At the ICML Congress, the audience gained insight into long-term data from two phase III trials in mantle cell lymphoma and chronic lymphocytic leukemia. The new results confirm the statements made in the respective initial analyses.
With the introduction of anti-CD20 antibodies, survival of patients with diffuse large B-cell lymphoma (DLBCL) has improved, but still approximately one-third of the lymphomas in question have a primary refractory or relapsed response to therapy. But how many years of life do those affected actually lose, and how severely is life expectancy reduced?
Using Swedish registries, researchers evaluated data from more than 7,000 patients, including those who were still alive two years after their DLBCL diagnosis. They concluded:
- Men aged 50 at the time of diagnosis still lost about seven years of life expectancy compared with the general population in 2000, compared with only 1.6 years in 2012.
- Men aged 60 years at the time of diagnosis lost 6.6 years at the same time points and another 2.1 years later compared with their non-diseased country counterparts.
- For men aged 70 and 80 years at diagnosis, the difference over the years was still 4.6 vs. 1.8 years and 1.9 vs. 0.5 years, respectively.
Although, overall, the patients lost 5.5 years of life expectancy at the end of the study compared to their non-diseased peers, the data presented impressively demonstrate the progress that medicine has made in recent years. The under-60s in particular benefit greatly. The increase in life expectancy over time may be due not only to the primary therapy itself – rituximab first came on the market around the turn of the millennium – but also to improved supportive measures.
Indeed, another analysis presented at the congress showed: infection prophylaxis during chemotherapy with rituximab may be critical. Comparing the results of two prospective studies, there is a significant difference in favor of this supportive measure. In RICOVER-60 [1], where patients received ciprofloxacin (500 mg/d) only in severe leukocytopenia, ie. <1000/mm3, received ciprofloxacin (500 mg/d), there were significantly more grade 3/4 infections than in OPTIMAL >60 [2] with mandatory aciclovir/cotrimoxazole use – the former at a dose of 4× 400 mg/d, the latter 2× as a double dose on two days of the week, in addition to ciprofloxacin. This was despite poorer demographics in OPTIMAL >60. Significantly more therapy-associated deaths also occurred without aciclovir/cotrimoxazole prophylaxis.
In both studies, patients had received growth factors (granulocyte colony stimulating factors, G-CSF) in the form of (PEG)filgrastim, which cause white blood cells to not drop as much and to rise more quickly.
RAY Study: Mantle Cell Lymphoma
The first of the two studies for which long-term data were presented is the RAY study. The study compared the Bruton tyrosine kinase inhibitor ibrutinib and the mTOR inhibitor temsirolimus. Both had shown activity in relapsed/refractory mantle cell lymphoma (MCL) in previous studies. After a median of 20 months, patients had benefited significantly from the former agent. The risk of progression or death was reduced by 57% compared with temsirolimus (primary endpoint). Progression-free survival was 14.6 and 6.2 months, respectively. The active substance was also better tolerated.
The German-led phase III trial followed a randomized open-label design, meaning patients and researchers knew which drug they were dealing with. All participants had received at least one prior therapy with rituximab [3].
Today’s status
In the meantime, three years have passed. Ibrutinib is still proving to be an agent with a better benefit-risk ratio in the long term. The dose was 560 mg/d, which was in accordance with the approval text; temsirolimus was administered at 175 mg on days 1, 8, and 15 in the first cycle and at 75 mg on the same days in subsequent cycles. A total of 280 patients had participated in the study.
After 39 months of follow-up, the basic message remains unchanged: Ibrutinib reduced the risk of death or progression by half compared with temsirolimus (55%, p<0.0001). Median progression-free survival is still about the same at 15.6 vs. 6.2 months. Patients with only one prior line of therapy benefited the most, surviving a median of 25.4 months without progression when they received ibrutinib but only 6.2 months when they received temsirolimus. However, the benefit persisted after two prior lines of therapy at 26.2 vs. 15.4 months (p<0.0079).
Overall, more than one-third of patients had switched from the temsirolimus to the ibrutinib arm. Considering this, overall survival still showed a trend towards superiority with ibrutinib, but just missed significance (p=0.0621). The corresponding values were 30.3 vs. 23.5 months. Again, patients with a prior line of therapy benefited more (42 vs. 27 months).
Overall, these findings support the early use of Bruton tyrosine kinase inhibitor in refractory/relapsed MCL. There were no new safety signals. Despite longer exposure, patients on ibrutinib experienced fewer (severe) adverse events and discontinued therapy correspondingly less frequently.
RESONATE study: chronic lymphocytic leukemia
Ibrutinib is also approved by Swissmedic for the indication chronic lymphocytic leukemia (CLL). The results of the RESONATE study [4], which demonstrated in phase III that the compound was superior to the anti-CD20 monoclonal antibody ofatumumab in relapsed/refractory CLL in terms of PFS (primary endpoint) and OS, made a decisive contribution. A median of nine months had passed by the time of this interim analysis. The dose was 420 mg (until progression) according to approval; again, the 391 randomized patients had received at least one prior therapy. The median age was 67 years, and more than half suffered from advanced stages.
After disclosure of the data, all participants were recommended to switch to ibrutinib. More than two-thirds of ofatumumab patients complied with the request.
Today’s status
The long-term results were presented at several congresses, including ASCO and the ICML. In the meantime, almost four years have passed (median 44 months). Approximately half (46%) of all patients initially randomized to ibrutinib continue to take the drug. Still, progression-free survival is significantly better in the ibrutinib arm across all subgroups resp. prolonged – even in patients with genomic abnormalities traditionally associated with poor outcome. At three years, PFS was 59% vs. 3%.
Overall survival is also longer, keeping in mind that the crossover rate was very high and these cases were censored for OS evaluation. 74% in the ibrutinib arm were still alive after three years.
No new safety signals were found in this study either. Many more serious adverse events became less frequent after the first year, including neutropenia, pneumonia, and VCF. Patients discontinued ibrutinib therapy due to side effects in 12% of cases and due to progression in 27%.
Source:14th International Conference on Malignant Lymphoma, June 14-17, 2017, Lugano.
Literature:
- Pfreundschuh M, et al: Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008 Feb; 9(2): 105-116.
- Murawski N, et al: Anti-infective prophylaxis with aciclovir and cotrimoxazole significantly reduces the rate of infections and therapy-associated deaths in elderly patients with dlbcl undergoing r-chop immunochemotherapy. ICML 2017; Abstract 203.
- Dreyling M, et al: Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet 2016 Feb 20; 387(10020): 770-778.
- Byrd JC, et al: Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014 Jul 17; 371(3): 213-223.
InFo ONCOLOGY & HEMATOLOGY 2017; 5(4): 41-42.
