Ibrutinib for Chronic Lymphocytic Leukemia with TP53 Alterations
To the Editor:
Targeted agents replace chemoimmunotherapy for most patients with chronic lymphocytic leukemia (CLL). In randomized trials of ibrutinib or venetoclax, the risk of progression or death in patients with CLL was up to 75% lower than that with chemoimmunotherapy.1-3 Venetoclax-based, fixed-duration regimens led to high rates of undetectable minimal residual disease (MRD).3 These findings contrast with those for continuous treatment with Bruton’s tyrosine kinase (BTK) inhibitors, including ibrutinib, which have been associated with a durable response despite low rates of undetectable MRD. The presence of a tumor protein p53 (TP53) mutation or 17p deletion predicts an increased risk of relapse and death after chemoimmunotherapy. However, the durability of the response to targeted therapy in previously untreated patients with TP53 alterations is ill defined.
Overall and Progression-free Survival among the Study Patients Receiving Ibrutinib. Panel A shows Kaplan–Meier estimates of overall survival and progression-free survival among 34 patients with chronic lymphocytic leukemia with TP53 alterations who were treated with ibrutinib as first-line therapy. Tick marks indicate censored data. Panel B shows a summary of survival estimates with the percentage and 95% confidence interval (CI) at each selected time point.
We report follow-up data from an investigator-initiated phase 2 trial, in which 34 patients who had CLL with TP53 alterations were treated with ibrutinib as first-line therapy (ClinicalTrials.gov number, NCT01500733).4 The median age of the cohort was 63 years (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). As the best response, 30% had a complete response to treatment (Fig. S1). One patient had undetectable MRD (Fig. S2). At a median follow-up of 6.5 years, 17 patients (50%) remained in the study, including 6 patients with a complete response. Data regarding the side-effect profile were consistent with the results of previous studies.1,2,4 Dose reductions were uncommon (in 6% of the patients). The most common reason for treatment discontinuation was disease progression (35%), followed by withdrawal of consent and death unrelated to CLL (6% each). At 6 years, the estimated percentage of patients with progression-free survival and overall survival was 61% and 79%, respectively (Figure 1).
The median time until disease progression was 53 months (Fig. S3). Of the 12 patients who had disease progression while receiving ibrutinib, 4 had histologic transformation and 8 had progressive CLL (Table S2). In 11 of the 12 patients with disease progression (92%), the gene encoding the immunoglobulin heavy-chain variable domain (IGHV) was unmutated. Overall, the percentage of patients with progression-free survival was lower among those with unmutated IGHV than among those with mutated IGHV (Fig. S4). Mutations in BTK or phospholipase C gamma 2 (PLCG2) were detected in 83% of the patients with disease progression. Of the patients who had progression while receiving ibrutinib, 75% were switched to an alternative targeted agent; the median post-progression survival was 25 months (Fig. S5).
The data that are summarized here underscore the longer durability of response with ibrutinib than with chemoimmunotherapy in this population of patients. Ongoing randomized trials of first-line therapy are comparing the results of regimens containing ibrutinib with those containing venetoclax. Awaiting data from the randomized trials, we determined that 2-year progression-free survival as reported here was 85% in patients with TP53 alterations treated with continuously administered ibrutinib, as compared with 74% in those treated with fixed-duration venetoclax and obinutuzumab in a multicenter trial.3 Notably, we observed long-term benefit with ibrutinib despite the lack of achievement of undetectable levels of MRD. This finding suggests that deep remission is not a prerequisite for a durable response, an observation that has also been supported by findings involving patients with relapsed or refractory disease.5
Inhye E. Ahn, M.D.
Xin Tian, Ph.D.
Adrian Wiestner, M.D., Ph.D.
National Heart, Lung, and Blood Institute, Bethesda, MD
[email protected]
Supported by the intramural program of the
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
1. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 2018;379:2517-2528.
2. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib–rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med 2019;381:432-443.
3. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 2019;380:2225-2236.
4. Ahn IE, Farooqui MZH, Tian X, et al. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood 2018;131:2357-2366.
5. O’Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol 2016;17:1409-1418.
Supplementary Material
