Page 111 - Haematologica August 2018

BR in frail elderly patients with DLBCL
were considered ineligible due to violation of inclusion cri- teria (one patient was not confirmed as frail, one did not undergo CGA evaluation, one case was HCV positive). One additional patient was excluded from the study analy- sis due to death before treatment start. The clinical charac- teristics of the remaining 45 patients are shown in Table 2. A full list of comorbidities with observed rates is provided in Online Supplementary Table S1.
Feasibility and Efficacy
Treatment was started in 45 eligible patients. Nine patients were at low risk (aaIPI 0 and non-bulky disease) and had to receive 4 BR cycles followed by two doses of rituximab. All the other patients (n=36) were at high risk and had to receive all 6 BR cycles followed by two doses of rituximab. Overall, 25 patients received all planned ben- damustine doses (55%); 7 of 9 at low risk, and 18 of 36 at high risk. Treatment was discontinued due to progressive disease (12 patients), eeAEs (8 patients) and physician's decision (7 patients). Four non-bulky patients (3 with stage I-II, 1 with stage IV) received consolidation radiotherapy. In 4 high-risk cases, treatment was interrupted before administration of the 2 consolidation doses of rituximab. Three additional patients interrupted treatment after cycle 4 (n=1) and 5 (n=2) due to physician's decision. The calcu- lated administered dose intensity for rituximab and ben- damustine was 0.990 (25-75 percentiles: 0.901-1.016), and 0.996 (25-75 percentiles: 0.877-1.017).
The efficacy analysis was based on all 45 cases. After the enrollment of the first 19 patients, 5 CRs were observed and the accrual to study stage 2 opened. Overall, 24 patients achieved a CR at the end of treatment (53%; 95%CI: 38-68%), 4 patients achieved a partial remission (PR), one patient had a stable disease (SD), 13 patients had progressive disease (PD), and in 3 patients response was not evaluable (due to AEs: pelvic fracture, pneumonia, heart attack). The overall response rate (ORR) was 62% (95%CI: 47-76%). The observed CRR was higher than that initially required for efficacy assessment by the study design (Table 3).
Safety
The safety analysis was available for all 45 eligible patients and for 244 cycles. Thirty-five grade 3-4 AEs were reported in 23 patients (51.1%; 95CI: 35.8-66.3%); the most frequent grade 3-4 AE was neutropenia with 17 events (37.8%) (Table 4). Though not mandatory, G-CSF was used in 26 patients (58%; 95CI: 42-72%).
The rate of grade 3-4 eeAE was monitored during stage 1 and stage 2 of the study. Overall, grade 3-4 eeAEs were reported in 7 patients (15.6%; 95CI: 6.5-29.5%) and grade 3-4 hematologic AEs were reported in 21 cases (46.7%; 95CI: 31.7-62.1%). The most frequent grade 3-4 eeAE was infection (n=2 patients, 4.4%); no grade 4 infections were reported. A detail of all reported AEs is provided in Table 4. Both for study stage I and stage II, the rate of grade 3-4 eeAEs never fell beyond the maximum rate allowed.
Survival analysis
The median follow up was 33 months (range 1-52). Thirty-two patients experienced PD, including 13 PD at the end of induction therapy, 12 relapses, and 7 deaths for causes unrelated to lymphoma (pneumonia, heart failure, hepatocarcinoma, neurological disorder, respiratory disor- der, cachexia, unknown). The 2-year PFS was 38%
(95%CI: 24-51%) and the median PFS was 10 months (95%CI: 7-25%) (Figure 1).
Overall, 24 patients died: 8 during treatment and 16 dur- ing follow up. Cause of death was lymphoma progression in 14 patients (58%), and unrelated causes in 8 patients (the 7 deaths reported above, plus one patient who died due to secondary acute myeloyd leukemia after lym- phoma progression). Two-year OS was 51% (95%CI: 35- 65%) and median OS was 30 months (95%CI: 10-NA). The results of the CGA scales used during patients’ base- line assessment were correlated with OS and PFS in uni- variate analysis, and no association was found (Table 5). In addition, no association was found between results of CGA scales and safety results (data not shown).
Discussion
We report the results of a phase II study to investigate the activity and toxicity of a combination regimen of ritu- ximab and bendamustine for the initial treatment of patients with DLBCL who were classified as frail based on
Table 2. Baseline characteristics of patients eligible for the study (n=45).
Status Missing N (%)
Sex Male - 26(58)
Age (years) Hb (g/dL) Stage
Median (range) Median (range) I
II III IV
- - -
81 (71-89)
12.9 (7.8-16.1)
7 (16) 10 (23) 6 (14) 22 (48)
16 (36)
11(24)
16(36)
25(57)
35 (78) 10 (22)
60 (43-70)
ECOGPS >1 1 ENS >1 - LDH >ULN - IPI 3-5 1
CGA Unfit with age ≥80 years frail
LVEF (%) Median (range)
- 4
Hb: hemoglobin; ECOG PS: Eastern Cooperative Oncology Group Performance Status; ENS: extra nodal site; LDH: lactate dehydrogenase; ULN:upper limit of normal; IPI: International Prognostic Index; CGA: comprehensive geriatric assessment; LVEF: left ventricular ejection fraction.
Table 3. Response after planned rituximab plus bendamustine treat-
ment.
Response
CR
Status
R8+B6 (n=36) N (%)
19 (53)
Missing
R6+B4 (n=9) N (%)
5 (56)
N (%)
Total (n=45) N (%, %95CI)
24 (53; 38-68)
PR
ORR
SD 1(3) - 1(2;0-12)
4 (11)
-
4 (44) -
-
4 (9; 2-21) 28 (62; 47-76)
PD
Not assessed
Death in treatment *
9 (25) 1 (3) 2 (6)
13 (29; 16-44) 1 (2; 0-12) 2 (4; 1-15)
*Dead for heart failure and pneumonia. R8+B6: rituximab for 8 cycles and bendamus- tine for 6 cycles; R6+B4: Rituximab for 6 cycles and bendamustine for 4 cycles; n/N:: number; CI: Confidence Interval; CR: complete remission; PR: partial remission; ORR: overall response rate; SD: stable disease; PD: progression disease.
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