CLL is an aging-associated neoplasm with median age at diagnosis > 65 years. Little is known about safety and efficacy of FC/FCR regimens in elderly CLL patients with multiple comorbidities. We retrospectively revised medical records of 90 patients treated with FC/FCR regimens in our clinic. Data on demographic and biological characteristics, comorbidities, response to therapy, and treatment-associated adverse events were analyzed. Compared to FC, FCR yielded higher rates of OR (93.6 vs. 81.4%, p = .109) and CR (72.3 vs. 46.5%, p = .018). This translated in longer EFS (median 52 vs. 19 months, p = <.001) and OS (median 89 vs. 45 months, p = .001). Elderly patients (≥ 65 years) had more comorbidities and higher median CIRS-G score (7 vs. 4, p < .001). However, no association was found between CIRS-G score and survival. Decreased renal function was associated with dismal prognosis in patients treated with FCR.
4616 Background Fludarabine-containing regimens are widely used as the first-line treatment for CLL. In recent phase III trial (CLL8) significantly superior results in terms of response rates, PFS and OS were shown in FCR arm compared to FC. FCR regimen has thus become standard for initial CLL treatment. However CLL8 trial included patients with relatively low CIRS (median 1). Our retrospective study shows application of this regimen to everyday practice without special selection of patients according to CIRS. Aims To estimate survival benefit produced by the addition of rituximab to standard FC regimen for treatment-naïve not selected CLL pts and measure the influence of CIRS on OS and PFS. Methods 90 consecutive pts were included (43 in FC and 47 in FCR arm) between 2002 and 2010 according to intent-to-treat. Informed consent was obtained in each case. Assignment to FCR was based predominantly on the availability of rituximab and starting from 2007 all pts received it as part of treatment. All patients were personally supervised by one of us (E.S.) and there were no losses at follow-ups. Arms were well balanced with regard to sex (M-to-F ratio ∼2:1), age (median 59 years, range 43–78) and disease stage. CIRS score for each patient was measured retrospectively based on available medical records. Median comorbidity index was 4 (range 0–10) for the whole cohort and it was the same for both FC and FCR subgroups, however max CIRS was 10 for FC and 8 for FCR. Both treatment arms were well-balanced for patients with CIRS score >6 (17/40% in FC arm and 22/45% in FCR arm). All CLL patients with standard indications for start of the treatment according to IWCLL criteria were included except those with acute infections, severe dysfunction of liver, heart or kidneys (grade 4 in CIRS), psychiatric disorders, active hemolytic anemia or active hepatitis B infection. Pts were divided into 2 groups according to CIRS: those with low (lCI, CIRS≤6) and high comorbidity index (hCI, CIRS>6). Treatment schedules were standard. Response was assessed according to IWCLL criteria (in patients included before 2008 this type of response was assessed retrospectively). Only 11 pts received less than 6 cycles (range 4–5). Statistical analysis was done with SPSS17. Results OR and CR rates in FCR and FC groups were 94% vs 81% (p=0,15) and 70% vs 46% (p=0,045) respectively. PR rates were 24% for FCR and 35% for FC (p=0,2). 47 patients died during follow-up: 10 (21%) due to disease progression (incl. 2 Richter’s transformations), 7 (15%) – secondary malignancies, 30 (64%) – infections. 33 deaths were registered in FC arm (77%) and 14 in FCR (32%), p=0,001. After 9 years of follow-up, median OS in FCR arm was not achieved and was 45 mos in FC arm (p=0,009). Median PFS in FCR arm was 43 mos compared to 19 mos in FC arm (p=0,001) - Fig1. There were 40 events in FC (93%) and 25 in FCR arm (53%). According to CIRS, 39 and 51 pts had respectively high and low comorbidity index. Pts with hCI and lCI differed in their age (medians respectively 64,5 and 55 years). This difference was statistically significant (p=0,001). CIRS didn’t influence significantly the survival in the whole group of patients: median PFS was 37 and 50 mos in hCI and lCI patients (p=0,28) respectively. Median OS was 53 and 60 mos, respectively (p=0,7). In FCR group median PFS was 40 mos in hCI pts and 64 mos in lCI pts (p=0,3), medians of OS were 79 and 79 mos respectively (p=0,9). In FC group, median PFS was 20 mos in hCI pts and 19 mos in lCI (p=0,4), medians of OS were 45 and 44 mos respectively (p=0,5) - Fig 2. FCR was advantageous over FC in both CI groups. In lCI group, median PFS was 20 mos in FC pts and 60 mos in FCR pts, p=0,01, medians OS 44 mos and not achieved, p=0,005 respectively. In hCI median, PFS was 20 mos in FC and 40 mos in FCR, p=0,01 and median OS 45 and not achieved, p=0,02 respectively. Conclusions Addition of rituximab to FC regimen in first line improves long-term OS and PFS. Comorbidity measured by CIRS seems not to influence PFS and OS in our cohort. Even in patients with high CIRS score (without severe organ dysfunction) FCR is well tolerated and provides survival advantage over FC regimen. Disclosures: No relevant conflicts of interest to declare.
CLL is the disease of the elderly. Many CLL pts have high comorbidity burden, which makes them ineligible for intensive chemotherapy regimens like FCR. Recently, DCLLSG CLL10 trial proved comparable efficacy of BR and FCR regimens, but better tolerability of BR. It is thus conceivable that BR is a good treatment alternative for slow-go pts, particularly those with advanced chronic kidney disease. In February 2012 a Russian prospective multicenter observational non-interventional clinical study of BR use in previously untreated CLL pts in routine clinical practice was initiated (BEN-001, NORMA). There are no strict incl./excl. criteria in this study, facilitating unbiased analysis of efficacy and toxicity under real world conditions. Here we report our preliminary results. Materials and methods By the time of writing (30 Jun 2014) 123 pts have been included by 25 participating centers. 68 pts have completed therapy and another 28 have completed at least 3 cycles. 55 pts continue treatment. Median duration of observation is 13 mos. Patient characteristics are as follows: median age 59 years (39–79); M-to-F ratio 1.7:1; Binet stage (А/B/C) - 13%/68%/19%; CD38-pos. 30%; IGHV-UM/M ratio 2.1:1; FISH (del13q/del11q/del17p/tri12) - 46%/41%/8%/17%; mut. NOTCH1 - 7%. Also, two FISH abnormalities were detected in 23% pts, three in 2% and four in 1%. IGHV stereotypy was found in 18% of analyzed cases. Median ECOG status was 1 (1-3). Median CIRS score was 3 (0-11), 20% pts had CIRS ≥6. CKD (stage II/III-IV) was documented in 53%/27% pts, 43% pts had GFR <70 ml/min. Enlargement of abdominal lymph nodes was seen in 52% pts. Rituximab and bendamustine were given in standard doses of 375/500 mg/m2 and 90 mg/m2 respectively. As per IWCLL recommendations remissions were confirmed by CT and BM MRD evaluation was done after 3 cycles and at least 2 mos after the last therapy cycle. MRD was evaluated by flow cytometry according to ERIC protocol. Data was entered to eCRF by investigators and centrally analyzed. Results Data on response after 3 cycles is available for 79 pts. Of these 40.5% had CR and 53% had PR. Another 3 pts had progression and 1 ptn had SD. 14% of CRs were MRD-negative. All 4 refractory pts had del17p and IGHV-UM. Ptn with SD after 3 cycles developed progressive disease at final restaging. Of 68 pts who completed all 6 cycles data on response is currently available for 48 pts. Of these 42 (87.5%) had CR and 5 (10.4%) had PR. Among pts with confirmed CR 25 underwent MRD evaluation, giving 13 MRD-neg. and 12 MRD-pos. responses. MRD evaluation after 6 cycles of therapy was done in 33 pts. All MRD-negative pts (n=13) were in CR group, all of them having had MRD levels <10-2 after 3 cycles (4 pts had MRD-neg. already at that time). Among MRD-positive pts (n=20) 12 had CR and 8 had PR. Notably, all of them had MRD levels ≥10-2 (average 10-1) after 3 cycles. In general, the speed of tumor clone eradication, as measured by MRD level after 3 cycles of therapy, correlated well with further response to therapy (р=.0001). Table. MRD levels<10-4≥10-4–< 10-2≥10-2After 3 cycles, N pts.4920After 6 cycles, N pts.13155 There was no statistically significant difference in response rates among pts younger and older than 60 (р>.05), those with CIRS ≥6 and <6 (р>.05), those with early (A) and advanced (B+C) disease stages (р>.05); those with (GFR<70 ml/min) and without (GFR≥70 ml/min) meaningful renal dysfunction (р>.05). With regard to toxicity, only 4 cases of anemia grade II, 2 cases of thrombocytopenia grade II and 14 cases of neutropenia grade III-IV were reported. In addition there were 14 cases of infections with the need of systemic antibacterial or antiviral treatment, particularly one case of HBV reactivation. Mild to moderate skin reactions were seen in 7 pts. Two pts had grade II hepatotoxicity. Conclusions Our preliminary results show outstanding clinical efficacy of BR regimen in 1st line treatment of CLL as the majority of our pts completed therapy with CR. Notably, response rates were not inferior in pts with advanced age, disease stage or high comorbidity burden. All refractory pts had known adverse biological factors like del17p and IGHV-UM haplotype. Reported toxicity was very low. Particularly, pts with renal dysfunction tolerated therapy equally well. One important consideration for the future is that MRD level <10-2 as early as after 3 treatment cycles is a robust predictor for MRD negativity after completion of therapy. ClinicalTrials.gov id NCT02110394 Disclosures No relevant conflicts of interest to declare.
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