CLL

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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REFERENCES

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V(D)J Recombination Excision Circles of B- and T-cells as Prognostic Marker in B-Cell Chronic Lymphocytic Leukemia

LYMPHOID TUMORS , , , ,

IV Obraztsov1,2, MA Gordukova 3, NA Severina4, BV Biderman4, SYu Smirnova4, AB Sudarikov4, EA Nikitin5, AG Rumyantsev1

1 Dmitrii Rogachev Federal Scientific Clinical Centre of Pediatric Hematology, Oncology and Immunology under the Ministry of Health of the Russian Federation, 1 Samory Mashela str., Moscow, Russian Federation, 117198

2 AN Ryzhikh State Scientific Center for Coloproctology under the Ministry of Health of the Russian Federation, 2 Salyama Adilya str., Moscow, Russian Federation, 123423

3 GN Speranskii Municipal Children’s Hospital No. 9, 29 Shmitovskii pr-d, Moscow, Russian Federation, 123317

4 Hematology Research Center under the Ministry of Health of the Russian Federation, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

5 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

For correspondence: Igor’ Vladimirovich Obraztsov, junior researcher, 1 Samory Mashela str., Moscow, Russian Federation, 117997; е-mail: igor_obraztsov@yahoo.com

For citation: Obraztsov IV, Gordukova MA, Severina NA, et al. V(D)J Recombination Excision Circles of B- and T-cells as Prognostic Marker in B-Cell Chronic Lymphocytic Leukemia. Clinical oncohematology. 2017;10(2):131–40 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-131-140

ABSTRACT

Background & Aims. T-cell receptor excision circles (TREC) and κ-deleting recombination excision circles (KREC) are extrachromosomal DNA segments generated during V(D)J re combination process that characterize the diversity of the antigen repertoire of T- and B-cells. The aim of our study is to identify the prognostic value of the excision circles in the chronic lymphocytic leukemia (CLL) setting.

Methods. The excision circles’ levels were assessed by means of real time PCR in 109 patients with high-risk CLL and 16 matched healthy individuals.

Results. KREC levels were signifi cantly (p < 0.001) lower in CLL patients vs. the reference group. TREC levels were lower in groups with unmutated status of immunoglobulin heavy chain variable region genes (p < 0.05) and 11q deletions (p < 0.1). Moreover, the KREC levels were higher in NOTCH1 mutation carriers than in noncarriers (p < 0.05). The comparison of treatment outcomes demonstrated a correlation between a high TREC level and achievement of complete remission. The prognostic value of the biomarker was confirmed by ROC-analysis: AUCTREC = 0.713 (p = 0.001)

Conclusion. Association between excision circles’ levels and clinical/laboratory CLL prognostic factors, as well as complete remission achievement, makes possible the implementation of the test for early prediction of the treatment outcome.

Key words: CLL, TREC, KREC, naive T-cells, naive B-cells, biomarkers, outcome predictors.

Received: November 10, 2016

Accepted: January 13, 2017

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Role of Patient’s Age and Comorbidities in Therapy of Chronic Lymphocytic Leukemia

LYMPHOID TUMORS , ,

VV Strugov1, EA Stadnik1,2, YuV Virts1, TO Silina1, AYu Zaritskii1,2

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

2 Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Vladimir Vladimirovich Strugov, scientific worker, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(906)277-86-64; e-mail: strugov@almazovcentre.ru

For citation: Strugov VV, Stadnik EA, Virts YuV, et al. Role of Patient’s Age and Comorbidities in Therapy of Chronic Lymphocytic Leukemia. Clinical oncohematology. 2016;9(2):162–75 (In Russ).

DOI: 10.21320/2500-2139-2016-9-2-162-175

ABSTRACT

Background & Aims. New schemes of the antitumor therapy of CLL resulted in improvement of survival of relatively young patients. However, the therapy outcomes of elderly patients are still unsatisfactory. Erroneous overestimation of expected toxicity of standard therapeutic regimens in some elderly patients may play a certain role, thus leading to prescription of less effective regimens. Therefore, the urgent problem is to find objective criteria for risk stratification in CLL. The aim of the study is to evaluate the prognostic significance of patient’s age and the CIRS-G index in elderly patients treated with fludarabine-containing regimens in first line treatment outside clinical trials.

Methods. A retrospective analysis of 90 elderly CLL patients, treated with standard FC and FCR regimens in the clinic of internal medicine of the First St. Petersburg State Medical University from 2001 till 2011. The age median was 59 years (range from 43 to 78 years). The comorbidity index was determined for each patient using the CIRS-G score.

Results. The overall response rate did not significantly differ between FC and FCR groups and was equal to 81.6 % and 93.4 %, respectively (p = 0.109). Complete remissions were achieved in 72.3 % of FCR group patients and only in 46.5 % of FC group patients (p = 0.018). The retrospective analysis of treatment tolerability in primary elderly patients with different CIRS-G scores in the routine clinical practice demonstrated that the index has no independent prognostic significance. Among all CIRS-G components (14 organs and systems), only renal and hepatic diseases demonstrated significant correlation with the overall survival rate (p < 0.001 and p = 0.028, respectively).

Conclusion. The creatinine clearance value in the beginning of treatment is the most important predictor of FC and FCR regimen efficacy in elderly patients. The use of the comorbidity index with a 6-score threshold as a contraindication for fludarabine-containing regimens proved to be unjustified.

Keywords: chronic lymphocytic leukemia, CLL, comorbidity index, CIRS-G, FCR.

Received: January 15, 2016

Accepted: February 3, 2016.

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