CLL/SLL

Inferior outcomes in elderly (over 75 years) compared to younger Chronic Lymphocytic Leukemia patients: real world findings from The Connect CLL registry

On 16th March 2017, in BMC Cancer, Chadi Nabhan from Cardinal Health Specialty Solutions, Waukegan, IL, US, and colleagues published an analysis of the Connect CLL registry (NCT01081015), a prospective, multicenter, observational cohort study.

Between March 2010 and January 2014, 1,494 CLL patients were treated at 199 US community and academic centers. In this current analysis by Nabhan et al., patients were allocated to one of two groups: LOT1 (first line of therapy; n=889) or LOT≥2 (second line of therapy or more; n=605). The number of elderly patients (≥75 yrs) in each group were 259/889 for LOT1 and 196/605 for LOT≥2.

Patients were followed-up for up to 60 months or until early discontinuation due to death, withdrawal of consent, loss to follow-up, or study termination.

Key highlights:
Response and survival
  • For all pts:
    • LOT1: ORR = 60.2%; CR = 38.1%
    • LOT≥2: ORR = 42.6%; CR = 17.0%
  • In LOT1, ORRs were significantly lower in elderly vs younger pts (ORR: 48.3 vs1%, P < 0.0001; CR: 25.9 vs 42.3%, P < 0.0001)
  • Elderly pts were less likely to be evaluated by imaging than younger pts (65.4 vs0%; P = 0.004)
Outcomes
  • For all pts: median follow-up = 32.6 months; 433 pts (29%) died
  • OS significantly lower in elderly than younger pts in LOT1 and LOT≥2 (P < 0.0001 each)
  • Elderly pts were more likely to die from CLL than younger pts:
    • LOT1: 12.6 vs 1% (P = 0.0005)
    • LOT≥2: 31.3 vs 5% (P = 0.0277)
  • Time to death from CLL or infection was significantly shorter in elderly than younger pts in LOT 1 and LOT≥2 (P < 0.0001; P < 0.0014)
  • Multivariate analysis found that age at enrollment of ≥75 yrs (HR, 3.66; 95% CI, 1.92–7.00) and del(17p) by FISH or cytogenetic testing (HR, 2.63; 95% CI, 1.20–5.78) were independent predictors of a higher risk of death
Serious Adverse Events
  • Elderly pts were more likely to experience SAEs than younger pts:
    • LOT1: 50.0 vs 4%
    • LOT≥2: 68.4 vs 9%
  • In LOT1, ≥grade 3 SAEs were more frequent in elderly pts (51.4 vs 8%)
  • ≥Grade 3 pneumonia was more frequent in elderly pts (9.7%) compared to younger pts (4.0%) in LOT1, however in LOT≥2 rates were similar (12.8 and 13.7%, respectively)
  • In LOT≥2, pyrexia, thrombocytopenia, and febrile neutropenia were more frequent in younger pts
Prognostic model for early death from CLL or infection in elderly CLL patients
  • Three predictors identified; each weighted and assigned a score based on the relative magnitude of effect:
    • Anemia at enrollment (scored 1)
    • Time from diagnosis to treatment <3 months (scored 2)
    • Enrollment therapy other than BR (scored 2)
  • Pts allocated to low- (score ≤4) or high-risk (score = 5) groups
  • Mortality due to CLL or infection was 10.3% (n = 145) vs 6% (n = 36) in low- and high-risk groups, respectively (P = 0.0002)

The authors concluded that their “data represent the real-world experiences of a large population of CLL patients treated across the USA.”

They demonstrated that elderly patients with CLL have poorer outcomes and an increased risk of death from CLL, irrespective of line of therapy, and they stressed that novel therapeutic strategies are required to improve the prognoses of elderly patients.

Nabhan et al. also concluded that their novel model of prognosis for elderly patients “could identify those patients who would benefit from early treatment or treatment with novel therapies.”

Abstract:

BACKGROUND: Median age at diagnosis of patients with chronic lymphocytic leukemia (CLL) is > 70 years. However, the majority of clinical trials do not reflect the demographics of CLL patients treated in the community. We examined treatment patterns, outcomes, and disease-related mortality in patients ≥ 75 years with CLL (E-CLL) in a real-world setting.

METHODS: The Connect® CLL registry is a multicenter, prospective observational cohort study, which enrolled 1494 adult patients between 2010-2014, at 199 US sites. Patients with CLL were enrolled within 2 months of initiating first line of therapy (LOT1) or a subsequent LOT (LOT ≥ 2). Kaplan-Meier methods were used to evaluate overall survival. CLL- and infection-related mortality were assessed using cumulative incidence functions (CIF) and cause-specific hazards. Logistic regression was used to develop a classification model.

RESULTS: A total of 455 E-CLL patients were enrolled; 259 were enrolled in LOT1 and 196 in LOT ≥ 2. E-CLL patients were more likely to receive rituximab monotherapy (19.3 vs. 8.6%; p < 0.0001) and chemotherapy-alone regimens (p < 0.0001) than younger patients. Overall and complete responses were lower in E-CLL patients than younger patients when given similar regimens. With a median follow-up of 3 years, CLL-related deaths were higher in E-CLL patients than younger patients in LOT1 (12.6 vs. 5.1% p = 0.0005) and LOT ≥ 2 (31.3 vs. 21.5%; p = 0.0277). Infection-related deaths were also higher in E-CLL patients than younger patients in LOT1 (7.4 vs. 2.7%; p = 0.0033) and in LOT ≥ 2 (16.2 vs. 11.2%; p = 0.0786). A prognostic score for E-CLL patients was developed: time from diagnosis to treatment < 3 months, enrollment therapy other than bendamustine/rituximab, and anemia, identified patients at higher risk of inferior survival. Furthermore, higher-risk patients experienced an increased risk of CLL- or infection-related death (30.6 vs 10.3%; p = 0.0006).

CONCLUSION: CLL- and infection-related mortality are higher in CLL patients aged ≥ 75 years than younger patients, underscoring the urgent need for alternative treatment strategies for these understudied patients.

TRIAL REGISTRATION: The Connect CLL registry was registered at clinicaltrials.gov: NCT01081015 on March 4, 2010.

Reference:
  1. Nabhan C. et al. Characterizing and prognosticating chronic lymphocytic leukemia in the elderly: prospective evaluation on 455 patients treated in the United States. BMC Cancer. 2017 Mar 16;17(1):198. DOI: 10.1186/s12885-017-3176-x.

 

Expert Opinion

This is an analysis of a considerable number of older CLL patients (n = 455) treated between 2010 and 2014 at various sites in the US with treatment and outcome data captured within a US registry (Connect CLL registry). Median age was over 80 years. Reported data confirms that such patients, when having been treated front-line or further-line for CLL, will die from CLL-unrelated causes but at great proportion also from CLL and from infections. In fact, CLL- and infection-related mortality was higher than in younger counterparts in this study, hence providing a rationale to rigorously treat CLL even in such very old patients and not leave the patient without treatment based on a wrong assumption that he/she will most likely die from other comorbidities/causes.