chronic lymphocytic leukemia

Ibrutinib in the Treatment of Relapsed Chronic Lymphocytic Leukemia

NOVEL DRUGS , , ,

EA Stadnik, NS Timofeeva, VV Strugov, AYu Zaritskey

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

For correspondence: Elena Aleksandrovna Stadnik, PhD, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(921)575-54-55; e-mail: elena_stadnik@mail.ru

For citation: Stadnik EA, Timofeeva NS, Strugov VV, Zaritskey AYu. Ibrutinib in the Treatment of Relapsed Chronic Lymphocytic Leukemia. Clinical oncohematology. 2018;11(1):42–9.

DOI: 10.21320/2500-2139-2018-11-1-42-49

ABSTRACT

Aim. To estimate ibrutinib efficacy in the treatment of first early CLL relapses and in patients with ≥ 2 lines of preceding therapy. Analysis of treatment results in patients with del(17p) and monitoring of minimal residual disease (MRD) and ibrutinib safety profile.

Materials & Methods. The analysis included the results of ibrutinib treatment in 31 patients with CLL. Twenty eight patients were treated by bendamustine and fludarabine containing regimens. The median prior treatment lines were 2 (range 1–10). The indications for the treatment initiation were the first early relapse in 51 % of cases (n = 16) and a relapse after 2 and more lines of therapy in 49 % of cases (n = 15). Ibrutinib was administered in mono- (n = 15) and combined therapy (n = 14) as well as in the R-BAC scheme (n = 2). Using FISH analysis del(17p) was found in 9 patients (34 %).

Results. Within the median follow up of 18 months (range 7–42+) the overall survival (OS) rate was reported to be 87 %, and the progression-free survival (PFS) rate was 77 %. The maximum MRD after a year of ibrutinib treatment was observed in case of combination with immunochemotherapy (e.g., R-BAC). Within the period of 18 months OS rate was 100 %, in the patient group with first early relapses and 66 % in the group with a relapse after 2 and more therapy lines (p = 0.02). Within the same examination period PFS was significantly higher (94 %) in the patient group with first early relapses compared to the previously treated patients (60 %) (p = 0.034). The most common adverse events were grade 1–2 purpura (30 %), grade 1–2 diarrhea (10 %), atrial fibrillation paroxysms (10 %) and arterial hypertension (10 %). Severe infectious complications registered in 6 % (n = 3) patients were successfully solved in the course of combined antibacterial and antimycotic treatment.

Conclusion. Ibrutinib was shown to be effective drug for treatment of relapsed CLL. The OS and PFS values were more favourable in patients with first early relapses compared to the patients with relapses after ≥ 2 lines of therapy prior to ibrutinib treatment. The maximum elimination of the tumor clone was observed after combined ibrutinib/immunochemotherapy treatment. The tolerance of ibrutinib was reported to be satisfactory with acceptable toxicity profile. No mortality due to infection complications was observed.

Keywords: chronic lymphocytic leukemia, first early relapse, del(17p), ibrutinib, minimal residual disease.

Received: August 20, 2017

Accepted: November 16, 2017

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Ibrutinib in the Treatment of Refractory Chronic Lymphocytic Leukemia

NOVEL DRUGS , , , ,

EA Nikitin1, EA Dmitrieva1, MA Panteleev2, EI Emelina3, VL Ivanova1, YuB Kochkareva1, EG Arshanskaya1, IE Lazarev1, EE Markova1, LA Mukha1, NG Novitskaya1, MM Pankrashkina1, VV Glazunova1, AV Shubina1, SA Chernysh1, NK Khuazheva1, EV Naumova4, SA Lugovskaya4, ME Pochtar’4, TN Obukhova5, OYu Vinogradova1, GE Gendlin3, VV Ptushkin1

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

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

3 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

4 Department of Clinical Laboratory Diagnostics, Russian Medical Academy of Postgraduate Education, 7 bld. 2 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

5 Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Evgenii Aleksandrovich Nikitin, DSci, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Tel.: +7(916)572-06-44; e-mail: eugene_nikitin@mail.ru

For citation: Nikitin EA, Dmitrieva EA, Panteleev MA, et al. Ibrutinib in the Treatment of Refractory Chronic Lymphocytic Leukemia. Clinical oncohematology. 2017;10(3):271–81 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-271-281

ABSTRACT

Background & Aims. This paper presents the results of the observational study of ibrutinib in patients with chronic lymphocytic leukemia (CLL), conducted in SP Botkin Municipal Clinical Hospital. The main objective was the analysis of complications of ibrutinib and identification of factors, influencing the dosage regimen; the secondary objective was the estimation of the total response to treatment, event-free and overall survival.

Materials & Methods. The study included 96 patients with CLL with indications for ibrutinib therapy. The median age was 64,9 years (range 32–91 years), the study population consisted of 69 (72 %) men and 27 (28 %) women. The condition of 25 (26 %) patients according to the ECOG scale was of > 3 points. The disease of stage C were diagnosed in 36 (37 %) patients . Deletion of 17p/TP53 mutations were detected in 29 (33 %) of 87 patients. Seventy patients had refractory CLL. The median of the number of the lines of the previous therapy was 3 (range 1–9). Adverse events were assessed in accordance with the CTCAE criteria, version 4.0; the bleeding severity was evaluated using ITP-specific bleeding score; hematological complications were classified according to the recommendations of IWCLL-2008.

Results. Ibrutinib was administered at a dosage of 420 mg per day daily until progression or intolerable toxicity. The median duration of ibrutinib therapy was 10.3 months. Ibrutinib was shown to have moderate toxicity, mostly of grade I or II. The bleeding was the most frequent complication. Of the hematological complications, thrombocytopenia was the most common (35 %); neutropenia < 1 × 109/L was observed in 4 patients. GIT complications were identified in 51 (53 %) patients. Atrial fibrillation was registered in 5 patients, who initially had sinus rhythm. The total of 144 infections were diagnosed in 64 (66 %) patients. Severe infections (> grade III) developed in 26 % of patients. The treatment response was assessed in 92 patients. The overall response to treatment was 89 %. Complete remission, partial remission and partial remission with lymphocytosis were achieved in 4 (4 %), 57 (62 %), and 21 (23 %) patients, respectively. The event-free survival and overall survival by the month 10 was 90 % and 91 %, respectively. For this observation period, ECOG status and the number of the lines of therapy prior to ibrutinib had the prognostic value.

Conclusion. Ibrutinib was shown to have high efficiency in relapsed/refractory forms of CLL. The nature of the ibrutinib toxicity is fundamentally different from that of the conventional chemotherapy. The frequency of ibrutinib therapy complications and patients’ non-compliance depends on the intensity of the previous treatment of CLL. Despite a short observation period, it can be concluded that ibrutinib had the greatest impact on the patient’s quality of life when administered for the first relapse. The low toxicity of ibrutinib is likely to allow the combination with other antitumor agents.

Keywords: chronic lymphocytic leukemia, del 17p, TP53, refractory CLL, ibrutinib, bleeding, atrial fibrillation.

Received: March 14, 2017

Accepted: April 14, 2017

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Role of Superficial CD200 Marker in Differential Diagnosis of Malignant B-Cell Lymphoproliferative Diseases

LYMPHOID TUMORS , , , , ,

YuV Mirolyubova, EA Stadnik, TS Nikulina, VV Strugov, TO Andreeva, YuV Virts, RV Grozov, AYu Zaritskey

Federal Almazov North-West Medical Research Centre, 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, Nikulina TS, et al. Role of Superficial CD200 Marker in Differential Diagnosis of Malignant B-Cell Lymphoproliferative Diseases. Clinical oncohematology. 2017;10(2):169–75 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-169-175

ABSTRACT

Background & Aims. Flow cytometry is successfully used for diagnosis of malignant lymphoproliferative disorders. However, there are atypical cases that are difficult to interpret; thus, new markers relevant for the differential diagnosis are to be searched for. The aim is to analyze CD200 expression in patients with B-cell lymphoproliferative disorders.

Materials & Methods. 187 patients with chronic lymphocytic leukemia (CLL), 14 patients with mantle cell lymphoma (MCL), 9 patients with marginal zone lymphoma (MZL), and 5 patients with hairy cell leukemia (HCL) were enrolled in the study. Neoplasm was not confirmed in 12 subjects. The patients underwent the following tests: CBC, immunophenotyping of peripheral blood or bone marrow lymphocytes, and a cytogenetic test. In some cases, an additional immunohistochemical test of bone marrow trepanobiopsy or lymph node biopsy samples was required.

Results. In all cases of CLL and HCL, the CD200 expression was positive; mean fluorescence intensity was higher in these cases as compared to other groups. Negative expression of CD200 prevailed in MCL patients; however, at the same time 2 cases of intermediate and positive expression were reported, both showing moderate fluorescence intensity values. CD200 expression was heterogeneous in MZL patients.

Conclusion. The CD200 negative expression excludes typical HCL and CLL. Additional cytogenetic and immunnohistoсhemical tests should be performed in such cases to verify the diagnosis, first of all, MCL or MZL.

Keywords: CD200, flow cytometry, diagnosis, chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, hairy cell leukemia.

Received: September 7, 2016

Accepted: January 3, 2017

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REFERENCES

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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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REFERENCES

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  6. Baliakas P, Hadzidimitriou A, Sutton LA, et al. Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study. Lancet Haematol. 2014;1(2):e74–84. doi: 10.1016/S2352-3026(14)00005-2.
  7. Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928–42. doi: 10.1016/S1470-2045(16)30051-1.
  8. Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012;30(26):3209–16. doi: 10.1200/JCO.2011.39.2688.
  9. Agathangelidis A, Darzentas N, Hadzidimitriou A, et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood. 2012;119(19):4467–75. doi: 10.1182/blood-2011-11-393694.
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  14. Hamblin TJ, Davis ZA, Oscier DG. Determination of how many immunoglobulin variable region heavy chain mutations are allowable in unmutated chronic lymphocytic leukaemia – long-term follow up of patients with different percentages of mutations. Br J Haematol. 2008;140(3):320–3. doi: 10.1111/j.1365-2141.2007.06928.x.
  15. Davis Z, Forconi F, Parker A, et al. The outcome of Chronic lymphocytic leukaemia patients with 97% IGHV gene identity to germline is distinct from cases with <97% identity and similar to those with 98% identity. Br J Haematol. 2016;173(1):127–36. doi: 10.1111/bjh.13940.
  16. Kryachok I, Abramenko I, Bilous N, et al. IGHV gene rearrangements as outcome predictors for CLL patients: experience of Ukrainian group. Med Oncol. 2012;29(2):1093–101. doi: 10.1007/s12032-011-9872-5.
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  19. Marinelli M, Ilari C, Xia Y, et al. Immunoglobulin gene rearrangements in Chinese and Italian patients with chronic lymphocytic leukemia. Oncotarget. 2016;7(15):20520–31. doi: 10.18632/oncotarget.7819.
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  22. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373(25):2425–37. doi: 10.1056/NEJMoa1509388.
  23. Stamatopoulos K, Agathangelidis A, Rosenquist R, Ghia P. Antigen receptor stereotypy in chronic lymphocytic leukemia. Leukemia. 2016;31(2):282–91. doi: 10.1038/leu.2016.322.

 

Factors Affecting Course and Outcome of Chronic Lymphocytic Leukemia: Data from Hematological Hospitals of Krasnoyarsk Region

LYMPHOID TUMORS , , , ,

VI Bakhtina1,2, IV Demko2, AN Narkevich2, DS Gushchin3

1 Regional Clinical Hospital, 3а Partizana Zheleznyaka Str., Krasnoyarsk, Russian Federation, 660022

2 Professor VF Voyno-Yasenetsky Krasnoyarsk State Medical University, 1 Partizana Zheleznyaka Str., Krasnoyarsk, Russian Federation, 660022

3 Norilsk Inter-District Hospital No. 1, Solnechnyi pr-d, 7a Norilsk, Russian Federation, 663300

For correspondence: Varvara Ivanovna Bakhtina, 1 Partizana Zheleznyaka Str., Krasnoyarsk, Russian Federation, 660022; Tel: +7(923)357-57-77; е-mail: doctor.gem@mail.ru

For citation: Bakhtina VI, Demko IV, Narkevich AN, Gushchin DS. Factors Affecting Course and Outcome of Chronic Lymphocytic Leukemia: Data from Hematological Hospitals of Krasnoyarsk Region. Clinical oncohematology. 2016;9(4):413–419 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-413-419

ABSTRACT

Background & Aims. B-cellular chronic lymphocytic leukemia (CLL) is a disease with heterogeneous clinical manifestations and biological characteristics. The age of 70 % of patients is more than 65 years by the date of the diagnosis; most of them have several comorbidities. The aim of the study is to identify factors affecting the survival, as well as to determine causes of mortality in CLL patients (according to data from hematological hospitals of Krasnoyarsk Region).

Methods. In order to identify the most significant factors affecting the course and the outcome of CLL, a retrospective analysis of data on patients who died in hematological hospitals was carried out. 45 cases with the lethal outcome were registered within six years. All patients were under hematologist’s supervision after diagnosing the disease, and they were followed throughout the treatment period up to the lethal outcome.

Results. Тhe overall and progression-free survival depended, first of all, on the type of the first line therapy and its efficacy. The progression of the underlying disease and infectious complications became the main reason of the lethal outcome in CLL patients.

Conclusion. Most patients received ineffective treatment as first line therapy. The analysis of the comorbidities showed that a more effective chemotherapy could be performed with achievement of longer complete remissions.

Keywords: chronic lymphocytic leukemia, oncohematological diseases, comorbidities, survival, treatment.

Received: May 16, 2016

Accepted: June 17, 2016

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REFERENCES

  1. Gribben JG. How I treat CLL up front. Blood. 2010;115(2):187– doi: 10.1182/blood-2009-08-207126.
  2. Lee JS, Dixon DO, Kantarjian H, et al. Prognosis of chronic lymphocytic leukemia: a multivariate regression analysis of 325 untreated patients. Blood. 1987;69(3):929–36.
  3. Molica S. Infections in chronic lymphocytic leukemia: risks factors and impact on survival and treatment. Leuk Lymphoma. 1994;13(3–4):203–14. doi: 10.3109/10428199409056283.
  4. Albertsen PC, Moore DF, Shih W, et al. Impact of comorbidity on survival among men with localized prostate cancer. J Clin Oncol. 2011;29(10):1335–41. doi: 10.1200/jco.2010.31.2330.
  5. Etienne A, Esterni B, Charbonnier A, et al. Comorbidity is an independent predictor of complete remission in elderly patients receiving induction chemotherapy for acute myeloid leukemia. Cancer. 2007;109(7):1376– doi: 10.1002/cncr.22537.
  6. Kos FT, Yazici O, Civelek B, et al. Evaluation of the effect of comorbidity on survival in pancreatic cancer by using “Charlson Comorbidity Index” and “Cumulative Illness Rating Scale”. Wien Klin Wochenschr. 2014;126(1–2):36– doi: 10.1007/s00508-013-0453-9.
  7. Della Porta MG, Malcovati L. Clinical relevance of extra-hematologic comorbidity in the management of patients with myelodysplastic syndrome. Haematologica. 2009;94(5):602– doi: 10.3324/haematol.2009.005702.
  8. Wang S, Wong ML, Hamilton N, et al. Impact of age and comorbidity on non-small-cell lung cancer treatment in older veterans. J Clin Oncol. 2012;30(13):1447–55. doi: 11200/jco.2011.39.5269.
  9. Strati P, Chaffe K, Achenbach S, et al. Comorbidity and cause of death in patients with chronic lymphocytic leukemia (CLL). Cancer Res. 2015;75(15): Abstract 5267. doi: 10.1158/1538-7445.am2015-5267.
  10. Goede V, Paula Cramer P, Busch R, et al. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German Chronic Lymphocytic Leukemia Study Group trials. 2014;99(6):1095–100. doi: 10.3324/haematol.2013.096792.
  11. Thurmes P, Call T, Slager S, et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocyticleukemia. Leuk Lymphoma. 2008;49(1):49–56. doi: 10.1080/10428190701724785.
  12. Linn BS, Linn MW, Gurel L. Cumulative illness rating scale. J Am Geriatr Soc. 1968;16(5):622–6. doi: 10.1111/j.1532-5415.1968.tbx.
  13. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. 2010;376(9747):1164–74. doi: 10.1016/S0140-6736.
  14. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–83. doi: 10.1016/0021-9681(87)90171-8.
  15. Anaissie EJ, Kontoyiannis DP, O’Brien S, et al. Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med. 1998;129(7):559– doi: 10.7326/0003-4819-129-7-199810010-00010.
  16. Badoux XC, Keating MJ, Wang X, et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. 2011;117(11):3016–24. doi: 10.1182/blood-2010-08-304683.
  17. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007;370(9583):230–9. doi: 10.1016/s0140-6736(07)61125-8.
  18. Bouvet E, Borel C, Oberic L, et al. Impact of dose intensity on outcome of fludarabine, cyclophosphamide, and rituximab regimen given in the first-line therapy for chronic lymphocytic leukemia. 2013;98(1):65–70. doi: 10.3324/haematol.2012.070755.
  19. Miller MD, Paradis CF, Houck PR, et al. Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res. 1992;41(3):237–48. doi: 10.1016/0165-1781(92)90005-n.
  20. Parmlee PA, Thuras PD, Katz IR, et al. Validation of Cumulative Index Rating Scale in a geriatric residential population. J Am Geriatr Soc. 1995;43(2):130–7. doi: 10.1111/j.1532-5415.1995.tb06377.x.
  21. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis. 1987;40(5):373–83. doi: 1016/0021-9681(87)90171-8.

Factors Affecting Course and Outcome of Chronic Lymphocytic Leukemia: Data from Hematological Hospitals of Krasnoyarsk Region

LYMPHOID TUMORS , , , ,

VI Bakhtina1,2, IV Demko2, AN Narkevich2, DS Gushchin3

1 Regional Clinical Hospital, 3а Partizana Zheleznyaka Str., Krasnoyarsk, Russian Federation, 660022

2 Professor VF Voyno-Yasenetsky Krasnoyarsk State Medical University, 1 Partizana Zheleznyaka Str., Krasnoyarsk, Russian Federation, 660022

3 Norilsk Inter-District Hospital No. 1, Solnechnyi pr-d, 7a Norilsk, Russian Federation, 663300

For correspondence: Varvara Ivanovna Bakhtina, 1 Partizana Zheleznyaka Str., Krasnoyarsk, Russian Federation, 660022; Tel: +7(923)357-57-77; е-mail: doctor.gem@mail.ru

For citation: Bakhtina VI, Demko IV, Narkevich AN, Gushchin DS. Factors Affecting Course and Outcome of Chronic Lymphocytic Leukemia: Data from Hematological Hospitals of Krasnoyarsk Region. Clinical oncohematology. 2016;9(4):413–419 (In Russ).

DOI: http://dx.doi.org/10.21320/2500-2139-2016-9-4-413-419

ABSTRACT

Background & Aims. B-cellular chronic lymphocytic leukemia (CLL) is a disease with heterogeneous clinical manifestations and biological characteristics. The age of 70 % of patients is more than 65 years by the date of the diagnosis; most of them have several comorbidities. The aim of the study is to identify factors affecting the survival, as well as to determine causes of mortality in CLL patients (according to data from hematological hospitals of Krasnoyarsk Region).

Methods. In order to identify the most significant factors affecting the course and the outcome of CLL, a retrospective analysis of data on patients who died in hematological hospitals was carried out. 45 cases with the lethal outcome were registered within six years. All patients were under hematologist’s supervision after diagnosing the disease, and they were followed throughout the treatment period up to the lethal outcome.

Results. Тhe overall and progression-free survival depended, first of all, on the type of the first line therapy and its efficacy. The progression of the underlying disease and infectious complications became the main reason of the lethal outcome in CLL patients.

Conclusion. Most patients received ineffective treatment as first line therapy. The analysis of the comorbidities showed that a more effective chemotherapy could be performed with achievement of longer complete remissions.

Keywords: chronic lymphocytic leukemia, oncohematological diseases, comorbidities, survival, treatment.

Received: May 16, 2016

Accepted: June 17, 2016

Read in PDF (RUS) pdficon

REFERENCES

  1. Gribben JG. How I treat CLL up front. Blood. 2010;115(2):187– doi: 10.1182/blood-2009-08-207126.
  2. Lee JS, Dixon DO, Kantarjian H, et al. Prognosis of chronic lymphocytic leukemia: a multivariate regression analysis of 325 untreated patients. Blood. 1987;69(3):929–36.
  3. Molica S. Infections in chronic lymphocytic leukemia: risks factors and impact on survival and treatment. Leuk Lymphoma. 1994;13(3–4):203–14. doi: 10.3109/10428199409056283.
  4. Albertsen PC, Moore DF, Shih W, et al. Impact of comorbidity on survival among men with localized prostate cancer. J Clin Oncol. 2011;29(10):1335–41. doi: 10.1200/jco.2010.31.2330.
  5. Etienne A, Esterni B, Charbonnier A, et al. Comorbidity is an independent predictor of complete remission in elderly patients receiving induction chemotherapy for acute myeloid leukemia. Cancer. 2007;109(7):1376– doi: 10.1002/cncr.22537.
  6. Kos FT, Yazici O, Civelek B, et al. Evaluation of the effect of comorbidity on survival in pancreatic cancer by using “Charlson Comorbidity Index” and “Cumulative Illness Rating Scale”. Wien Klin Wochenschr. 2014;126(1–2):36– doi: 10.1007/s00508-013-0453-9.
  7. Della Porta MG, Malcovati L. Clinical relevance of extra-hematologic comorbidity in the management of patients with myelodysplastic syndrome. Haematologica. 2009;94(5):602– doi: 10.3324/haematol.2009.005702.
  8. Wang S, Wong ML, Hamilton N, et al. Impact of age and comorbidity on non-small-cell lung cancer treatment in older veterans. J Clin Oncol. 2012;30(13):1447–55. doi: 11200/jco.2011.39.5269.
  9. Strati P, Chaffe K, Achenbach S, et al. Comorbidity and cause of death in patients with chronic lymphocytic leukemia (CLL). Cancer Res. 2015;75(15): Abstract 5267. doi: 10.1158/1538-7445.am2015-5267.
  10. Goede V, Paula Cramer P, Busch R, et al. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German Chronic Lymphocytic Leukemia Study Group trials. 2014;99(6):1095–100. doi: 10.3324/haematol.2013.096792.
  11. Thurmes P, Call T, Slager S, et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocyticleukemia. Leuk Lymphoma. 2008;49(1):49–56. doi: 10.1080/10428190701724785.
  12. Linn BS, Linn MW, Gurel L. Cumulative illness rating scale. J Am Geriatr Soc. 1968;16(5):622–6. doi: 10.1111/j.1532-5415.1968.tbx.
  13. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. 2010;376(9747):1164–74. doi: 10.1016/S0140-6736.
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Chronic Lymphocytic Leukemia: Prognostic Significance of Minimal Residual Disease and Potential of Modern Methods of Its Diagnosis and Therapy (Literature Review)

LYMPHOID TUMORS , ,

AYu Kuvshinov, SV Voloshin, IS Martynkevich, EV Kleina, MA Mikhaleva, KM Abdulkadyrov

Russian Scientific Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

For correspondence: Sergei Vladimirovich Voloshin, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)274-37-70; e-mail: kuvshinovmd@gmail.com

For citation: Kuvshinov AYu, Voloshin SV, Martynkevich IS, et al. Chronic Lymphocytic Leukemia: Prognostic Significance of Minimal Residual Disease and Potential of Modern Methods of Its Diagnosis and Therapy (Literature Review). Clinical oncohematology. 2016;9(2):191–8 (In Russ).

DOI: 10.21320/2500-2139-2016-9-2-191-198

ABSTRACT

Achieving a complete remission (CR) in patients with chronic lymphocytic leukemia (CLL) has become a feasible goal directly correlating with a prolonged survival. However, a certain number of tumor cells may be present in the patient’s body even when CR has been achieved, and this phenomenon is called a minimal residual disease (MRD). A lot of data confirming the necessity of MRD diagnosing and monitoring has emerged recently, since the MRD has a significant impact on the prognosis of CLL. Achieving MRD-negative remission is an independent predictor of long-term progression-free survival and overall survival. The occurrence of new diagnostic techniques has allowed to define the MRD and to develop standards for its assessment. This paper presents an overview of literature data about MRD, methods of its evaluation, prognostic significance, as well as the methods of eradication.

Keywords: chronic lymphocytic leukemia, minimal residual disease, flow cytometry.

Received: January 5, 2016

Accepted: January 10, 2016

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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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Immunophenotypical and cytogenetic features of tumor cells in a patient with chronic lymphocytic leukemia associated with prolonged exposure to irradiation

LYMPHOID TUMORS , , , ,

S.N. Kolyubaeva1, I.A. Sukhina1, V.Yu. Nikitin1, T.V. Isakova1, A.S. Polyakov1, S.N. Malakhova1, N.V. Il’yin2, J.N. Vinogradova2, and L.А. Myakoshina2

1 Military Medical Aсademy, Saint Petersburg, Russian Federation

2 Russian Research Centre for Radiology and Surgical Technologies, RF Ministry of Health, Saint Petersburg, Russian Federation

ABSTRACT

In this article, we describe immunoрhenotypical and cytogenetic features of tumor cells in the patient with chronic lymphocytic leukemia (CLL) and prolonged exposure to irradiation in the history. Finding of 0.67% to 0.73% of metaphases with dicentric chromosomes confirmed the effect of radiation in this patient. Chromosome banding with mitogen stimulation of peripheral lymphocytes revealed 2% of cells with 47,XY, +12 karyotype, while FISH detected the greater number of cells with trisomy 12 in interphase bone marrow cells and peripheral lymphocytes. Immunophenotyping of bone marrow cells revealed the difference from “classic” CCL, i.e. simultaneous low-positive CD22 and CD79b expression as well as CD38 expression on the surface of tumor cells.

Keywords: chronic lymphocytic leukemia, fluorescence in situ hybridization, trisomy 12, irradiation, radiation-specific damage.

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High-risk chronic lymphocytic leukemia: history, definition, diagnosis, and management

DIAGNOSIS AND TREATMENT OF LYMPHOID TUMORS , ,

E.A. Nikitin, A.B. Sudarikov

FSBI «Haematological Research Center» Russian Ministry of Health, Moscow, Russian Federation

 ABSTRACT

High-risk chronic lymphocytic leukemia is an emerging concept that was first established in fludarabine era. While fludarabine and fludarabine-containing regimens are highly effective in the majority of patients, a small subgroup of patients show poor response to standard regimens. The prognosis of these patients is dismal with a median overal survival of 2 – 3 years. The article present historical review and modern definition of high risk CLL, describes known molecular mechanisms of refractoriness to fludarabine and focuses on different treatment approaches.

 

Keywords: chronic lymphocytic leukemia, TP53, 17p deletion, fludarabine

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