL2‑BCG, and CLL2‑GIVe (Figure 1). The targeted agents examined in these trials were venetoclax, ibrutinib, and idelalisib; treatment with CD20-antibodies plus chemotherapy was not considered targeted therapy for the purposes of this analysis. Study inclusion criteria included an age of ≥80 years and for a patient to have received at least one dose of a targeted agent in a first-line setting.

In addition, data from the GCLLSG registry of patients ≥80 years at the time of first-line treatment initiation who were treated with BTK inhibitor monotherapy outside of clinical trials were also included for analysis.

Figure 1. Study population* 

BTK, Bruton’s tyrosine kinase; GCLLSG, German CLL Study Group.
*Adapted from Simon, et al.1

The included patients and details of their treatment, according to the GCLLSG trial, are shown in Table 1.

Table 1. Treatment overview*

Trial

Therapy

Protocol

Number of patients included for analysis

CLL14

Obinutuzumab + venetoclax

Six cycles of obinutuzumab + venetoclax followed by six cycles of venetoclax

27

CLL2-GIVe

Obinutuzumab + ibrutinib + venetoclax

Six cycles of obinutuzumab + ibrutinib + venetoclax, followed by six cycles of venetoclax + ibrutinib

2

CLL2-BIO

Ibrutinib + ofatumumab

Up to two cycles of optional bendamustine debulking followed by six cycles of induction treatment and up to eight cycles of maintenance treatment, depending on MRD status

1

CLL2-BIG

Ibrutinib + obinutuzumab

3

CLL2-BAG

Venetoclax + obinutuzumab

0

CLL2-BCG

Idelalisib + obinutuzumab

0

GCLLSG, German CLL Study Group; MRD, minimal residual disease.
*Data from Simon, et al.1

Results

Baseline characteristics of the 33 clinical trial patients aged ≥80 years selected for analysis are presented in Table 2.

Table 2. Baseline characteristics of the clinical trial patients*

Baseline characteristic

Clinical trial patients ≥80 years
(n = 33)

Mean age, years

82.7

Median age, years

82.0

Male, n (%)

18 (54.5)

Female, n (%)

15 (45.5)

ECOG performance status, n (%)

 

                                   01

31 (93.9)

                                   >1

2 (6.1)

Total CIRS score (categorical), n (%)

 

                                   6

9 (29.0)

                                   >6

22 (71.0)

                                   Missing information

2 (6.1)

Genetic aberration, type according to hierarchical model, n (%)

 

                                   del(17p)

2 (6.1)

                                   del(11q)

5 (15.2)

                                   Trisomy 12

6 (18.2)

                                   No del

8 (24.2)

                                   del(13q) alone

12 (36.4)

IGHV mutational status, n (%)

 

                                   Unmutated

18 (56.3)

                                   Mutated

14 (43.7)

                                   Missing information

1 (3.0)

CLL-IPI risk group, n (%)

 

                                   Low

0 (0.0)

                                   Intermediate

9 (31.0)

                                   High

17 (58.6)

                                   Very high

3 (10.3)

                                   Missing information

4 (12.1)

CLL, chronic lymphocytic leukemia; del, deletion; ECOG, Eastern Cooperative Oncology Group; IGHV, immunoglobulin heavy chain gene; IPI, International Prognostic Index.
*Adapted from Simon, et al.1

The median time from initial diagnosis to start of first-line treatment was 38 months. A total of 17 (51.5%) patients completed the treatment according to protocol, with 16 patients discontinuing treatment early.

Efficacy

Efficacy data from the clinical trial patients are presented in Table 3.

Among the GCLLSG registry, for patients aged <80 years, there was an overall response rate of 35.7%, with a 28.6% non-response rate and 35.7% missing response assessment. The median time to next treatment was 78 months for patients <80 years and 47 months for patients ≥80 years. The median overall survival was 35.6 months for patients ≥80 years, while it was not reached in patients <80 years.

Table 3. Efficacy data for all clinical trial patients*

Response, % (unless otherwise stated)

Clinical trial patients 80 years
(n = 33)

Clinical trial patients <80 years
(n = 324)

ORR

72.7

95.7

                                   CR or CRi

36.4

37.4

                                   PR

36.4

58.4

Stable disease

9.1

0.9

Missing response assessment

18.2

3.4

uMRD

72.7

71

4-year PFS

62.5

75.1

Median PFS, months

49.2

Not reached

4-year OS

67.8%

91.7

Median OS, months

Not reached

Not reached

CR, complete response; CRi, CR with incomplete bone marrow recovery; GCLLSG, German CLL Study Group; ORR, overall response rate; OS, overall survival, PFS, progression-free survival; uMRD, undetectable minimal residual disease.

*Data from Simon, et al.1

Safety

  • A total of 11 patients from the clinical trial population aged ≥80 years died (33.3%), with five of these deaths attributed to an adverse event (AE).
  • Two of the AE deaths (40%) were from infections related to treatment, while three were deemed to be unrelated to treatment.
  • Additional causes of death in the clinical trial population (not assessed as AEs due to a shorter reporting period) were progressive disease, infection, cardiac arrest, cardiac failure, respiratory insufficiency in the context of an adenocarcinoma of the lung, and unknown cause. Each of these causes accounted for one death.
  • Among the clinical trial population of <80 years, six patients died, accounting for 8% of the analysis population. The most frequent cause of death was an AE (50%).
  • Seven patients (21.2%) experienced a secondary malignancy, with two of these patients experiencing two secondary cancers.

Conclusion

The results presented above demonstrate that targeted therapy represents an effective and relatively safe treatment option for elderly patients with CLL, albeit to a lesser extent than in younger patient populations. While these data are encouraging, a key limitation of the study was its small sample size. In addition, most trial patients were from the CLL14 study, skewing the results towards treatment with venetoclax + obinutuzumab. The additional analysis of patients from the GCCLSG registry treated with BTK inhibitor is not particularly robust due to the observational nature of the registry. The high rate of therapy discontinuation and deaths in this patient population underscores the fact that patients aged >80 years need to be differentiated by more than age alone.

While targeted treatment in patients aged ≥80 years appears to be an effective strategy, further data and increased inclusion of elderly patients aged ≥80 years in clinical trials is warranted to fully inform clinical decision making.

  1. Simon F, Giza A, Robrecht S, et al. Pooled analysis of first-line treatment with targeted agents in patients with chronic lymphocytic leukemia aged 80 years and older. Leuk Lymphoma. 2022. Online ahead of print. DOI: 1080/10428194.2022.2123223

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