Page 137 - Haematologica July

Efficacy of BR as first salvage treatment in CLL
Table 4. Overall survival after univariate and multivariate analysis. Univariate
Multivariate
HR (95% CI) P
Age, years ≤65 vs. >65
Sex,Mvs.F
Stage, others vs. Rai III/IV or Binet C
Bulky lymph nodes (>5 cm) yes vs. no Comorbidities0-1vs. ≥2
Creatinine clearance (mL/min) ≤70 vs. >70 CD38 (>20%) neg vs. pos
FISH 17p- vs. others
IGHV mutated vs. unmutated
Months between 1st and 2nd treatment <36 vs. ≥36 First-line chemo vs. CIT
<6 cycles and/or dose reductions no vs. yes
HR (95% CI)
0.741 (0.439-1.250) 0.836 (0.491-1.425) 0.501 (0.296-0.846) 1.161 (0.464-2.905) 1.069 (0.671-1.702) 1.401 (0.850-2.308) 0.722 (0.356-1.465) 1.500 (0.734-3.064) 0.604 (0.290-1.254) 1.496 (0.934-2.398) 0.977 (0.609-1.565) 0.706 (0.444-1.123) 0.330 8 (0.197-0.552)
P
0.2612 0.5107 0.0098 0.7492 0.7797 0.1855 0.3665 0.2663 0.1761 0.0941 0.9216 0.1419 <.0001
--
--
0.547 (0.320-0.935) 0.0276
-- - - - - - - - - - - - - - - - -
ORR CR; Cri; PR; nPR/vs. PD; SD; NR
HR: Hazard Ratios; CI: Confidence Interval; Chemo: chemotherapy; CIT: chemoimmunotherapy; ORR: overall response rate; CR: complete remission with incomplete marrow
0.344 (0.198-0.595) 0.0001
recovery; nPR: nodular partial response; F: female; M: male; NR: no remission; PD: progressive disease; PR: partial remission; SD: stable disease.
Table 5. Baseline characteristics of patients treated with chemoimmunotherapy in first-line in the bendamustine and rituximab (BR) and in the ibrutinib cohorts (UK + NPP GIMEMA).
Variable
Median age, years (range)
Age, years (%) ≤65/>65
Sex, (%) M/F
ECOG PS (%) 0-1/≥2
Months between 1st line and 2nd line
BR (n=137)
68.2 (39.4-84.6) 39 (34.5)/74 (65.5) 91 (66.4)/46 (33.6) 113 (91.9)/10 (8.1)
30.60 (0.40, 79.40)
81 (59.1)/56 (40.9)
28 (20.4)/109 (79.6)
17 (19.5)/70 (80.5)
16 (14.8)/92 (85.2)
Ibrutinib (n=71)
67.1 (27.5-85.3) 27 (38.6)/43 (61.4) 45 (63.4)/ 26 (36.6) 57 (82.6)/ 12 (17.4)
19.40 (1.80, 77.60)
54 (76.1)/17 (23.9)
8 (15.1)/45 (84.9)
8 (32.0)/17 (68.0)
22 (36.1)/39 (63.9)
P
0.603 0.691 0.777 0.090
0.001
0.023
0.524
0.295
0.003
Median (range)
n. <36/≥36 (%)
Response to 1st line treatment (%) no/yes
IGHV (%) mutated/unmutated
17p- (%) yes/no
NPP GIMEMA: Named Patient Program-Gruppo Italiano Malattie Ematologiche dell'Adulto; ECOG: Eastern Cooperative Oncology Group; n: number. F: female; M: male; PS: per- formance status.
was minimal, if any, patient selection bias in our study. The number of grade 3-4 infections (6.7%) is similar to the 4.2% incidence of severe infections in a trial using ben- damustine and ofatumumab in patients who had received 1-2 previous lines of treatment.16 In another trial using the BR regimen, the incidence of grade 3 infections was 12.8% in patients who had received 1-5 previous lines of treatment.15 Thus, our data show that BR is a relatively safe second-line regimen in terms of infectious complica- tions in a real-life population. The lower incidence of grade 3-4 cytopenias in this study compared to other prospective studies showing a 50-78% incidence of grade 3-4 cytopenias15,16 reflects the policy not to perform a blood count in the routine practice at the nadir time point at many centers.
With a 78.6% PFS rate at 12 months (median 25 months), a 31.3-month median TTNT, and a 92.7% OS rate at 12 months (median 74.5 months), our data show that the BR regimen is an effective first salvage regimen. Interestingly, the efficacy of this regimen in terms of PFS, TTNT and OS was not influenced significantly by age, creatinine clearance, by the presence of 2 or more comor- bidities. PFS was negatively influenced by advanced stage,
del(17p) and U-IGHV, confirming the strong prognostic significance of these parameters24 also in the second-line setting. Patients without any of these unfavorable charac- teristics experienced a prolonged median PFS (40.4 months).
Although PFS estimation should be interpreted with caution in a retrospective analysis, our data are similar to those observed in a prospective phase II GIMEMA trial16 that reported a median PFS of 23.6 months with ben- damustine and ofatumumab in 49 R/R CLL (61% with 1 previous treatment, 39% with 2 previous lines). In another analysis of BR in patient who had received a median num- ber of 2 previous treatments (range 1-5), the median PFS was 15.2 months (95%CI: 12.5-17.9 months).15 A 18- month median PFS was reported with BR as first salvage after fludarabine, cyclophosphamide and rituximab in 62 patients.13
Time to next treatment was longer in those patients who had received chemotherapy as first-line treatment. It is worth noting that even though published guidelines proposed the preferential usage of CIT, 27.9% of our patients who started treatment after 2010 had received only chemotherapy as initial treatment.
haematologica | 2018; 103(7)
1215