MYELOID TUMORS

Efficacy of Chemotherapy in Acute Leukemia Patients Resistant to Previous Standard Treatment According to the Series Measurement of WT1 Gene Expression

MYELOID TUMORS , ,

NN Mamaev, YaV Gudozhnikova, TL Gindina, IM Barkhatov, AI Shakirova, VA Katerina, MV Gubina, ES Nikolaeva, EV Semenova, OV Paina, EI Darskaya, OV Pirogova, VV Porunova, IS Moiseev, IA Mikhailova, BI Ayubova, VM Kravtsova, SN Bondarenko, LS Zubarovskaya, BV Afanas’ev

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

For correspondence: Nikolai Nikolaevich Mamaev, PhD, Professor, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)233-12-43; e-mail: nikmamaev524@gmail.com

For citation: Mamaev NN, Gudozhnikova YaV, Gindina TL, et al. Efficacy of Chemotherapy in Acute Leukemia Patients Resistant to Previous Standard Treatment According to the Series Measurement of WT1 Gene Expression. Clinical oncohematology. 2018;11(1):78-88.

DOI: 10.21320/2500-2139-2018-11-1-78-88

ABSTRACT

Aim. To estimate the efficacy of chemotherapy in acute leukemia patients resistant to previous standard treatment according to the series measurement of WT1 expression.

Materials & Methods. The series measurement of WT1 expression formed the basis of the efficacy estimation of induction chemotherapy in 31 patients (15 men and 16 women aged from 3 months to 68 years; the median age was 28 years) with prognostically unfavourable variants of acute myeloid (AML) and lymphoblastic leukemia (ALL) (23 AML and 8 ALL patients). The WT1 gene expression was measured at baseline and 2–3 weeks after the treatment by the quantitative real-time PCR. The threshold level for detection was 250 copies of WT1/104 copies of ABL. The cytogenetic profile of leukemia cells was assessed by standard cytogenetics and FISH.

Results. The baseline expression level of WT1 varied from 305 to 58,569 copies/104 copies of ABL. The expected reduction of WT1 expression after the first induction chemotherapy treatment was reported in 22/23 (96 %) AML patients and in 6/8 (75 %) ALL patients. According to our results WT1 expression reached the threshold in 13/31 (42 %) patients, including 9 AML patients and 4 ALL patients. After 11/31 (35 %) patients received the second course of treatment, WT1 expression level became normal in 8 cases (5 ALL and 3 AML patients). Despite high dose chemotherapy, HSCT and such agents as blinatumomab and gemtuzumab, an unfavourable outcome was observed in 18/31 (58 %) patients including 6 patients with complex karyotype (CK+) and 2 patients with monosomal karyotype (MK+). Once the MK+ and CK+ combination was observed, in another case the MK+ was combined with the prognostically unfavourable inv(3)(q21q26) inversion.

Conclusion. Our results show that the molecular monitoring should be included as part of treatment of the prognostically unfavourable acute leukemia. The WT1 gene was shown to be the most appropriate marker. WT1 expression was shown to correlate with the common fusion genes allowing to estimate the blast cell count at the molecular level.

Keywords: acute leukemia, induction chemotherapy, molecular monitoring, WT1.

Received: August 18, 2017

Accepted: November 12, 2017

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Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia

MYELOID TUMORS , ,

LL Girshova, IG Budaeva, EG Ovsyannikova, SO Kuzin, DV Motorin, RSh Badaev, DB Zammoeva, VV Ivanov, KV Bogdanov, OS Pisotskaya, YuV Mirolyubova, TS Nikulina, YuA Alekseeva, AYu Zaritskii

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

For correspondence: Irina Garmaevna Budaeva, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(931)351-07-06; e-mail: irina2005179@mail.ru

For citation: Girshova LL, Budaeva IG, Ovsyannikova EG, et al. Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia. Clinical oncohematology. 2017;10(4):485–93 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-485-493

ABSTRACT

Background. Acute myeloblastic leukemia (AML) with NPM1 mutation amounts to 30 % of all AML and is characterized by good prognosis with the exception of cases with FLT3-ITD mutation. Despite the good prognosis, the likelihood of relapses in patients with NPM1 mutation may significantly differ. Thus, the estimation of the minimal residual disease (MRD) after chemotherapy and during follow-up is becoming increasingly important. This approach will make it possible to predict the sensitivity of a tumoral clone to chemotherapy.

Aim. To evaluate the prognostic value of highly specific marker (NPM1 mutation) and non-specific marker (WT1 overexpression) of MRD, as well as to identify the correlation between the levels of NPM1 and WT1 at different stages of therapy and in the follow-up period.

Materials & Methods. The research included 14 patients with AML. All patients had the NPM1 mutation and WT1 overexpression: 50 % of patients had additional molecular markers (BAALC overexpression, FLT3-ITD, DNMT3A, and MLL mutations). Real-time PCR was used for long-term monitoring of WT1 expression levels and NPM1 mutation.

Results. The median decrease of NPM1 levels after the induction therapy was 3 log. All patients had relapses, NPM1 mutation, and lower rates of OS/RFS, which significantly correlated with prognostically negative molecular markers. There were no statistically significant differences in RFS in groups with the decrease of WT1 expression level < 2 log and > 2 log on day 28 of treatment. At the same time, the decrease of WT1 expression by > 2 log was associated with significant differences in early relapses, which correlated with the decrease of NPM1 levels (> and < than 3 log) is revealed. RFS rates were higher in patients with WT1 expression level of < 100 per 104 copies ABL on day 28 and WT1 of < 250 per 104 copies ABL on day 14 of treatment. WT1 expression was significantly lower on days 14 and 28 in patients with NPM1 decrease of > 3 log on day 28. The decrease in WT1 expression of < 100 per 104 copies ABL on day 28 was more common in patients with isolated NPM1 mutation, compared to patients with additional negative molecular markers.

Conclusion. The decrease in NPM1 levels after the induction therapy may serve as reliable prognostic marker of RFS and OS rates. New correlation between the degree of NPM1 reduction and the presence of additional molecular markers was established. Highly specific (NPM1 mutation) was shown to be more specific compared to non-specific markers (WT1 overexpression). The research showed the predictive value of a lower limit level of WT1 on day 28 of treatment (100 per 104 copies ABL), and for the first time, the importance of the early assessment WT1 expression reduction on day 14 of induction therapy.

Keywords: acute myeloblastic leukemia, AML, NPM1, WT1, molecular monitoring.

Received: February 22, 2017

Accepted: May 26, 2017

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  47. Balsat M, Renneville A, Thomas X, et al. Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia With NPM1 Mutation: A Study by the Acute Leukemia French Association Group. J Clin Oncol. 2016;35(2):185–93. doi: 10.1200/JCO.2016.67.1875.
  48. Rossi G, et al. Comparison between multiparameter flow cytometry and WT1-RNA quantification in monitoring minimal residual disease in acute myeloid leukemia without specific molecular targets. Leuk Res. 2012;36(4):401–6. doi: 10.1016/j.leukres.2011.11.020.

Pro- and Antifibrotic Factors in the Serum of Patients with Chronic Myeloproliferative Disorders

MYELOID TUMORS , , , ,

AA Silyutina, NM Matyukhina, EG Lisina, VI Khvan, SN Leleko, NT Siordiya, OV Sirotkina, PA Butylin

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

For correspondence: Pavel Andreevich Butylin, PhD, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; e-mail: butylinp@gmail.com

For citation: Silyutina AA, Matyukhina NM, Lisina EG, et al. Pro- and Antifibrotic Factors in the Serum of Patients with Chronic Myeloproliferative Disorders. Clinical oncohematology. 2017;10(4):479–84 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-479-484

ABSTRACT

Background. The study of pro- and antifibrotic factors in the serum of patients with Ph-negative chronic myeloproliferative disorders (CMPDs) will allow to understand better the mechanisms of myelofibrosis development, as well as to identify new diagnostic markers.

Aim. To assess the correlation between the levels of classic (TGF-β, bFGF, MMP-2, -9, -13 and VEGF) and new proinflammatory serum factors (galectin-3), involved into development of myelofibrosis in different Ph-negative forms of CMPDs and genetic abnormalities.

Materials & Methods. The research included 55 CMPD patients (13 with polycythemia vera, 17 with essential thrombocythemia, 25 with primary myelofibrosis) and 8 healthy controls. Whole blood genomic DNA extraction was used to evaluate mutations JAK2V617F, CALR (deletions and insertions), MPLW515L, and MPLW515K. Antibody-immobilized ELISA was used to evaluate the levels of galectin-3, TGF-β, bFGF, VEGF, MMP-2, MMP-9 and MMP-13.

Results. The analysis showed the differences in serum MMP-9, VEGF, TGF-β and galectin-3 levels in patients with different CMPDs. A tendency towards the decrease of serum MMP-9 levels in patients with CALR mutations was shown.

Conclusion. The shown differences between patients with different CMPDs may serve as a basis for improving diagnostic protocols in challenging differential diagnosis of CMPDs.

Keywords: Ph-negative chronic myeloproliferative disorders, pro- and antifibrotic factors, JAK2V617F, CALR, MPLW515L, MPLW515K, MMP-2, MMP-9, MMP-13, galectin-3.

Received: April 26, 2017

Accepted: July 5, 2017

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Targeted Therapy of Myelofibrosis

MYELOID TUMORS , , , , ,

OYu Vinogradova1,3,4, VA Shuvaev2, IS Martynkevich2, MM Pankrashkina1,3, MS Fominykh2, EV Efremova2, KYu Krutikova2, LB Polushkina2, NN Sharkunov1, SV Voloshin2, AV Chechetkin2

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

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

3Dmitrii Rogachev National Medical Pediatric Hematology, Oncology and Immunology Research Center, 1 Samory Mashela str., Moscow, Russian Federation, 117198

4NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

For correspondence: Ol’ga Yur’evna Vinogradova, MD, PhD, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; Tel.: 8(495)945-97-61; e-mail: olgavinz@mail.ru.

For citation: Vinogradova OYu, Shuvaev VA, Martynkevich IS, et al. Targeted Therapy of Myelofibrosis. Clinical oncohematology. 2017;10(4):471–8 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-471-478

ABSTRACT

Background. Myelofibrosis (primary myelofibrosis, post-essential trombocythemia myelofibrosis, post-polycythemia myelofibrosis) is the most complex and pressing problem among all Ph-negative myeloproliferative diseases. The present article summarizes the author’s experience of using new Janus kinase inhibitors in routine clinical practice, and compares the data with the results of other clinical research.

Aim. To evaluate the use of ruxolitinib in patients with myelofibrosis.

Materials & Methods. Our analysis includes 48 patients (21 men and 27 women) with histologically verified myelofibrosis (primary myelofibrosis in 36 cases, post-essential trombocythemia myelofibrosis in 10 cases, and post-polycythemia myelofibrosis in 2 cases) in a chronic stage. All patients received ruxolitinib. Median age at the start of therapy was 60 years (range from 35 to 79). Massive splenomegaly (≥ 10 cm below the costal margin) was found in 34 (71 %) of 48 patients. The initial dose of ruxolitinib was determined by the platelet level. The efficacy of the therapy was evaluated in accordance with ELN 2013 criteria.

Results. Median duration of treatment was 18 months (range from 1 to 50 months). Symptoms of intoxication were relieved in 33 of 37 patients (89 %). The spleen size decreased in 64 % of patients. In 33 % of cases spleen size did not change, whereas an increase was observed in 3 % of patients. In the majority of patients hemoglobin level remained stable through the course of treatment. Three of 14 transfusion dependent patients did not require blood transfusions after 3 months of therapy. In patients with high thrombocyte levels prior to ruxolitinib therapy the mean level was approaching normal by the end of the 1st month of treatment. The median JAK2V617F mutant allele burden at the beginning treatment was 56.5 % (n = 20; 22.5–126.1 %). After 6 moths of treatment it accounted for 62.3 % (n = 11; 25.4–79.7 %) and in 12 months accounted for 47.4 % (n = 12; 14.2–102.2 %). By the time of the analysis 42 of 48 patients continued the ruxolitinib treatment (88 %). Death occurred in 4 patients. Overall 1-year (92 %) and 2-year (87 %) survival corresponds to the data of COMFORT-I, COMFORT-II and JUMP clinical trials.

Conclusion. Ruxolitinib showed to be an effective treatment for myelofibrosis. The most pronounced and rapid effect ruxolitinib had on the spleen size and the symptoms of intoxication. The tolerability of ruxolitinib was satisfactory in the majority of patients. According to the author’s data, ruxolitinib had a small impact on the JAK2V617F mutant allele burden. The overall survival rate in patients with myelofibrosis, receiving ruxolitinib in the clinical setting was similar to that of in the clinical trials.

Keywords: primary myelofibrosis, post-essential trombocythemia myelofibrosis, post-polycythemia myelofibrosis, JAK2V617F, ruxolitinib, clinical practice, targeted therapy.

Received: February 11, 2017

Accepted: May 22, 2017

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REFERENCES

  1. Абдулкадыров К.М., Шуваев В.А., Мартынкевич И.С. Миелопролиферативные новообразования. М.: Littera, 2016. 304 с.[Abdulkadyrov KM, Shuvayev VA, Martynkevich IS. Mieloproliferativnye novoobrazovaniya. (Myeloproliferative Neoplasms.) Moscow: Littera Publ.; 2016. 304 p. (In Russ)]
  2. Абдулкадыров К.М., Шуваев В.А., Мартынкевич И.С. Первичный миелофиброз: собственный опыт и новое в диагностике и лечении. Онкогематология. 2015;10(2):25–35. doi: 10.17650/1818-8346-2015-10-2-26-36.[Abdulkadyrov KM, Shuvayev VA, Martynkevich IS. Primary myelofibrosis: own experience and news from diagnostic and treatment. Oncohematology. 2015;10(2):25–35. doi: 10.17650/1818-8346-2015-10-2-26-36. (In Russ)]
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  13. Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013;122(8):1395. doi: 10.1182/blood-2013-03-488098.
  14. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701–7. doi: 10.1038/leu.2016.148.
  15. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55. doi: 10.1186/s13045-017-0417-z.
  16. Al-Ali HK, Griesshammer M, le Coutre P, et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica. 2016;101(9):1065–73. doi: 10.3324/haematol.2016.143677.

Molecular Genetic Markers and Clinical Characteristics of Essential Thrombocythemia

MYELOID TUMORS ,

AA Zhernyakova, IS Martynkevich, VA Shuvaev, LB Polushkina, MS Fominykh, VYu Udal’eva, II Zotova, DI Shikhbabaeva, MN Zenina, NA Potikhonova, SV Voloshin, SS Bessmel’tsev, AV Chechetkin, KM Abdulkadyrov

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

For correspondence: Anastasiya Andreevna Zhernyakova, MD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(921)343-01-05; e-mail: zhernyakova.a@mail.ru

For citation: Zhernyakova AA, Martynkevich IS, Shuvaev VA, et al. Molecular Genetic Markers and Clinical Characteristics of Essential Thrombocythemia. Clinical oncohematology. 2017;10(3):402–8 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-402-408

ABSTRACT

Background & Aims. The presence of different molecular genetic markers of clonality (mutations in JAK2, MPL, CALR) or their absence (triple negative status, TN) in essential thrombocythemia (ET) indicates a biological heterogeneity of the disease and can determine its clinical forms. The aim was to evaluate the association of molecular genetic markers with the clinical form and the prognosis of ET.

Materials & Methods. We analyzed the data of 240 patients with ET at the age of 20–91 years (median age 58.7 years), who were observed in the Russian Research Institute of Hematology and Transfusiology from 1999 to 2016 (median observation period 37.2 months).

Results. The JAK2V617F (JAK2+) mutation was found in 182 (75.9 %) of 240 patients. CALR (CALR+) mutations were found in 30 (12.5 %): type 1 (CALR1+) mutations in 13/30 (43.3 %) and type 2 (CALR2+) in 17/30 (56.7 %). MPL (MPL+) mutations were found in only 2 (0.8 %) of 240 patients. None of the mutations were detected in 26 (10.8 %) of 240 patients (TN status). Significantly higher platelet counts were observed in CALR1+ and CALR2+ subgroups during the primary diagnosis of ET compared with JAK2+ and TN groups. The mean platelet counts were 1252 × 109/L for CALR2+ and 1079 × 109/L for CALR1+ vs 841 × 109/L (p < 0.001; p = 0.06) and 775 × 109/L (p < 0.001; p = 0.04) for JAK2+ and TN, respectively. Thrombosis was diagnosed in 50 (27.4 %) of 182 patients of the JAK2+ subgroup, in 8 (30.7 %) of the 26 patients of the TN subgroup, and in 2 (18.2 %) of 11 patients of the CALR1+ subgroup. No thrombosis was found in the CALR2+ and MPL+ subgroups (p < 0.001). In general, the CALR1+ status was characterized as the most favorable in terms of prognosis (5-year overall survival rate of 100 %), compared to the least favorable TN status (5-year overall survival rate of 85 %).

Conclusion. Mutations in the CALR gene were characterized by a more favorable prognosis in comparison with JAK2+ and TN, as well as a decrease in the risk and frequency of thrombosis, despite higher platelet counts. TN-status of ET was associated with unfavorable prognosis.

Keywords: essential thrombocythemia, CALR, JAK2V617F, MPL.

Received: December 26, 2016

Accepted: March 6, 2017

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REFERENCES

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Chronic Myeloid Leukemia Patient Registry in the Russian Federation: From Observational Studies to the Efficacy Evaluation in Clinical Practice

MYELOID TUMORS , , ,

AG Turkina1, NV Novitskaya2, AK Golenkov3, VA Shuvaev4, LI Napso5, IV Krylova6, AM Savrilova7, GSh Safuanova8, AV Korobkin9, TYu Klitochenko10, EV Burnasheva11, EV Vasil’ev12, OM Senderova13, EYu Fedorova14, LM Yalunina15, EK Nekhai16, GB Kuchma17, AS Lyamkina18, NG Shchedrova19

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

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

3 NF Vladimirskii Moscow Regional Research Clinical Institute, 61/2 Shchepkina str., Moscow, Russian Federation, 129110

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

5 Clinical Oncology Dispensary No. 1, 146 Dimitrova str., Krasnodar, Russian Federation, 350040

6 Sverdlovsk Regional Clinical Hospital No. 1, 185 Volgogradskaya str., Ekaterinburg, Russian Federation, 620102

7 Republican Clinical Hospital, 138 Orenburgskii trakt, Kazan’, Russian Federation, 420064

8 GG Kuvatov Republican Clinical Hospital, 132 Dostoevskogo str., Ufa, Russian Federation, 450005

9 Chelyabinsk Regional Clinical Hospital, 70 Vorovskogo str., Chelyabinsk, Russian Federation, 454076

10 Volgograd Regional Clinical Oncology Dispensary, 78 Zemlyachki str., Volgograd, Russian Federation, 400138

11 Rostov State Medical University, 29 Nakhichevanskii per., Rostov-na-Donu, Russian Federation, 344022

12 Regional Clinical Hospital, 3A Partizana Zheleznyaka str., Krasnoyarsk, Russian Federation, 660022

13 Irkutsk Order of the Badge of Honor District Clinical Hospital, 100 Yubileinyi microdistrict, Irkutsk, Russian Federation, 664049

14 VD Seredavin Samara Regional Clinical Hospital, 159 Tashkentskaya str., Samara, Russian Federation, 443095

15 SV Belyaev Kemerovo Regional Clinical Hospital, 22 Oktyabr’skii pr-t, Kemerovo, Russian Federation, 650066

16 Regional Clinical Hospital No. 2, 55 Russkaya str., Vladivostok, Russian Federation, 690105

17 Orenburg Regional Clinical Hospital No. 1, 5/3 Tsvillinga str., Orenburg, Russian Federation, 460006

18 Novosibirsk State Medical University, 52 Krasnyi pr-t, Novosibirsk, Russian Federation, 630091

19 Novartis Pharma, 72 bld. 3, Leningradskii pr-t, Moscow, Russian Federation, 125315

For correspondence: Anna Grigor’evna Turkina, DSci, Professor, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: turkianna@yandex.ru

For citation: Turkina AG, Novitskaya NV, Golenkov AK, et al. Chronic Myeloid Leukemia Patient Registry in the Russian Federation: From Observational Studies to the Efficacy Evaluation in Clinical Practice. Clinical oncohematology. 2017;10(3):390–401 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-390-401

ABSTRACT

Background. Due to the significant increase in life expectancy and the quality of life in patients with chronic myeloid leukemia (CML) as well as the growing need for expensive tyrosine kinase inhibitors (TKI), the analysis of cost-effectiveness and lifelong monitoring of patients is especially important.

Aim. We present the results of a multicenter observational study “The Russian Registry of Chronic Myeloid Leukemia in routine clinical practice (2011–2016)”.

Materials & Methods. The study included Russian patients with CML, confirmed by the detection of a Ph-chromosome or a BCR-ABL transcript. The statistical analysis (July 1, 2016) included 7609 patients from 80 regions of the Russian Federation (covering 95 % of the population). The annual increase in the number of patients with newly diagnosed CML was 600–650 patients. At the time of the statistical analysis, 6995 (92 %) patients remained under observation, 473 (6 %) died and 141 (2 %) were withdrawn. The registry included 44 % of men and 56 % of women, the median age was 49 years (range 2–94 years). The peak incidence (46.3 %) occurred at the age of 40–60 years. The median disease duration by the time of the analysis was 6 years (range 0.1–30 years).

Results. The disease was diagnosed in the chronic phase (CP), acceleration phase, and blast crisis in 6560 (93.8 %), 380 (5.5 %) and 47 (0.7 %) patients, respectively. The proportion of risk groups according to Sokal for low, intermediate and high risk in CP was 49 %, 30 %, and 21 %, respectively. TKI were administered to 6473 (92.5 %) patients. Imatinib and the second generation TKI (TKI2) were administered to 5570 (86 %) and 903 (14 %) patients, respectively. The total of 30.4 % of patients received the increased imatinib dose of 600–800 mg. In the TKI2 group, 558 (61.7 %) patients received nilotinib and 345 (38.2 %) patients received dasatinib. The proportion of patients with completed molecular genetic studies (MGS) in 2014, 2015 and the first 6 months of 2016 amounted to 61 %, 58 % and 23 %, respectively. The proportion of patients with cytogenetic studies (CS) for the same period was 28 %, 26 % and 7 %, respectively. No CS or MGS data were presented for 34 %, 35 % and 63 % of patients during this period. Optimal molecular response and major molecular response (MMR) for TKI therapy were observed in 23 % and 58 % of patients treated < 12 months and > 12 months, respectively. When nilotinib was used in the second line, MMR was obtained in 42 % of patients, and a deep molecular response was obtained in 25 % of patients (BCR-ABL < 0.01 %).

Conclusion. The high efficacy of TKI therapy was observed in the majority of patients with the possibility of achieving a minimal residual disease. The problems concerning untimely monitoring and suboptimal administration of second line treatment were identified. In general, the CML patient registry allowed the data integration of data and information management of population with CML in Russia.

Keywords: chronic myeloid leukemia, registry, tyrosine kinase inhibitors, imatinib, nilotinib, quality of medical care.

Received: January 17, 2017

Accepted: April 27, 2017

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REFERENCES

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  4. Виноградова О.Ю. Клиническая эволюция хронического миелолейкоза в процессе лечения ингибиторами тирозинкиназ. Дис. … д-ра мед. наук. М., 2011.
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A Case Report of Myeloid Sarcoma in a Child

MYELOID TUMORS , ,

TT Valiev1, AM Kovrigina2, TR Panferova1, TL Ushakova1, IN Serebryakova3, NN Tupitsyn3, LYu Grivtsova3, II Matveeva3, EV Mikhailova1, AV Popa1, GL Menkevich1

1 Institute of Pediatric Oncology and Hematology, NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

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

3 Institute of Clinical Oncology, NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Timur Teimurazovich Valiev, DSci, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel: +7(499)324-42-87; е-mail: timurvaliev@mail.ru

For citation: Valiev TT, Kovrigina AM, Panferova TR, et al. A Case Report of Myeloid Sarcoma in a Child. Clinical oncohematology. 2017;10(2):218–26 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-218-226

ABSTRACT

The diagnosis of myeloid tumors is based on a complex approach and causes significant difficulties especially in young children. Morphologic, immunologic, cytogenetic, molecular and biologic data on myeloid sarcoma are presented based on the literature data and own clinical case. Treatment results of myeloid sarcoma (especially in the high risk group) are unsatisfactory and should be improved.

Keywords: myeloid sarcoma, diagnosis, children.

Received: November 14, 2016

Accepted: February 9, 2017

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Dasatinib in First- and Second-Line Therapy of Chronic Myeloid Leukemia: Efficacy, Safety and Quality of Life

MYELOID TUMORS , , , , ,

TI Ionova1,2, NB Bulieva3, OYu Vinogradova4,5,6, TA Gritsenko7, LK Kozlova8, GB Kuchma8, EG Lomaia9, ER Machyulaitene10, TP Nikitina1,2, NV Novitskaya4, AYu Rodionova2, EI Usacheva11, TV Shneider12

1 Saint Petersburg Multifield Medical Center under the Ministry of Health of Russia, 154 Nabereznaya Reki Fontanki, Saint Petersburg, Russian Federation, 198103

2 Multinational Center for Quality of Life Research, 1 Artilleriiskaya str., office 152, Saint Petersburg, Russian Federation, 191014

3 I Kant Baltic Federal University, 14 A Nevskogo str., Kaliningrad, Russian Federation, 236041

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

5 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

6 NI Pirogov Russian National Research Medical University under the Ministry of Health of the Russian Federation, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

7 Samara State Medical University under the Ministry of Health of the Russian Federation, 89 Chapaevskaya str., Samara, Russian Federation, 443099

8 Orenburg State Medical University, 6 Sovetskaya str., Orenburg, Russian Federation, 460000

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

10 Outpatient Department, Academician IP Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

11 RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

12 Leningrad District Clinical Hospital, 43/49 Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

For correspondence: Tat’yana Ivanovna Ionova, DSci, 1 office 152 Artilleriiskaya str., Saint Petersburg, Russian Federation, 191014; Tel: +7(812)579-61-38; e-mail: qlife@rambler.ru

For citation: Ionova TI, Bulieva NB, Vinogradova OYu, et al. Dasatinib in First- and Second-Line Therapy of Chronic Myeloid Leukemia: Efficacy, Safety and Quality of Life. Clinical oncohematology. 2017;10(2):206–17 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-206-217

ABSTRACT

Background & Aims. The article presents results of two observational, prospective, multicenter studies “Quality of Life, Symptom Profile, and Adherence to Treatment in Adult Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Receiving Dasatinib” (2012–2015) and “Quality of Life and Symptom Profile in Imatinib-Resistant or Intolerant Patients with Chronic Myeloid Leukemia” (2011–2014).

Methods. Data of 107 patients with chronic myeloid leukemia in chronic phase were involved in the real-world analysis — 32 newly diagnosed patients on first-line treatment with dasatinib or after yearly switch to dasatinib after imatinib treatment failure and 75 imatinib-resistant or intolerant patients on second-line treatment with dasatinib. Treatment effectiveness and safety of dasatinib were assessed during first and second-line dasatinib treatment using clinical outcomes as well as quality of life and symptom profile assessment.

Results. The real-world data obtained during observational study in limited population of CML patients conform the results of clinical trials devoted to evaluation of treatment efficacy and safety of dasatinib treatment in first and second-line treatment and demonstrate the importance of patient-reported outcomes. Patient’s quality of life improved within 12 months of the first-line dasatinib therapy according to the following scales: role physical functioning, pain, vitality, social functioning and role emotional functioning. The most pronounced and clinically significant improvement was observed for the role emotional functioning (51.1 vs. 68.9). During the second-line dasatinib treatment, stabilization of quality of life parameters was registered for the following scales: vitality, social functioning, mental health, and pain. Significant improvement of the Integral Quality of Life Index was observed (p < 0.05). Positive dynamics of relevant symptoms was registered. The symptom severity decreased during both the first and second-line therapy.

Conclusion. Quality of life and symptom assessment in CML patients contribute to a better disease control in accordance with the principles of risk-adaptive therapy.

Keywords: quality of life, chronic myeloid leukemia, dasatinib, therapy effectiveness, therapy safety, routine clinical practice.

Received: November 10, 2016

Accepted: February 10, 2017

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Chromothripsis in Oncology: Literature Review and Case Report

MYELOID TUMORS , , ,

NN Mamaev1, TL Gindina1, EG Boichenko2

1 RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

2 Municipal Children’s Hospital No. 1, 14 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

For correspondence: Tat’yana Leonidovna Gindina, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel: +7(812)233-12-43; e-mail: cytogenetics.bmt.lab@gmail.com

For citation: Mamaev NN, Gindina TL, Boichenko EG. Chromothripsis in Oncology: Literature Review and Case Report. Clinical oncohematology. 2017;10(2):191–205 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-191-205

ABSTRACT

The article presents a clinical case and literature review dwelling on the recently discovered chromothripsis phenomenon in oncology. Chromothripsis is a type of complex genome changes when a chromosome is first torn into dozens and even thousands of fragments, and then these fragments are bound in a random manner. Sometimes, several chromosomes are involved in the restructuring. As a result, genome mutant zones are formed which trigger malignancies and congenital diseases. In other words, the use of certain methodological approaches (multicolor fluorescence in situ hybridization, SKY technique, and some others) permits to observe under a microscope the splitting of two or more chromosomes and further reunification of these fragments into new unusual two- or multicolor structures, chromosomal markers. Chromothripsis is a rare phenomenon with a peculiar pattern observed in clones of cells of various tumors including hematopoietic and lymphoid tissue malignancies. There are published data on a higher incidence of this phenomenon in patients with myelodysplastic syndromes and bone tumors. TP53 gene mutations play an important role in the development of chromothripsis. The use of paired-sequencing DNA or SNP approaches in oncology is promising both in theoretical and clinical application. The first subject cohort should include patients with TP53 and MLL gene mutations, complex chromosomal aberrations, EVI-1 gene overexpression, and some others. The article presents the chromothripsis phenomenon in an 8-month-old girl with M7 acute myeloid leukemia.

Keywords: chromothripsis, oncohematology, cancer, TP53 gene mutations.

Received: October 2, 2016

Accepted: January 6, 2017

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Genetic Markers of Hereditary Thrombophilia and Risk of Thrombotic Complications in Patients with Polycythemia Vera

MYELOID TUMORS , ,

DI Shikhbabaeva, LB Polushkina, VA Shuvaev, IS Martynkevich, SI Kapustin, TB Zamotina, MS Fominykh, VU Udal’eva, II Zotova, VM Shmeleva, OA Smirnova, SV Voloshin, SS Bessmel’tsev, AV Chechetkin, KM Abdulkadyrov

Russian Scientific Research Institute of Hematology and Transfusiology under the Federal Medico-Biological Agency, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

For correspondence: Dzhariyat Ismailovna Shikhbabaeva, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel: +7(931)201-71-28; e-mail: djeri.shih@mail.ru

For citation: Shikhbabaeva DI, Polushkina LB, Shuvaev VA, et al. Genetic Markers of Hereditary Thrombophilia and Risk of Thrombotic Complications in Patients with Polycythemia Vera. Clinical oncohematology. 2017;10(1):85–92 (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-85-92

ABSTRACT

Background. Thrombotic complications are one of the main problems of polycythemia vera (PV) treatment. They significantly impair the quality of life of these patients and may lead to the lethal outcome. A thrombotic event often precedes the diagnosis of this hematological disease. The pathogenesis of thrombosis in myeloproliferative neoplasms, PV, in particular, is a complex one. Prescription of antiaggregants in the absence of thrombosis and anticoagulants after a thrombotic event requires special attention and development of corresponding recommendations. The prescription of anticoagulants is impossible without taking into account the risks of hemorrhagic complications, which are also typical for myeloproliferative neoplasms.

Aim. Assessment of the impact of hereditary thrombophilia genetic markers on the risk of thrombotic complications in patients with PV.

Methods. The study examined 116 patients with PV, who were screened for markers of hereditary thrombophilia: factor V (G1691A, FV Leiden), prothrombin, methylenetetrahydrofolate reductase (MTHFR), fibrinogen (FI), plasminogen activator inhibitor (PAI-1), and platelet fibrinogen receptor type IIIA (GPIIIA). The incidence of these markers and their role in thrombosis in such patients was investigated.

Results. The study provided data on the incidence of hereditary thrombophilia markers in patients with PV. Statistically significant differences in the incidence of these markers and homocysteine level were found between patients with thrombosis and without them.

Conclusion. The information about the hereditary thrombophilia markers presence may be useful for the prescription of adequate antiaggregant and anticoagulant therapy for PV patients. Further research in this field is justified and it will probably demonstrate the relevance of hereditary thrombophilia markers as prognostic factors for thrombotic complications risk assessment.

Keywords: polycythemia vera, hereditary thrombophilia, thrombosis.

Received: December 11, 2016

Accepted: December 21, 2016

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