Ibrutinib-Based 1L Therapy Sustains Efficacy, Safety in TP53+ Chronic Lymphocytic Leukemia

Article

The sustainability of efficacy and safety with frontline ibrutinib-based therapy used to treat patients with chronic lymphocytic leukemia who have TP53 aberrations was demonstrated, according to 4-year follow-up result of a pooled analysis.

The sustainability of efficacy and safety with frontline ibrutinib (Imbruvica)-based therapy used to treat patients with chronic lymphocytic leukemia (CLL) who have TP53 aberrations was demonstrated, according to 4-year follow-up results from the pooled analysis published in Blood.

In multiple phase 3 studies of ibrutinib in CLL and small lymphocytic leukemia, the agent demonstrated improvement in survival outcomes. Ibrutinib is, in fact, the only targeted therapy that has been shown to improve both progression-free survival (PFS) and overall survival (OS). The agent alone and in combination with other therapies demonstrated improvement in survival outcomes for patients with TP53 aberration also, but the clinical data supporting its use in this high-risk patient population is limited.

A group of investigators, led by John N. Allan, MD, of Weill Cornell Medicine, conducted a pooled analysis of phase 2 and 3 clinical trials to help paint a better picture of the efficacy and safety of ibrutinib-containing frontline therapy for patients with CLL and TP53 aberrations. The studies assessed included the phase 2 PCYC-1122e study of single-agent ibrutinib (NCT01500733) as treatment of del(17p) and TP53-mutant CLL, the phase 3 RESONATE-2 study of single-agent ibrutinib as treatment of TP53-mutant CLL (NCT01722487), the phase 3 iLLUMINATE trial of ibrutinib in combination with obinutuzumab (Gazyva) for the treatment of del (17p)- and TP53-mutant disease (NCT02264574), and the phase 3 ECOG1912 study of ibrutinib plus rituximab (Rituxan) as treatment of patients with TP53-mutant CLL (NCT02048813).

To assess efficacy in the pooled analysis, Allan et al looked at PFS, OF, overall response rate (ORR), and complete response (CR) rate. The safety of ibrutinib alone or in a combination regimen was determined by the prevalence of adverse events (AEs).

Between the 4 studies, data from 89 patients with TP53-mutant CLL who received frontline ibrutinib was evaluated. Overall, 91% of the patients enrolled have a TP53 aberration and 53% had a del(17p) mutation. Many of the patients with del(17p) also had a TP53 aberration. The analysis population had a median age of 65 years (range, 33-87) and was 69% male. The Rai stage at baseline was 0-II for 47% of patients and III o IV for the remaining 53%. Notably, 38% of the population had bulky disease. At screening, patients showed a median lactate dehydrogenase of 233 (range, 52-2568), and 68% of the patients had unmutated IGHV.

Fifty-one percent of patients received single-agent ibrutinib, and 49% received ibrutinib in combination with an anti-CD20 antibody.

At a median follow-up of 50 months (range, 0.1-95.9), the 4-year PFS rate was 79% with the median PFS not reached (95% CI, 67- not estimable [NE]). PFS was evaluated in detail based on whether patients have only a TP53 mutation or a TP53 mutation and del(17p) mutation. Of the 47 patients with only a TP53 mutation, the median PFS was also not reached (95% CI, 60-NE). For the 11 patients who had both mutations, the median PFS was 42.8 months (95% CI, 7-NE). Frontline ibrutinib-based therapy also achieved a 4-year OS rate of 88%.

The majority of patients in the analysis had a response to the ibrutinib-based therapy which led to an ORR of 94%. Responses included CRs in 39% of patients.

Ibrutinib was discontinued due to progressive disease (PD) in 20% of patients, study closure in 11%, AEs in 10%, patient withdrawal in 7%, death in 3%, and investigator decision in 2%.

Regarding patients who discontinued treatment due to an AE, Allan stated that “rates of grade 3 AEs were highest during our first year of therapy and generally decreased after that first year of treatment,” during his presentation of the pooled analysis data for the 2020 American Society of Hematology (ASH) Annual Meeting.

A look at the prevalence of grade 3 AEs over the 4-year period, grade 3 AES were seen in 89% of patients in the first year, 81% in years 1–2, 76% in years 2–3, 57% in years 3–4, and 41% in year 4. The most common grade 3 AEs were hypertension, atrial fibrillation, infection, and bleeding. Allan et al noted that 20% of the patient population who experienced these grade 3 AES had a secondary malignancy of skin cancer in 12 patients, prostate cancer in 2 patients, and myeloma in 1 patient. Overall, no new safety signals were observed through the pooled analysis.

Based on these combined clinical trial results, Allan et all concluded that although patients with TP53-mutant CLL are still at risk for disease progression, the use of ibrutinib in the frontline setting can improve the currently poor outcomes for these patients.

Reference:

Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukemia (CLL) with 4 years of follow-up in patients with TP53 aberrations (del(17p) or TP53 mutation): a pooled analysis from 4 clinical trials. Blood. 2020; 136 (Suppl 1): 23–24. doi: 10.1182/blood-2020-134431

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