WT1 Gene Overexpression in Differential Diagnosis of Ph-negative Myeloproliferative Disorders

EG Lomaia1, NT Siordiya1, EG Lisina2, OM Senderova3, AA Silyutina1, AYu Zaritskey1

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

2 Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182

3 Irkutsk Regional Clinical Hospital, 100 Yubileinyi microdistrict, Irkutsk, Russian Federation, 664049

For correspondence: Nadiya Tamazovna Siordiya, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(921)358-31-32; e-mail: siordian@list.ru

For citation: Lomaia EG, Siordiya NT, Lisina EG, et al. WT1 Gene Overexpression in Differential Diagnosis of Ph-Negative Myeloproliferative Disorders. Clinical oncohematology. 2019;12(3):297–302 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-297-302


ABSTRACT

Aim. To assess the rate of WT1 gene overexpression and its clinical value in Ph-negative myeloproliferative disorders (MPD).

Materials & Methods. The trial included 72 patents with Ph-negative MPD. Among them there were patients with primary myelofibrosis (MF; n = 32), post-polycythemia vera MF (n = 7), polycythemia vera (PV; n = 17), and essential thrombocythemia (ET; n = 16) with median age of 57 years (range 19–78 years). Median (range) time from diagnosis to the date of evaluating WT1 expression in PV, ET, and MF was 9.4 (0–309), 14.4 (0–55), and 21.4 months (0–271 months), respectively. WT1 expression in terms of WT1 copies/104 ABL copies was measured by quantitative PCR.

Results. WT1 gene overexpression is revealed solely in patients with MF (in 34/39; 87 %). In PV/ET no WT1 gene overexpression was observed. Median WT1 expression in MF was 230/104 ABL copies (range 42.2–9,316.45/104 ABL copies). Sensitivity and specificity of WT1 gene overexpression in MF with respect to PV/ET were 87 % and 100 %, respectively. A distinct correlation was identified between WT1 gene expression level and spleen size, duration of the disease, blast cell count, and DIPSS risk group. WT1 gene expression level could be correlated neither with age and sex, nor with MF mutation status and leucocyte, thrombocyte, and haemoglobin levels.

Conclusion It appears that due to a high specificity and sensitivity of WT1 gene expression in MF it can be used as a marker for differential diagnosis of Ph-negative MPD. A correlation between WT1 gene expression and tumor mass in MF cannot be excluded. It is advisable to analyze the dynamics of WT1 expression level to predict the efficacy of current targeted therapy.

Keywords: WT1 gene, Ph-negative myeloproliferative disorders, myelofibrosis, polycythemia vera, essential thrombocythemia.

Received: December 27, 2018

Accepted: June 2, 2019

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Prediction of FLAG ± Ida Regimen Efficacy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

IG Budaeva, EG Ovsyannikova, EN Goryunova, OV Kulemina, DV Zaitsev, DV Motorin, RSh Badaev, DB Zammoeva, VV Ivanov, KV Bogdanov, OS Pisotskaya, YuV Mirolyubova, TS Nikulina, YuA Alekseeva, AYu Zaritskey, LL Girshova

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: Budaeva IG, Ovsyannikova EG, Goryunova EN, et al. Prediction of FLAG ± Ida Regimen Efficacy in Patients with Relapsed/Refractory Acute Myeloid Leukemia. Clinical oncohematology. 2019;12(3):289-96 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-289-296


ABSTRACT

Aim. To assess the efficacy of FLAG/FLAG-Ida regimen and to identify factors that influence remission, duration of disease-free survival (DFS) and overall survival (OS) of patients with relapsed/refractory acute myeloid leukemia (AML).

Materials & Methods. The trial included 54 patients (28 men and 26 women), median age was 37 years (range 18–70 years). 27 (50 %) out of 54 patients had refractory AML and 27 (50 %) patients had relapsed AML. FLAG and FLAG-Ida regimens were administered as induction therapy. 37 (68.5 %) patients received bone marrow transplantation. Molecular genetic and cytogenetic examinations were performed prior to therapy and on the 28th day after the start of treatment. WT1 gene expression was evaluated on the 14th–16th day of treatment.

Results. Complete remission (CR) was achieved in 42 (77.8 %) out of 54 patients. Refractoriness to therapy was observed in 9 (16.7 %) out of 54 patients, mortality was 5.5 % (3/54). Remission rate was higher in patients with relapsed AML compared with refractory AML: 85.2 % (23/27) and 70.4 % (19/27), respectively. On the 14th–16th day of treatment patients with blast cell count ≥ 10 % in bone marrow (BM) showed significantly lower CR rate (60 %) compared with the group of patients with < 10 % blast cells in BM (89.6 %; = 0.024) and shorter DFS (median 7.6 vs. 17.6 months, respectively; = 0.03). Median DFS in patients with WT1 expression reduction to < 1 log on the 14th–16th day was 5 vs. 18 months in patients without WT1 expression reduction (= 0.01). DFS varied in groups of patients with blast cell count < 10 % in BM on the 14th–16th day of treatment based on the level of WT1 expression reduction (= 0.04). MRD-negative patients (57.1 %) showed significantly longer DFS and OS compared with MRD-positive patients (median DFS was 17.6 vs. 5.2 months, respectively, = 0.02; median OS was 19 vs. 6.9 months, = 0.0002). Median DFS and OS were different only in ELN low- and high-risk groups (median not reached vs. 5.2 months, respectively, = 0.039; median not reached vs. 10.2 months, = 0.039).

Conclusion. FLAG and FLAG-Ida are effective and safe regimens in the treatment of relapsed/refractory AML. Achieving remission depends on neither the risk group nor the time of relapse occurrence. The blast cell count in BM on the 14th–16th day of FLAG/FLAG-Ida treatment is a prognostic factor determining achievement and duration of remission. WT1 expression level in the early post-induction period is a sensitive DFS marker. MRD status and molecular genetic risk (ELN) group affiliation are essential prognostic factors determining DFS and OS.

Keywords: acute myeloid leukemia, relapse, refractoriness, FLAG and FLAG-Ida regimens.

Received: November 2, 2018

Accepted: May 28, 2019

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Prognostic Value of Genetic Mutations in Patients with Acute Myeloid Leukemias: Results of a Cooperative Study of Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Germany)

EV Motyko1, OV Blau2, LB Polushkina1, LS Martynenko1, MP Bakai1, NYu Tsybakova1, YuS Ruzhenkova1, EV Kleina1, NB Pavlenko1, AM Radzhabova1, EV Karyagina3, OS Uspenskaya4, SV Voloshin1, AV Chechetkin1, IS Martynkevich1

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

2 Charite Clinic, Berlin Medical University, 30 Hindenburgdamm, Berlin, Germany, 12200

3 Municipal Hospital No. 15, 4 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

4 Leningrad Regional Clinical Hospital, 45–49 Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

For correspondence: Ekaterina Vadimovna Motyko, PhD in Biology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)925-05-62; e-mail: genetics.spb@mail.ru

For citation: Motyko EV, Blau OV, Polushkina LB, et al. Prognostic Value of Genetic Mutations in Patients with Acute Myeloid Leukemias: Results of a Cooperative Study of Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Germany). Clinical oncohematology. 2019;12(2):211–9.

DOI: 10.21320/2500-2139-2019-12-2-211-219


ABSTRACT

Aim. To analyze the effect on prognosis of mutations that are typical of acute myeloid leukemia (AML) patients.

Materials & Methods. The study included 620 AML patients surveyed at Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Berlin, Germany). G-banding of chromosomes was employed for cytogenetic testing. Aberration screening in DNMT3A, IDH1/2 genes was based on real-time polymerase chain reaction (PCR) with subsequent analysis of melting and sequencing profiles. Mutations in FLT3, NPM1 genes were revealed by PCR.

Results. Mutations were identified in 343 (55.3 %) out of 620 patients. Significantly more often mutations were discovered in patients with normal karyotype (NK) (= 0.001). FLT3-ITD mutation was associated with reduced medians of overall survival (OS) and disease-free (DFS) survival: 11.3 vs. 15.8 months with FLT3-ITD– (= 0.005) and 10.0 vs. 13.3 months with FLT3-ITD+ (= 0.009), respectively. The relation of FLT3-ITD allele burden to OS duration was also assessed. In the ITDlow/ITD– group the OS median was considerably longer than in the ITDhigh group (= 0.028). In the group of patients with 1 mutation in NPM1 gene OS and DFS were much better in comparison with other patients (medians of 27.4 and 13.9 months, respectively, = 0.040; 19.3 and 12.0 months, = 0.049). Negative impact of mutations in DNMT3A gene was noticed while assessing OS median: 12 (DNMT3A+) and 15 months (DNMT3A–), respectively (= 0.112). Mutations in IDH1 gene correlated with a better OS than in the group without mutations (= 0.092). The rs11554137 polymorphism in IDH1 gene was associated with worse OS in the group of patients with NK (= 0.186). In 144 patients various mutation combinations (from 2 to 5) were identified. It was demonstrated that mutations in FLT3 (FLT3-ITD), NPM1, DNMT3A, and IDH2 were identified significantly more often in combinations with other mutations (= 0.001): NPM1+/FLT3-ITD+ (20.8 %), NPM1+/FLT3-ITD+/DNMT3A+ (8.3 %), and FLT3-ITD+/DNMT3A+ (8.3 %). Patients with 1 mutation had a noticeably longer OS median compared with patients with 2 mutations (18.1 and 12.2 months; = 0.003). In patients with NPM1+ according to their OS the most unfavorable additional mutation was FLT3-ITD (median 27.4 vs. 9.2 months; = 0.019) and the combination of NPM1+/FLT3-ITD+/DNMT3A+ (median 27.4 vs. 14.6 months; = 0.141). OS of patients with DNMT3A+ showed a downward trend if FLT3-ITD additional mutation was identified (17.3 vs. 7.1 months; = 0.074).

Conclusion. Mutations in FLT3, DNMT3A, IDH1/2, NPM1 genes frequently occur in AML intermediate-risk patients, i.e. they determine the intermediate prognosis group in AML. The studied mutations considerably impact prognosis. It is important to take into consideration mutation type, its allele burden, and the presence of additional mutations. A patient with 2 mutations has a considerably worse OS compared with a patient with 1 mutation. The studied group of patients with the combination of NPM1+/FLT3-ITD+, NPM1+/FLT3-ITD+/DNMT3A+, DNMT3A+/FLT3-ITD+ mutations has the poorest prognosis. Comprehensive analysis of genetic damages in AML patients allows to most accurately predict the course and prognosis of the disease and to plan targeted therapy.

Keywords: acute myeloid leukemias, mutations in FLT3, NPM1, DNMT3A, IDH1/2 genes, karyotype, prognosis.

Received: July 13, 2018

Accepted: January 16, 2019

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Management of Chronic Myeloid Leukemia Patients During Pregnancy (Analysis of Literature and Practical Recommendations)

EYu Chelysheva1, AG Turkina1, ES Polushkina2, MA Vinogradova2, RG Shmakov2

1 National Medical Hematology Research Center, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

2 VI Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 4 Akademika Oparina str., Moscow, Russian Federation, 117997

For correspondence: Ekaterina Yur’evna Chelysheva, MD, PhD, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-48-60; e-mail: denve@bk.ru

For citation: Chelysheva EYu, Turkina AG, Polushkina ES, et al. Management of Chronic Myeloid Leukemia Patients During Pregnancy (Analysis of Literature and Clinical Experience). Clinical oncohematology. 2019;12(2):202–10.

DOI: 10.21320/2500-2139-2019-12-2-202-210


ABSTRACT

Background. The tyrosine kinase inhibitors (TKI) era is marked by a long-term favorable prognosis of chronic myeloid leukemia (CML). In this context CML patients of reproductive age are faced with major issues of family planning with due regard to the risk of TKI treatment interruption during pregnancy. Additionally, TKI impact is another potential risk to the fetus.

Aim. To develop differentiated approach to CML treatment during pregnancy.

Materials & Methods. Analysis includes literature data and clinical experience based on 166 pregnancies of 120 CML patients from CML Pregnancy Registry.

Results. Pregnancy planning is recommended after achieving stable and deep molecular response (with BCR-ABL > 0.01 %, IS) within the period of at least 2 years. At conception TKI therapy does not have to be interrupted. However, early pregnancy detection and TKI treatment interruption after pregnancy confirmation are of vital importance due to teratogenic risks. Furthermore, no TKI may be administered during organogenetic period, i.e. up to the 15th week of gestation. In the absence or loss of complete hematologic response and growth of BCR-ABL > 1 % after the 15th week of gestation imatinib or nilotinib administration is justified in the interest of pregnant patients taking into account limited transfer of these drugs through placenta. In the absence of complete hematologic response before the 15th week of gestation interferon-α can be administered. With BCR-ABL < 1 % patients can be either followed-up without therapy or they can receive interferon-α throughout pregnancy. Dasatinib, bosutinib, and other TKI are contraindicated at any stage of pregnancy. There are no special recommendations for childbirth, delivery is to be adapted to obstetric conditions. Breast feeding is not recommended because of the lack of practical evidence for its safety.

Conclusion. A regular molecular monitoring of BCR-ABL and hematologic status is indispensable, health condition of fetus should be continuously monitored as well. CML patient management should be conducted by cooperating hematologists and gynecologists.

Keywords: chronic myeloid leukemia, pregnancy, tyrosine kinase inhibitors, imatinib, nilotinib, dasatinib, bosutinib.

Received: January 9, 2019

Accepted: March 20, 2019

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    [Chelysheva EYu, Turkina AG. Protocol of chronic myeloid leukemia treatment during pregnancy. In: Savchenko VG, ed. Algoritmy diagnostiki i protokoly lecheniya zabolevanii sistemy krovi. (Diagnostic algorithms and treatment protocols for blood system diseases.) Moscow: Praktika Publ.; 2018. Vol. 2. pp. 927–49. (In Russ)]

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Treatment of Chronic Myeloid Leukemia According to Current Guidelines: The Results of the Pilot Prospective Study “Early Induction Therapy and Monitoring” (РИТМ)

OA Shukhov, AG Turkina, EYu Chelysheva, AV Bykova, AN Petrova, GA Gusarova, IS Nemchenko, AO Abdullaev, TN Obukhova, AB Sudarikov

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

For correspondence: Oleg Aleksandrovich Shukhov, MD, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: shuhov@list.ru

For citation: Shukhov OA, Turkina AG, Chelysheva EYu, et al. Treatment of Chronic Myeloid Leukemia According to Current Guidelines: The Results of the Pilot Prospective Study “Early Induction Therapy and Monitoring” (РИТМ). Clinical oncohematology 2019;12(2):194–201.

DOI: 10.21320/2500-2139-2019-12-2-194-201


ABSTRACT

Background. Current clinical guidelines on diagnosis and treatment of chronic myeloid leukemia (CML) define indications for substitution of first-line tyrosine kinase inhibitor (TKI) at therapy failure during different phases of disease progression.

Aim. To assess the efficacy of CML treatment with implementing the protocol of timely monitoring and switching to another TKI.

Materials & Methods. Patients were included into pilot prospective study РИТМ during 5 years. Data on 100 CML patients were analyzed. Therapy and monitoring were conducted according to the Federal clinical guidelines on CML diagnosis and therapy, 2013.

Results. Median follow-up after initiation of treatment was 46 months (range 12–74). Imatinib mesylate was administered as first-line therapy to 91 (91 %) patients, 9 (9 %) patients received 2nd generation TKI (TKI2). Therapy failure was registered in 31 (31 %) patients; 26 (84 %) of them were switched to TKI2. At the time of analysis 95 (95 %) patients were followed-up. Cumulative incidence of CML-associated mortality was 2 %. By the fifth year of follow-up cumulative probability of complete cytogenetic, major and deep molecular responses was 93 %, 88 % and 66 %, respectively.

Conclusion. CML treatment according to current guidelines yields the results comparable with those achieved by first-line TKI2 therapy. This approach reduces CML treatment costs and lowers the risk of TKI2-associated adverse events. Due to a high rate of deep molecular response the proportion of CML patients in remission without treatment can be increased in the future.

Keywords: chronic myeloid leukemia, monitoring, tyrosine kinase inhibitors, TKI switch.

Received: October 21, 2018

Accepted: February 4, 2019

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Expression of the BCR-ABL1 Gene in Patients with Chronic Myeloproliferative Diseases with Signs of Progression

LA Kesaeva1, EN Misyurina2, DS Mar’in2, EI Zhelnova2, AYu Bulanov2, AE Misyurina3, AA Krutov4, IN Soldatova4, SS Zborovskii4, VA Misyurin1,4, VV Tikhonova1, YuP Finashutina1, ON Solopova1, NA Lyzhko1, AE Bespalova1, NN Kasatkina1, AV Ponomarev1, MA Lysenko2, AV Misyurin1,4

1 NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182

3 National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

4 GenoTekhnologiya, 104 Profsoyuznaya str., Moscow, Russian Federation, 117485

For correspondence: Andrei Vital’evich Misyurin, PhD in Biology, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)612-80-38; e-mail: and@genetechnology.ru

For citation: Kesaeva LA, Misyurina EN, Mar’in DS, et al. Expression of the BCR-ABL1 Gene in Patients with Chronic Myeloproliferative Diseases with Signs of Progression. Clinical oncohematology. 2018;11(4):354–9.

DOI: 10.21320/2500-2139-2018-11-4-354-359


ABSTRACT

Background. The V617F mutation of JAK2 is known to manifest in Ph-negative chronic myeloproliferative diseases (cMPD), such as polycythemia vera, thrombocythemia, and myelofibrosis. These diseases not infrequently advance into more aggressive forms up to acute leukemia. As the progression mechanism is still unknown, its study retains a high priority. JAK2 carrying the V617F mutation is believed to cause constant activation of V(D)J recombinase in myeloid tumor cells in cMPD patients. Aberrant activation of V(D)J recombinase in tumor cells in cMPD patients can lead to t(9;22)(q34;q11) chromosomal rearrangement.

Aim. To study the expression of BCR-ABL1 resulting from translocation t(9;22)(q34;q11) in cMPD patients at the progression stage in order to test the suggested hypothesis.

Materials & Methods. The BCRABL1 expression was assessed in peripheral blood granulocytes in cMPD patients by real-time PCR. The JAK2 V617F mutation was identified by quantitative allele-specific PCR. The JAK2 exon 12 mutations were determined using Sanger direct sequencing of PCR products.

Results. The BCR-ABL1 expression was discovered in 29 % of patients with cMPD progression. The BCR-ABL1 expression in these patients correlated with hepatosplenomegaly and hyperleukocytosis.

Conclusion. In a significant proportion of cMPD patients the disease progression can be associated with activation of the BCR-ABL expression.

Keywords: JAK2 V617F, BCR-ABL1, V(D)J recombinase, t(9;22)(q34;q11), polycythemia vera, essential thrombocythemia, myelofibrosis, chronic myeloid leukemia.

Received: April 2, 2018

Accepted: August 5, 2018

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Epidemiology of Chronic Myeloid Leukemia in the Republic of Bashkortostan

NR Ryabchikova, GSh Safuanova, VI Nikulicheva

Bashkir State Medical University, 3 Lenina str., Ufa, Russian Federation, 450008

For correspondence: Prof. Guzyal’ Shagbanovna Safuanova, MD, PhD, 3 Lenina str., Ufa, Russian Federation, 450008; Tel.: +7(927)639-03-73; e-mail: safuanova@bk.ru

For citation: Ryabchikova NR, Safuanova GSh, Nikulicheva VI. Epidemiology of Chronic Myeloid Leukemia in the Republic of Bashkortostan. Clinical oncohematology. 2018;11(4):349–53.

DOI: 10.21320/2500-2139-2018-11-4-349-353


ABSTRACT

Background. The planning of therapeutic, diagnostic, and preventive medical care for chronic myeloid leukemia (CML) patients implies the need of not only maintaining patient registries, but also conducting epidemiologic studies in each geographical area.

Aim. To study and analyze CML epidemiological indicators over the last 15 years in the Republic of Bashkortostan for the purposes of evaluation and rational planning of specialized medical care for CML patient population.

Materials & Methods. The incidence, prevalence, and mortality of CML patients of all age groups in the period of 2000–2016 was analyzed in the Republic of Bashkortostan.

Results. The analysis of epidemiological indicators over the period of 2000–2016 showed that the incidence of the disease in the Republic of Bashkortostan was increasing. Within the last 8 years the prevalence rate even quadrupled which is clearly connected with improved detectability of Ph-chromosome and/or BCR-ABL gene, creation and maintenance of CML patient registry since 2008, introduction of treatment using tyrosine kinase inhibitors resulting also in increase in life expectancy. Mortality rates are reported to have a tendency of decrease over the period under study.

Conclusion. Key epidemiological indicators of CML in the Republic of Bashkortostan are comparable with the data of international and Russian researchers. The results obtained can be used for comparative studies and improvement of specialized medical care for CML patients.

Keywords: chronic myeloid leukemia, epidemiology, incidence, prevalence, mortality.

Received: April 9, 2018

Accepted: August 3, 2018

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REFERENCES

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Tyrosine Kinase Inhibitor Resistance in Patients with Chronic Myeloid Leukemia: A 10-Year Study of BCR-ABL Gene Mutation Profile in Russia (2006–2016)

VV Tikhonova1,2, MA Isakov3, VA Misyurin1, YuP Finashutina1,2, LA Kesaeva1,2, NA Lyzhko 1, IN Soldatova2, NN Kasatkina1, EN Misyurina4, AV Misyurin1,2

1 NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 GenoTekhnologiya, 104 Profsoyuznaya str., Moscow, Russian Federation, 117485

3 Aston Consulting, 31g Shabolovka str., Moscow, Russian Federation, 115162

4 Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182

For correspondence: Vera Vyacheslavovna Tikhonova, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(967)008-02-84; e-mail: brilfor@mail.ru

For citation: Tikhonova VV, Isakov MA, Misyurin VA, et al. Tyrosine Kinase Inhibitor Resistance in Patients with Chronic Myeloid Leukemia: A 10-Year Study of BCR-ABL Gene Mutation Profile in Russia (2006–2016). Clinical oncohematology. 2018;11(3):227–33.

DOI: 10.21320/2500-2139-2018-11-3-227-233


ABSTRACT

Background. Kinase domain mutations of BCR-ABL gene is the most common cause of tyrosine kinase inhibitor resistance.

Aim. To present the data on prognostic value of BCR-ABL mutation burden in Russian patients over the last 10 years.

Materials & Methods. The study included 1885 chronic myeloid leukemia (CML) patients with tyrosine kinase inhibitor resistance who were followed up from 2006 to 2016. BCR-ABL point mutations in mRNA samples were analyzed by means of polymerase chain reaction and subsequent Sanger sequencing.

Results. In 1257 CML patients with signs of tyrosine kinase inhibitor resistance BCR-ABL expression level was > 1 %. BCRABL mutations were detected in 31.8 % of patients. Total mutation count was 467 (70 mutation types). Total count of patients with mutation-associated tyrosine kinase inhibitor resistance decreased from 36.6 % (2006–2008) to 24.95 % (2013–2016) and to marked decrease of 23.12 % in 2014. Detection rate of imatinib-resistant mutations and F359V mutation was shown to decrease within the period from 2010–2011 to 2014–2015. F317L level, which is responsible for dasatinib resistance, considerably increased in 2015. T315I frequency was the highest in 2014, afterwards it was gradually decreasing. Mutation-associated resistance rates varied by region of the Russian Federation.

Conclusion. The analysis of trends of mutation incidence in patients with CML can be of extreme significance in long-term prognosis of resistance development and in improvement of treatment planning.

Keywords: chronic myeloid leukemia, kinase domain mutations of BCR-ABL gene, targeted therapy, resistance.

Received: January 22, 2018

Accepted: April 16, 2018

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REFERENCES

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

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

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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