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A. Cuneo et al.
median time-to-next treatment was 31.3 months. Front-line treatment with a chemoimmunotherapy regimen was the only predictive factor for a shorter time to next treatment at multivariate analysis. The median overall survival (OS) was 74.5 months. Advanced disease stage (i.e. Rai stage III-IV or Binet stage C) and resistant disease were the only parameters significantly associated with a shorter OS. Grade 3-5 infections were recorded in 6.3% of patients. A matched-adjusted indirect comparison with ibrutinib given second-line within Named Patient Programs in the United Kingdom and in Italy was carried out with OS as objective end point. When restricting the analysis to patients with intact 17p who had received chemoimmunotherapy in first line, there was no difference in OS between patients treated with ibrutinib (63% alive at 36 months) and patients treated with BR (74.4% alive at 36 months). BR is an effi- cacious first salvage regimen in CLL in a real-life population, including the elderly and unfit patients. BR and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in patients without 17p deletion. (Registered at clinicaltrials.gov identifier: 02491398)
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Introduction
Treatment of chronic lymphocytic leukemia (CLL) has dramatically changed over the last years. Chemotherapy and anti-CD20 monoclonal antibodies produce high over- all response rates (ORR), including complete remissions (CR) with negative minimal residual disease, and pro- longed progression-free-survival (PFS) and overall survival (OS), both in fit1,2 and unfit patients.3 In patients with TP53 disruption and/or with relapsed/refractory (R/R) disease, who represent a difficult-to-treat patient population, mechanism-driven drugs targeting the Bruton tyrosine kinase (BTK), the phosphoinositide 3-kinase delta (PI3K d) or the BCL2 protein can induce durable responses.4-7
In the absence of TP53 disruption, a chemoim- munotherapy (CIT) regimen is recommended as front-line and second-line treatment in those patients who attained a long progression-free survival (PFS) with the previous regimen.8,9 On the other hand, the National Comprehensive Cancer Network recommends one of the new agents, ibrutinib, idelalisib with rituximab or veneto- clax, as alternatives to CIT for patients with relapsed or refractory disease.10
Uncertainty in the recommendations on first salvage treatment may partly derive from the consideration that the majority of studies on R/R CLL report efficacy data in an aggregate fashion, analyzing patients who had previ- ously received one or more lines of treatment all together. Consequently, little information is currently available on the outcome of second-line treatment.
Bendamustine and rituximab (BR) is one of the most widely adopted CIT regimens, both as front-line11 and sec- ond-line treatment.12-14 The BR regimen was followed by a median PFS of 18 months when used as first salvage treat- ment after fludarabine, cyclophosphamide and rituximab (FCR) in 62 patients regardless of TP53 aberrations and/or refractoriness to prior therapy.13 In 78 CLL patients who had received 1-3 previous lines of treatment, the BR com- bination was associated with a 59% ORR with a median PFS of 15.2-months.15 Bendamustine and ofatumumab produced a 23.6-month median PFS in 47 patients, 61% and 29% of whom had received 1 or 2 prior lines of treat- ment, respectively.16
The oral agent ibrutinib represents an effective therapy in the R/R setting.17 In a recent analysis describing a 5-year experience, a median PFS of 52 months was reported in R/R CLL treated with ibrutinib after 4 or more previous lines of treatment in more than 50% of patients.18 In a recent update of the phase III Resonate study comparing
ibrutinib and ofatumumab, the PFS rate appeared to be better in patients treated with ibrutinib in second line compared to patients who had received 2 or more previ- ous lines of treatment.19
Recent experiences with ibrutinib in a real-world setting have reported a higher rate of discontinuation compared to clinical trials,20,21 possibly due to older age and worse Performance Status (PS) of the patient population treated in the day-to-day clinical practice.22
On these grounds, we performed a retrospective obser- vational study within the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) and European Research Initiative on CLL (ERIC) networks to collect data on the efficacy and safety profile of the BR regimen used as second-line treatment in a real-world setting. We then set out to perform an indirect comparison with ibrutinib given as first salvage treatment in the UK and the Italian Named Patient Programs (NPP).
Methods
Patients
Patients treated between 2008 and 2014 at GIMEMA and ERIC centers were eligible. The inclusion criteria were: i) diagnosis of CLL according to the National Cancer Institute (NCI);23 ii) age ≥18 years; iii) one previous treatment using alkylating agents and/or purine analogs with or without monoclonal antibodies; iv) pro- gression requiring therapy (NCI criteria);23 v) second-line treat- ment with BR at the conventional dose of 70 mg/m2, as described.15
Patients were excluded if they had Richter’s syndrome transfor- mation, HIV infection, active HCV or HBV infection. The study was registered at clinicaltrials.gov identifier: 02491398. The study was approved by the local ethics committees.
Study design and end points
Data were obtained from the medical files and entered into case record forms (CRF) by treating physicians. Computerized and manual consistency checks were performed by the data manager of the GIMEMA data center.
Evaluation of bone marrow response and radiographic imaging at baseline and at response were performed according to local guidelines. Treatment response and disease progression were assessed according to the NCI criteria.23
Primary end point
The primary end point was PFS at 12 months from treatment start. Subjects who were withdrawn from the study without pro- gression were censored at the date of the last assessment. Subjects
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