Last month, on 7 thFebruary 2017, Preetesh Jainand Philip A. Thompson, from The University of Texas MD Anderson Cancer Center, et al.published results of a retrospective studyin the journal Cancer, which aimed to analyze long-term outcomes of CLL patients after they discontinued ibrutinib-based regimens.
Their analysis found that 320 CLL patients had been treated with ibrutinib during multiple clinical trials at The University of Texas MD Anderson Cancer Center, which had taken place between 2010 and 2015.
- Discontinued ibrutinib = 90/320 pts; after first-line = 10/68 pts; after salvage = 80/252 pts
- Pts receiving ibrutinib monotherapy = 47 (52%)
- Pts receiving ibrutinib plus rituximab = 31 (34%)
- Pts receiving ibrutinib plus bendamustine plus rituximab = 12 (13%)
- Reasons for ibrutinib discontinuation:
- In first-line pts (n=10): disease transformation (n=2), intolerance (n=6; atrial fibrillation and arrhythmias n=3, bleeding n=2, pneumonia n=1), transition to commercial supply (n=1), and death from unknown cause (n=1)
- In R/R pts (n=80): disease transformation (n=7), intolerance/toxicities (n=23; diarrhea n=7, atrial fibrillation n=5, bleeding n=4, pneumonia n=1, miscellaneous toxicities n=6), disease progression (n=19), miscellaneous reasons (n=27), and transition to commercial supply (n=4)
- Median time to ibrutinib discontinuation:
- Overall = 15 months (range, 1.2–54 months)
- Previously untreated pts = 19 months (range, 5–47 months)
- R/R pts = 14.5 months (range, 1.2–54 months)
- Two pts receiving ibrutinib as first-line therapy developed Richter Transformation (RT); both had unmutated IGHV, Rai stage I disease, overexpression of CD38 and ZAP-70, and del(17p) by FISH before commencing ibrutinib treatment
- Most pts had high-risk features before commencing ibrutinib treatment:
- Unmutated IGHV= 91%
- Advanced Rai stage disease = 55%
- Del(17p) by FISH = 41%
- Complex karyotype = 35%
- Median follow-up = 38 months; pts alive at last follow-up = 40 (44%)
- Median post-ibrutinib survival time:
- Overall = 20.6 months
- Pts who discontinued ibrutinib due to intolerance/toxicities = 33 months
- Pts who discontinued ibrutinib due to miscellaneous reasons = 11 months
- Pts with progressive disease = 16 months
- Pts who developed CLL transformation = 2.3 months ( P< 0.0001)
- Pts with PD had significantly better survival than pts who developed RT (HR, 6.7; P< 0.0003)
The authors stated that their long-term outcome analysis found that incidence of disease progression and treatment discontinuation is common. Their results also indicate that RT develops fairly early during ibrutinib treatment, but the risk significantly reduces after 12–18 months of therapy.
The authors concluded that effective salvage regimens are urgently needed for CLL patients who experience RT/progression during ibrutinib treatment. Moreover, they suggest that time-limited, combination therapies are more suitable for high-risk CLL patients, rather than relying on indefinite ibrutinib treatment or sequential treatment with multiple monotherapies which causes an outgrowth of resistant subclones.
Lastly, they conclude that more research is required to elucidate the pattern of mutations and dynamics of clonal evolution in patients who experience progression/RT with ibrutinib; this will help to identify novel therapeutic targets and improve outcomes of high-risk CLL patients.
BACKGROUND: Ibrutinib is a Bruton tyrosine kinase inhibitor and is approved for the treatment of patients with chronic lymphocytic leukemia (CLL) in frontline and relapsed/refractory settings. The authors previously reported poor outcomes for patients who discontinued ibrutinib; however, long-term outcomes were not reported.
METHODS: Data from 320 patients who received ibrutinib on clinical studies between 2010 and 2015 at The University of Texas MD Anderson Cancer Center were retrospectively analyzed.
RESULTS: Long-term outcomes among patients with CLL after they discontinued ibrutinib were analyzed. Ninety of 320 patients (28%) who were treated on ibrutinib-based regimens discontinued ibrutinib. Of these, 80 had relapsed/refractory disease, and 10 were treatment-naive. The median time to discontinuation was 15 months (range, 1.2-54 months). After a median follow-up of 38 months after starting ibrutinib, 40 patients (44%) remained alive. Major reasons for ibrutinib discontinuation were intolerance (n = 29; 32%), miscellaneous (n = 28; 31%), progression (n = 19; 21%), and Richter transformation (RT) (n = 9; 10%). The median survival according to the reason for discontinuation was 33 months for ibrutinib intolerance, 11 months for miscellaneous causes, 16 months for progressive CLL, and 2 months for RT. Among the 19 patients who had progressive CLL, 42% responded to subsequent therapy.
CONCLUSIONS: Ibrutinib discontinuation was observed during therapy. Patients with CLL who had disease transformation had especially poor outcomes, whereas those who developed progressive disease during ibrutinib therapy had a median survival of <1.5 years. Survival was associated with the reason for discontinuation; patients who had progressive CLL had better survival compared with those who had disease transformation. Effective salvage strategies for patients with CLL who progress on ibrutinib therapy is of critical importance. Cancer 2017. © 2017 American Cancer Society.