BR

Minimal Residual Disease and IGHV-Genes Mutational Status as the Main Predictors of Response to Bendamustine-Rituximab Therapy in Previously Untreated Chronic Lymphocytic Leukemia

LYMPHOID TUMORS , , , , , ,

YuV Mirolyubova, EA Stadnik, VV Strugov, TO Andreeva, TS Nikulina, YuV Virts, PA Butylin, AG Rumyantsev, AYu Zaritskey

VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Yuliya Vladimirovna Mirolyubova, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; e-mail: juli9702@yandex.ru

For citation: Mirolyubova YuV, Stadnik EA, Strugov VV, et al. Minimal Residual Disease and IGHV-Genes Mutational Status as the Main Predictors of Response to Bendamustine-Rituximab Therapy in Previously Untreated Chronic Lymphocytic Leukemia. Clinical oncohematology. 2018;11(2):167–74.

DOI: 10.21320/2500-2139-2018-11-2-167-174

ABSTRACT

Background. In patients with chronic lymphocytic leukemia (CLL) the eradication of minimal residual disease (MRD) is a prognostic factor of overall survival (OS) and progression-free survival (PFS). IGHV mutational status has also independent prognostic value.

Aim. To analyse the impact of mutational status and MRD eradication in CLL patients after first-line standard BR (bendamustine + rituximab) immunochemotherapy.

Materials & Methods. The prospective study included patients with immunophenotypically confirmed CLL who had not previously received anticancer therapy. All patients were treated by BR combination from 2012 to 2015. MRD level was determined in 109 patients after completing the 3rd and the 6th treatment courses. IGHV mutational status data were available for 98 patients. IGHV mutational status was evaluated in accordance with ERIC recommendations. MRD was assessed by standardized method of 4-color flow cytometry.

Results. MRD negativity was achieved in 37 (34 %) out of 109 patients. MRD eradication correlated with the best PFS (p = 0.04). IGHV mutational status had a statistically significant impact on PFS (p = 0.02). In patients with MRD-negative response and IGHV mutation no unfavorable events occurred during the period of monitoring. Conversely, PFS rates in MRD-negative patients having no IGHV mutation and in MRD-positive patients with mutation were significantly worse. MRD eradication resulted in statistically significant improvement of PFS rates after completing 3 treatment courses, compared with the cases with MRD persistence regardless of residual malignant clone level (p = 0.01).

Conclusion. BR therapy as first-line treatment statistically improved PFS in patients who achieved MRD-negative remission after completing the 3rd treatment course. PFS was significantly higher in MRD-negative patients with IGHV mutation after 6 treatment courses. MRD negativity resulting from 6 BR therapies in patients having no IGHV mutation was not accompanied by PFS improvement. It follows that by itself MRD negativity cannot be considered to be a universal prognostic factor.

Keywords: chronic lymphocytic leukemia, minimal residual disease, bendamustine, rituximab, BR, IGHV, mutational status.

Received: December 29, 2017

Accepted: February 27, 2018

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Effect of IGHV Gene Mutation Status and BCR Structure Stereotypy on Effectiveness of BR Regimen in First-Line Therapy of Chronic Lymphocytic Leukemia

LYMPHOID TUMORS , , , , , , ,

VV Strugov1, EA Stadnik1,2, AM Rumyantsev1, TO Andreeva1, YuV Virts1, YuV Mirolyubova1, PA Butylin1, AYu Zaritskey1,2

1 Federal Almazov North-West Medical Research Centre, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

2 Internal medicine clinic, Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Vladimir Vladimirovich Strugov, staff scientist, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel: +7(812)702-37-49; e-mail: strugov@almazovcentre.ru

For citation: Strugov VV, Stadnik EA, Rumyantsev AM, et al. Effect of IGHV Gene Mutation Status and BCR Structure Stereotypy on Effectiveness of BR Regimen in First-Line Therapy of Chronic Lymphocytic Leukemia. Clinical oncohematology. 2017;10(2):141–9 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-141-149

ABSTRACT

Background & Aims. The IGHV gene mutation status is a constant biological feature of tumor cells in chronic lymphocytic leukemia (CLL). This parameter is an important predictor of the efficacy of immunochemotherapy. It was included into the CLL international prognostic index CLL-IPI developed recently. The aim is to evaluate the prognostic significance of the BR regimen in patients with different variants of the B-cell receptor (BCR) structure.

Methods. The study examined immediate and delayed treatment outcomes for 183 CLL patients included in a Russian, prospective, observational BEN-001 trial (NCT02110394). The median age was 61 years (range: 35–79); 53/179 (29.6 %) patients were older than 65; and 14/179 (7.8 %) patients were older than 75. Prevalence of males (110/179, 61.5 %) in the male/female ratio (1.6:1.0) was observed. Most patients had advanced disease: Binet B 116/173 (67 %) or Binet C 38/173 (22 %). The patients received the first-line therapy according to the BR regimen at standard doses in 36 hematological institutions in the Russian Federation over the period from 2012 until 2015. The genome DNA isolated from mononuclear leukocytes in the peripheral blood was used to assess the mutation status of the IGHV-genes.

Results. The study demonstrated that unmutated CLL (≥ 98 % of homology to germline gene) is associated with worsening of the event-free and overall survival rates most of all; at that, the complete remission rate and the MRD-free survival rate were the same.

Conclusion. It is reasonable to analyze the IGHV mutation status in all patients prescribed with the BR regimen as the first-line therapy.

Keywords: chronic lymphocytic leukemia, CLL, bendamustine, rituximab, BR, IGHV, mutation status, stereotypy.

Received: January 8, 2017

Accepted: January 26, 2017

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