Effectiveness of ibrutinib as first‐line therapy for chronic lymphocytic leukemia patients and indirect comparison with rituximab‐bendamustine: Results of study on 486 cases outside clinical trials

Abstract

To The Editor: Ibrutinib (IB) has been initially approved for naïve patients treatment with chronic lymphocytic leukemia (CLL) based on its superiority over chlorambucil. Two subsequent large phase 3 randomized trials demonstrated a longer progression-free survival (PFS) in IB treated cases compared to those receiving rituximab (R) combined with fludarabine (F) and cyclophosphamide (C, FCR) or with bendamustine (BR). Explorative analyses, demonstrating the superiority of IB over chemotherapy or chemoimmunotherapy in cases with high-risk features, including unmutated IGHV (IGHV-UM) genes, del(17p) and/or TP53 mutations (TP53mut) and del(11q), justifies the attitude to limit FCR and BR only for low-risk and fit cases. However, these biomarkers practical prognostic relevance in the era of new drugs remains an open issue. Results investigating the clinical impact of IB in the current clinical practice mainly focused so far on relapsedresistant (RR) patients. Here, we conducted a multicenter, retrospective study to ascertain the predictive and prognostic relevance of well-known biological and clinical indicators in 165 patients treated with IB as first-line. In the same setting, we assessed the relative usefulness of IB versus BR, comparing the IB cohort with an additional retrospective multicenter cohort of 321 CLL cases treated with BR as first-line therapy outside clinical trials. The baseline characteristics of the IB cases are listed in Table S1. The majority of patients were Binet stages B and C (89.7%). The median age was 71.8 years, 104 cases (63%) were males, and 70.2% of cases were IGHV-UM; moreover, del(17p) and TP53mut were observed in 43.6% and 38.8% of cases, respectively. Of note, patients with del(17p) were not included in the Resonate-2 trial or in FCR versus IB study, and only 5% to 6% of cases with del (17p) were accrued in the IB arms of the BR versus IB trial. Here, the incidence of del(17p) or TP53mut cases, due to IB prescription indications, supported a reliable explorative TP53 disruption subanalysis. Forty-three patients (26.7%) discontinued IB, 24/43 for disease progression, including Richter s transformation (nine cases), and 19/43 for toxicity. After a median follow-up of 31.6 months, 36 patients progressed or died, and 88.4% remained progression-free and alive at 1 year. On univariate Cox regression analysis, patients with anemia [Hazard ratio (HR) 2.0, 95% CI 1.0–3.8, p = .042], Binet C (HR 2.0, 95% CI 1.0–3.8, p = .043), del(17p) (HR 3.4, 95% CI 1.7–6.9, p = .001), and TP53 mutation (HR 2.4, 95% CI 1.1–5.1, p = .025) had a significantly higher risk of progression or death (Table S2). We performed two different multivariate Cox analyses in which either del(17p) (model 1) or a TP53 mutation (model two) were introduced together with anemia and Binet stage (Table S2). Notably, del(17p) (HR 3.1 95% CI 1.5–6.5, p = .002) in model one and TP53 mutations (HR 2.4 95% CI 1.1–5.2, p = .025) in model two, remained unique predictors independently associated with PFS (Table S2). Moreover, we tested the hypothesis of whether the concomitant presence of del(17p) and TP53 mutations, the latter representing 70.5% of del(17p) cases, could provide a more precise risk assessment. A Cox regression analysis adjusted for anemia and Binet stage showed a significantly inferior PFS (HR 4.5, 95% CI 1.7–11.7, p = .002) for cases with both TP53 mutation and del(17p) compared with those with a wild-type TP53 status, while the single TP53 gene alteration, either mutation or deletion, failed to significantly increase the risk of progression (HR 1.5, 95% CI 0.5–4.6, p = .4) (Figure S1). Note, OS data revealed that 15/165 patients died, and 91.4% of cases were still alive at 2.5 years. Notably, none of the variables depicted in Table S2 were significantly associated with OS except that del(17p) (HR 4.1, 95% CI 1.3–13.3, p = .016). Again, cases with TP53 mutation and del(17p) disclosed a significant higher death risk (HR 5.5, 95% CI 1.7–25.8, p = .031) than the remaining groups of patients with unaltered or partially altered TP53 gene. Overall, our results suggest that the degree of TP53 function disruption [i.e., del (17p) or TP53mut versus del(17p) and TP53mut] appears to affect the response to IB in term of shorter PFS and possibly shorter OS. Our findings are germane to those of the largest cohort of IB-treated patients with del(17p), demonstrating an inferior PFS in cases with this chromosome abnormality. Notably, a landmark analysis evidenced that drug withdrawal predicted a significantly shorter OS than patients still on IB therapy, irrespective of whether discontinuation was driven by toxicity, disease progression, or Richter transformation (Figure S2). This finding is in keeping with previous reports indicating a poor outcome after IB discontinuation. The baseline characteristics of all patients who discontinued IB therapy for toxicity are listed in Table S3. A significantly higher rate of older patients was documented in this subset of patients (73.7% versus 54.1%, p = .02). New treatment regimens were initiated for 13/19 (68.4%) of the patients that discontinued IB, most commonly VEN-based (n = 9) or IDELA-based (n = 4) treatments. Received: 22 March 2021 Revised: 16 April 2021 Accepted: 19 April 2021