John N. Allan, MD – Assistant Professor of Medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine, New York-Presbyterian Hospital discusses ASH 2020 abstract – Presentation of pooled analyses looking at the durability of responses in patients with high-risk CLL (Abstract #2219)
Context:
A strong negative predictor of survival in patients (pts) with CLL is the existence of TP53 aberration (defined as del(17p) or TP53 gene mutation). In pts with CLL carrying TP53 aberrations, first-line chemoimmunotherapy is suboptimal, with 3-year progression-free survival (PFS) and overall survival (OS) rates of just 18 percent and 38 percent, with fludarabine, cyclophosphamide, and rituximab, respectively (Hallek, Lancet 2010). In many randomized phase 3 trials (e.g., RESONATE-2, ECOG1912) in the first-line treatment of CLL/small lymphocytic lymphoma, Ibrutinib is the only once-daily Bruton’s tyrosine kinase (BTK) inhibitor with substantial PFS and OS profit (SLL). Furthermore, previous studies of single-agent ibrutinib or ibrutinib-based combination therapy have shown promising PFS benefit in pts with TP53 aberrations both in first-line and relapsed/refractory environments. Despite these study-specific subgroup analyses, there is insufficient evidence on long-term outcomes in first-line BTK inhibitor-treated pts with TP53 aberrations. In order to assess the long-term efficacy and safety of first-line ibrutinib-based therapy in pts with CLL carrying TP53 aberrations, we conducted a pooled data study across 4 trials.
In order to assess the long-term efficacy and safety of first-line ibrutinib-based therapy in pts with CLL carrying TP53 aberrations, we conducted a pooled data study across 4 trials.
Methods:
Pts with del(17p) were excluded from ECOG1912 and RESONATE-2 but pts with TP53 mutations were not excluded. Long-term PFS (investigator-assessed), OS, and safety are documented.
Outcomes:
This pooled study included eighty-nine pts with TP53 aberrations undergoing first-line ibrutinib therapy. The median age was 65 (range 33-87) years, and 69% of the pts were male. 53% had Rai stage III/IV at baseline, 38% had the bulky disease (lymph nodes ⇠5 cm), and 69% (of 87 assessable) had unmutated IGHV. Both patients had either del(17p) or TP53 mutation; del(17p) had 53 percent (of 89 evaluable) and TP53 mutation had 91 percent (of 58 assessable). 11 (69 percent) of 16 pts with del(17p) who had TP53 sequencing results available had both del(17p) and TP53 mutations. 45 pts were treated with ibrutinib as a single agent and 44 pts were treated with ibrutinib in combination with an anti-CD20 agent. Median PFS was not achieved with a median follow-up of 50 months (range 0.1 to 95.9 months) (95 percent CI: 67 months to not estimable; Figure 1A). The PFS rate at 48 months was 79 per cent and the OS rate was 88 per cent (Figure 1B). The median period of treatment with ibrutinib was 46 months, and (range 0.1 to 95.5 months). Progressive disease (20 percent), research closure (12 percent), adverse events (10 percent), pt withdrawal (7 percent), death (3 percent), and other explanations for discontinuation of care were (physician decision due to scheduled pt surgery; 1 percent ). Infection (22 percent; most usually 7 percent pneumonia), hypertension (13 percent), atrial fibrillation (12 percent), and major bleeding were Grade ⇠3 adverse effects of clinical concern with up to 8 years of treatment with ibrutinib (7 percent ). With the latest follow-up, ibrutinib care maintained 46 percent of pts with TP53 aberrations.
Findings:
First-line care based on ibrutinib resulted in sustained efficacy with high PFS and OS rates in CLL pts with TP53 aberrations, a population with generally poor results, with a median follow-up of 4 years. Although pts with TP53 aberrations remain at risk for progression, in this high-risk population with 4-year PFS and OS rates of 79 percent and 88 percent, first-line treatment with ibrutinib partially overcame the poor prognosis. This study did not find any new safety signals. The long-term effect of first-line ibrutinib-based treatment in pts with TP53 aberration was demonstrated by these findings from a broad, pooled, multi-study data collection.