Page 138 - Haematologica July

1216
A. Cuneo et al.
The survival data in our analysis (92.7% alive at 12 months and 72.2% at 36 months) reflect previous experi- ences with bendamustine and anti-CD20 in clinical tri- als,16,25 showing that this combination is equally effective in clinical practice across many centers. Negative predic- tive factors on OS were represented by advanced stage and chemorefractory disease, whereas the presence of del(17p) was not associated in our analysis with a signifi- cantly shorter OS, possibly due to the relatively low num- ber of patients (n=23) and to the use of effective salvage regimens in subsequent lines of treatment. Accordingly, the survival in the BR arm of the Helios trial after adjusting for crossover to BR and ibrutinib was close to 90% at 12 months and more than 80% at 24 months.26
Thus, the data presented here show that BR is an effica- cious first salvage regimen in CLL in a real-life population, including elderly patients, patients with 2 or more comor- bidities and a creatinine clearance less than 70 mL/min. The outcome was better in patients with favorable genetic features and with early/intermediate disease stage. Importantly, no significant differences in terms of OS were noted in this real-life report with respect to the sur- vival data recently observed in clinical trials.
Because no direct comparison was performed between CIT and new oral agents in first relapse, we elected to compare our data with ibrutinib used in a real-life patient population treated in the UK and in Italy using OS as an objective end point. We restricted our comparative analy- sis to patients who had previously received CIT because this is the recommended initial treatment in CLL. The BR and ibrutinib cohorts had similar baseline risk factors and, when excluding patients with del(17p) from the analysis as nowadays they would no longer be exposed to second- line CIT, there was no difference in OS (Figure 3). Interestingly, no difference in OS was found with BR or ibrutinib when including in the subanalysis patients with a less than 36-month interval between front-line and first salvage treatment. The survival curve showed an excess of early deaths in the ibrutinib cohort compared to the BR cohort. Due to the small size of the patient population included in this analysis, there is no recurrent pattern or obvious explanation for this observation; severe infection and Richter’s syndrome in 2 patients each were the only recurrent causes of death in the first 12 months. It remains unclear as to whether ibrutinib directly contributed to any of these deaths.
The observed outcome for ibrutinib-treated patients in this observational study could be due to premature inter- ruption of ibrutinib exposure. It is noteworthy that in the UK and Ireland data on the overall cohort of R/R CLL treated with ibrutinib, discontinuations during the first year were due to AEs (54%), Richter’s transformation (26%), and progressive CLL (17%). Beyond the first year, the rate of discontinuations due to progressive CLL increased to 29%.27
When comparing CIT and novel inhibitors, one also has
to consider the long-term detrimental effects due to the clonal selection and DNA damage occurring with repeti- tive lines of chemotherapy-based treatments, resulting in second tumors, acute leukemias/myelodysplastic syn- dromes, that cannot be evaluated in the short follow up of our retrospective study. On the other hand, elegant in vitro studies have shown that treatment of mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, increased somatic hypermutation through enhanced expression of activation-induced cytidine deaminase.28
In another analysis including R/R CLL in second and subsequent lines of treatment,29 an OS advantage was noted when comparing ibrutinib (with or without BR) and BR alone.30 In other studies arriving at the same conclu- sion,31,32 chemotherapy +/- anti CD20 regimens used in a real-world setting were compared with ibrutinib data of the clinical trials Resonate and Helios. However, there is now evidence that adherence to treatment with ibrutinib in the real-world population did not reflect the data obtained in clinical trials,22,33 possibly due to the hetero- geneity of the patient populations or to a more limited experience of physicians in managing side effects occur- ring on treatment. Furthermore, the UK real-life data show that duration of ibrutinib therapy and OS seem very sim- ilar when ibrutinib is used at first or subsequent relapses, suggesting that the relative benefit for ibrutinib compared with chemotherapy is more evident in patients with mul- tiple relapse where re-treatment with further chemother- apy results in progressively worse response rates and remission duration. It is noteworthy that a highly signifi- cant PFS advantage with the BCL2 inhibitor venetoclax plus rituximab compared to BR has been recently reported in the planned interim analysis of the randomized phase III Murano study, where 42.8% of patients had received 2 or more lines of therapy.34 However, in this trial, an OS benefit has not yet been shown according to the prede- fined statistical model.
Although, obviously, data derived from different series must be treated with caution, these data suggest that BR and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in CLL patients with- out 17p deletion managed in the real-life setting. Whether this is due to limited compliance of patients and/or subop- timal management of side effects with the novel therapies remains to be established.
Funding
AIL-Ferrara, Italy, Ricerca Finalizzata project RF-2011- 02349712 Ministero della Salute, Rome, Italy to AC, RF, GG; MIUR-PRIN 2015ZMRFEA_004, Rome, Italy to AC, RF, PG, GG; Special Program Molecular Clinical Oncology 5 x 1000 N. 10007, Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy; Bloodwise grant 16003 to FF. AS is supported by the United Kingdom’s National Institute for Health Research (NIHR). The views expressed in this paper are those of the authors and not necessarily those of the NIHR.
References
1. Fischer K, Bahlo J, Fink AM, et al. Long- term remissions after FCR chemoim- munotherapy in previously untreated
patients with CLL: updated results of the
CLL8 trial. Blood. 2016;127(2):208-215.
2. Eichhorst B, Fink AM, Bahlo J, et al. First- line chemoimmunotherapy with ben-
patients with advanced chronic lympho- cytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-infe- riority trial. Lancet Oncol. 2016;17(7):928-
damustine and rituximab versus fludara- 942.
bine, cyclophosphamide, and rituximab in
3. Goede V, Fischer K, Engelke A, et al.
haematologica | 2018; 103(7)