First Line BR in Chronic Lymphocytic Leukemia Patients: Interim Results of Russian Norma Trial
Authors: Stadnik Elena , Strugov Vladimir , Silina Tatyana , Ilyina Natalya , Virts Yulia , Badaev Renat , Kuchma Galina , Volodicheva Elena , Sycheva Tatyana , Kaporskaya Tatyana , Kaplanov Kamil , Glonina Natalya , Anchukova Lyubov , Byalik Tatyana , Samoilova Olga , Kirillova Elena , Shklyaev Sergey , Mirolubova Yulia , Nikulina Tatyana , Rumyantsev Andrey , Proydakov Andrey , Lysenko Irina , Melnichenko Vladimir , Esefeva Natalya , Ksenzova Tatyana , Davidkin Igor , Vasilyeva Olga , Ochirova Oksana , Rukavitsyn Oleg , Bulieva Natalya , Zherebtsova Vera , Gubkin Andrey , Bogdanova Yulia , Chebykina Irina , Shukaeva Elena , Zaritskey Andrey 
Published: October 2019

Abstract
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.