Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia

Abstract

TO THE EDITOR Bruton tyrosine kinase (BTK) inhibitors have improved chronic lymphocytic leukemia (CLL) outcomes and offer a chemotherapyfree option [1]. The BTK inhibitor ibrutinib, alone or with a CD20 antibody, demonstrated better efficacy versus chemoimmunotherapy in treatment-naïve (TN) CLL [2][3][4]. However, cardiovascular toxicity is a concern with continuous ibrutinib use [5,6].Acalabrutinib is a next-generation, selective BTK inhibitor approved for CLL/small lymphocytic leukemia (SLL). Acalabrutinib, alone or with obinutuzumab, showed favorable efficacy in clinical trials [7,8]. ELEVATE-TN demonstrated superior efficacy for acalabrutinib-obinutuzumab versus obinutuzumab-chlorambucil with acceptable tolerability in TN CLL [9]. We report 4-year followup results from ELEVATE-TN.ELEVATE-TN is a phase 3, randomized, multicenter, open-label study (NCT02475681) that enrolled patients aged ≥65 years, or 18-65 years with comorbidities (Cumulative Illness Rating Scale-Geriatric score >6, creatinine clearance 30-69 mL/min by Cockcroft-Gault), who had TN CLL or SLL requiring treatment, Eastern Cooperative Oncology Group performance status score of ≤2, and adequate hematologic, hepatic, and renal function [9]. Patients were randomized (1:1:1) to acalabrutinib 100 mg twice daily (until disease progression or unacceptable toxicity) with or without obinutuzumab (fixed-duration, up to 6 cycles) or obinutuzumab plus chlorambucil (up to 6 cycles). Crossover to acalabrutinib monotherapy was permitted in patients who progressed on obinutuzumab-chlorambucil. The primary study endpoint was independent review committee (IRC)-assessed progression-free survival (PFS). After primary analysis, PFS was investigatorassessed.Key secondary/exploratory endpoints were investigator-assessed PFS, investigator-assessed overall response rate (ORR), overall survival (OS), undetectable minimal residual disease (uMRD) rate, and safety. The study was not powered to compare acalabrutinib versus acalabrutinib-obinutuzumab. Informed consent was obtained from all patients before enrollment. Study details were previously published [9].In total, 535 patients were randomized (acalabrutinib-obinutuzumab, n = 179; acalabrutinib, n = 179; obinutuzumab-chlorambucil, n = 177). Median age was 70 years (range, 41.0-91.0); 14% had del(17)(p13.1) and/or mutated TP53 and 63% had unmutated immunoglobulin heavy chain variable (IGHV) gene (Supplementary Table 1).At a median follow-up of 46.9 months (range, 0.0-59.4), treatment was ongoing in 74.9% (n = 134) and 69.3% (n = 124) of patients in the acalabrutinib-obinutuzumab and acalabrutinib monotherapy arms, respectively (Supplementary Table 2). Sixty-

Management of front line chronic lymphocytic leukemia

“…After 4 years of follow‐up within the ELEVATE TN trial, median PFS was not reached for the acalabrutinib‐containing arms versus 22.2 months for obinutuzumab‐chlorambucil in patients with unmutated IGHV. The 48‐month PFS rates were 86% for acalabrutinib‐obinutuzumab, 77% for acalabrutinib alone and only 4% for chlorambucil‐obinutuzumab 40 …”

“…Although the trial was not powered for this comparison, the addition of obinutuzumab seems to improve responses and should be considered when initiating treatment with acalabrutinib. 40 The ELEVATE RR trial has compared ibrutinib to acalabrutinib in relapsed/refractory CLL patients and has demonstrated a similar efficacy of both treatments with a median PFS of 38.4 months in both arms while the median OS was not reached. With regard to side effects, acalabrutinib should particularly be considered for patients with cardiac conditions, as all-grade atrial or flutter incidence was significantly lower for acalabrutinib (9.4% vs. 16.0% for ibrutinib).…”

“…Venetoclax‐obinutuzumab as fixed‐duration regimen has shown prolonged PFS but not OS in comorbid patients when compared to chlorambucil‐obinutuzumab 45 . Likewise, ibrutinib‐obinutuzumab as well as acalabrutinib‐obinutuzumab have led to an improved PFS in comparison to chlorambucil and obinutuzumab, but not to a prolonged OS 37,40 …”

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

“…Grade 3/4 AEs were reported in 71% of patients. The phase 3 ELEVATE TN (NCT02475681) study evaluated acalabrutinib treatment in previously untreated CLL patients (Table 3) [49,50]. A total of 535 patients were randomized to acalabrutinib alone, acalabrutinib + obinutuzumab, or chlorambucil + obinutuzumab arms.…”

Health‐related quality of life for patients with chronic lymphocytic leukaemia – A critical outcome measure in the era of highly effective therapies

“…In the CLL14 study, the venetoclax–obinutuzumab cohort reported similar changes in QoL compared to the chlorambucil–obinutuzumab group, 7 and formal QoL analyses of the ALLIANCE and iLLUMINATE cohorts are not available. More recently, the more selective BTKis acalabrutinib and zanubrutinib have demonstrated improved PFS compared to chemoimmunotherapy in the front‐line setting, 8,9 and reduced frequency of cardiovascular toxicities compared to ibrutinib in the relapse setting, 10,11 without demonstrating OS benefit. Overall, these trials reflect that OS benefits are difficult to demonstrate due to excellent outcomes achieved for most patients with currently available front‐line regimens and the wealth of salvage options 12–15 .…”