Page 113 - Haematologica August 2018

BR in frail elderly patients with DLBCL
majority of frail subjects of this study were treated with rituximab-containing therapy (39%) and 31 of them also received an anthracycline-containing regimen. Considering only the patients who were treated with chemo-immunotherapy, the 2-year and median OS were 48% and 20 months, respectively. These data compare favorably with those observed in the current study that used a more strict definition of frailty (i.e. unfit patients with intermediate profile at CGA were not included) and were obtained without the use of doxorubicin.
When this trial was started, data from a large observa- tional study on 173 consecutive elderly patients with DLBCL were already available. These suggested that the use of chemotherapy regimens with curative intent were not able to improve patients’ survival compared to pallia- tive therapies for the subgroup of patients who were clas- sified as frail according to the same CGA that we adopted in this trial.10 Based on this observation, we considered frail those patients ineligible to receive anthracycline-con- taining regimens, also if administered at lower doses, and identified an unmet need in the search of active therapies in this subset of patients. Unfortunately, lacking a ran- domized comparison, we cannot draw any conclusion on the relative efficacy of the BR regimen in comparison with other immunochemotherapy options. Due to its favorable safety profile, however, the use of a BR combination seems an excellent option and should be set as a reference to identify more effective treatment strategies in future tri- als. Regarding safety, the recent experience with BR in fol- licular lymphoma reported an increase in toxicities; with the limitations of a small number of patients, in our pop- ulation, BR was manageable and safe; the two deaths due to second malignancies is not an unexpected finding in a very elderly population.
In order to further improve these results, additional efforts should be made to attempt to increase the response rate and to prolong the short duration of response. New drugs such as lenalidomide and ibrutinib have shown activity against DLBCL, are both associated with an excel- lent safety profile,16,17 and could be used to improve the results with an acceptable toxicity. A phase II trial of ritux- imab in association with a lenalidomide combination in elderly frail patients is currently being conducted by our group and actively recruiting patients (clinicaltrials.gov iden- tifier: 02955823). In addition, the published results of the REMARC trial has demonstrated, for the first time after several unsuccessful attempts with other drugs,18 that a maintenance therapy with lenalidomide in elderly patients with DLBCL who responded to initial immunochemother-
apy is associated with a reduced risk of disease progression compared to observation.19 Finally, our study is part of a larger project for elderly patients with DLBCL for whom a preliminary CGA is required to define patient fitness status and to adapt treatment goals accordingly. Patients prospec- tively enrolled in this so called “elderly project” are evalu- ated by a simplified version of the CGA20 and are catego- rized into one of three groups: fit, unfit and frail (clinicaltri- als.gov identifier: 02364050). Fit patients are then offered a standard R-CHOP treatment with curative intent, and unfit patients are considered better candidates for adapted R- CHOP regimens with reduced drug doses to achieve a cure with reduced toxicity. Finally, no clear benefit was observed for frail patients treated with curative intent compared with those treated with palliative intent, and there was no standard or reference regimen.21 To the best of our knowledge, the elderly project is the first attempt to try to objectify the treatment approach to elderly patients with lymphoma and to promote clinical research in this population. With our study, and with the adoption of a prospective definition of patient fitness, we have been able to show that, also in the population of frail patients, the use of a low toxicity regimen allows a cure of the lym- phoma to be achieved in a good proportion of patients. These data, along with the adopted CGA evaluation, help
Table 5. Association of age, geriatric scales and IPI with OS and PFS (univariate analysis).
Variable
Age ≤80
>80
ADL 6 5
0-4
IADL 8
6-7 0-5
IPI 1-2
3-5
1yr-OS % (95CI)
68 (29-88) 62 (44-76)
70 (48-85) 50 (21-74) 63 (23-86)
33 (5-68) 71 (49-85) 62 (32-82)
77 (50-91)
52 (31-69)
Log-rank
P
0.694
0.335
0.350
0.531
1yr PFS % (95%CI)
60 (25-83) 46 (29-61)
56 (35-73) 25 (6-50) 62 (23-86)
33 (5-68) 56 (35-73) 43 (18-66)
58 (33-76)
40 (21-58)
Log-rank
P
0.685
0.536
0.020
0.581
Table 6. Summary of prospective studies of bendamustine in association with rituximab in diffuse large B-cell lymphoma.
yr: year; CI: Confidence Interval; ADL: Activities of Daily Living; IADL: Instrumental Activities of Daily Living; IPI: International Prognostic Index; OS: overall survival; PFS: progression-free survival.
Author Year (medAge)
Ohmachi et al.6 2013 Vacirca et al.7 2014 Weidmann et al.9 2011 Park et al.8 2016 Current report 2016
Patients
59 (65)
48 (74) 13 (85) 23 (80) 45 (81)
Phase
R/R
R/R Untr. Untr. Untr.
Benda dose Days mg/m2
120 21
90/120* 28 120 21 120 21
90 28
CRR% ORR% mPFS months
37.7 62.7 6.7
15.3 45.8 3.6 54 69 7.7 52 78 5.4 53 62 10
*Bendamustine (Benda) dosage 90 mg/m2 was administered for the first 2 patients on study. Following the US FDA approval, the dosage was amended to 120 mg/m2. R/R: relapsed/refractory; medAge: median age; Untr: untreated; CRR: complete remission rate; ORR: overall response rate; mPFS: median progression-free survival.
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