chronic myeloid leukemia

Diagnostic Strategy for Detection of Typical and Atypical BCR-ABL Fusion Gene Transcripts in Chronic Myeloid Leukemia

MYELOID TUMORS , ,

OV Nikulina1,2, GA Tsaur1,2,3, TO Riger1,2, YuA Yakovleva1,2, AS Demina1,2, ER Semenikhina1, TV Spil’nik3, LI Savel’ev1,2,3, LG Fechina1,2

1 Regional Children’s Hospital No. 1, 32 Serafimy Deryabinoy str., Yekaterinburg, Russian Federation, 620149

2 Research Institute of Medical Cell Technologies, 22a K. Marksa str., Yekaterinburg, Russian Federation, 620026

3 Ural State Medical University, 3 Repina str., Yekaterinburg, Russian Federation, 620219

For correspondence: Grigorii Anatol’evich Tsaur, PhD, 32 Serafimy Deryabinoy str., Yekaterinburg, Russian Federation, 620149; Tel.: +7(343)216-25-17; e-mail: tsaur@mail.ru

For citation: Nikulina O.V., Tsaur G.A., Riger T.O., Yakovleva Yu.A., Demina A.S., Semenikhina E.R., Spil’nik T.V., Savel’ev L.I., Fechina L.G. Diagnostic Strategy for Detection of Typical and Atypical BCR-ABL Fusion Gene Transcripts in Chronic Myeloid Leukemia. Klin. Onkogematol. 22015;8(2):161–8 (In Russ.).

ABSTRACT

Background & Aims. The diagnosis of chronic myeloid leukemia (CML) is confirmed when t(9;22)(q34;q11) translocation is found by the cytogenetic test method and/or chimeric BCR-ABL transcript is detected by the reverse transcription polymerase chain reaction (RT-PCR). It is known that two most common types of chimeric BCR-ABL transcript are determined in CML patients: e13a2 (b2a2) и e14a2 (b3a2). However, rare types of chimeric BCR-ABL transcript have been described and they may be overlooked. Moreover, timely diagnosing and detection of different types of the chimeric transcript are very important, because the clinical course of the disease and efficacy of the therapy with tyrosine kinases inhibitors depend on the structure of chimeric BCR-ABL gene. Since in some cases CML may be diagnosed without the standard cytogenetic test and be confirmed by RT-PCR alone, we consider it important to develop a diagnostic algorithm which might permit to determine almost any type of chimeric BCR-ABL transcript.

Methods. Over the period from January, 2004, till December, 2013, in the laboratory of molecular biology of the department of pediatric oncology and hematology in Regional Children’s Hospital No. 1 (Yekaterinburg), the diagnosis of CML was confirmed in 1082 patients: 531 (49 %) males and 551 (51 %) females. The median age was 50 years (range 5–88 years). All patients underwent standard cytogenetic and molecular genetic tests. Primers which are complementary to nucleotide ABL gene sequence are localized in 2 and 3 ABL exons and are used for detection of all transcript types. Primers which are complementary to nucleotide BCR gene sequence are localized either in 12 and 13 exons for detection of most typical e13a2 and e14a2 (M-bcr) transcripts or in exon 1 for detection of e12a (m-bcr) transcript. While detecting amplicons which size differs from that of e13a2, e14a2, and e1a2, their direct paired-end sequencing is performed using primers (applied during the second round of RT-PCR) and a Big Dye Terminator 3.1 kit.

Results. After having analyzed 1082 patients with confirmed CML, we have developed a diagnostic algorithm for detecting common and rare types of chimeric BCR-ABL transcript in CML using RT-PCR. We detected common chimeric BCR-ABL transcripts, e14a2 and e13a2, in 62.53 % and 35.89 % of cases, respectively, using this algorithm. Rare transcripts, e13a3, e14a3, e19a2, e1a2, e3a2, e6a2, and e8a2, were detected in 1.57 % of cases.

Conclusion. Therefore, the proposed diagnostic algorithm proved to be effective for detection of common and rare types of chimeric BCR-ABL transcripts in CML patients.

Keywords: chronic myeloid leukemia, molecular diagnostics, chimeric BCR-ABL transcript.

Received: December 31, 2014

Accepted: February 4, 2015

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Second Generation Tyrosine Kinase Inhibitors and Their Toxicity in Treatment of Patients in Chronic Phase of Chronic Myeloid Leukemia

MYELOID TUMORS , ,

N.S. Lazorko1, E.G. Lomaia1, E.G. Romanova1, E.I. Sbityakova1, E.R. Machyulaitene2, P.A. Butylin1,3, A.Yu. Zaritskii1,2

1 Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russia, 197341

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

3 Saint Petersburg State University of Information Technologies, Mechanics and Optics, Institute of Translational Medicine, 49 Kronverkskii pr-t, Saint Petersburg, Russia, 197101

For correspondence: Elza Galaktionovna Lomaia, PhD, 2 Akkuratova str., Saint Petersburg, Russia, 197341; Tel.: +7(812)702-37-65; e-mail: lomelza@gmail.com

For citation: Lazorko N.S., Lomaia E.G., Romanova E.G., Sbityakova E.I., Machyulaitene E.R., Butylin P.A., Zaritskii A.Yu. Second Generation Tyrosine Kinase Inhibitors and Their Toxicity in Treatment of Patients in Chronic Phase of Chronic Myeloid Leukemia. Klin. Onkogematol. 2015;8(3):302–8. (In Russ.)

ABSTRACT

Background & Aims. Certain experience in the use of new tyrosine kinase inhibitors (TKIs) in treatment of patients with chronic myeloid leukemia has been obtained over the last years. The article summarizes literature data on toxicity obtained in international clinical trials. The aim of the study is to evaluate adverse effects of second generation TKIs in the routine clinical practice and to assess their effect on patient future life.

Methods. We analyzed our own data obtained during routine clinical practice. 76 patients (36 men and 40 women) over 18 years of age (median age was 49 years, range 26–75) with chronic myeloid leukemia were enrolled in the retrospective trial. 48 patients were treated with nilotinib, 28 patients received dazatinib during the chronic phase of the disease as a second line therapy after withdrawal of imatinib mesylate. The toxicity degree was determined according to CTCAE 4.0 criteria.

Results. III–IV degree hematologic toxicity was registered in 36.8 % of patients. No significant difference in the incidence of complications between nilotinib and dazatinib groups was observed: 39.6 % and 32.1 %, respectively. II–IV degree non-hematologic toxicity was found in 35.4 % patients on nilotinib and in 25 % of patients on dazatinib. The incidence of individual types of toxicity did not exceed 15 %. A combination of different types of non-hematologic toxicity was observed in 9.2 % of patients. No TKI2 toxicity-related lethal outcomes were registered.

Conclusion. Hematologic and/or non-hematologic toxicity related to TKI2 was registered in more than 50 % of patients. In most cases, the complications were transient and eliminated after discontinuation of TKI2 or after dose reduction. TKI2-associated complications did not affect the possibility to achieve a complete cytogenetic response and its stability.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, toxicity.

Received: January 29, 2015

Accepted: June 1, 2015

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Role of tyrosine-kinase inhibitor selectivity in development of adverse effects during treatment of chronic myeloid leukemia

REVIEWS , , ,

A.A. Zeifman1,2, E.Yu. Chelysheva3, A.G. Tukrina3, and G.G. Chilov1,2

1 N.D. Zelinsky Institute of Organic Chemistry, RAS, Moscow, Russian Federation

2 Fusion Pharma LLC, Moscow, Russian Federation

3 Hematology Research Center, RF MH, Moscow, Russian Federation

ABSTRACT

This review focuses on association between the selectivity of Bcr-Abl kinase inhibitors and the spectrum of their adverse effects during treatment of patients with chronic myeloid leukemia. The data on the structure and natural biochemical functions of the well-known adverse targets for inhibitors of Bcr-Abl kinases, including BRAF, FMS, EGFR, PDGFR, PYK2, TIE2, and VEGFR1/2/3 are summarized, and the potential association between their off-target inhibition and adverse effects of tyrosine-kinase inhibitors is suggested.

Keywords: chronic myeloid leukemia, tyrosine-kinase inhibitors, selectivity, imatinib, nilotinib, dasatinib, ponatinib, PF-114, BRAF, FMS, EGFR, PDGFR, PYK2, TIE2, VEGFR1/2/3.

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Impact of molecular genetic and cytogenetic characteristics on outcomes of allogeneic hematopoietic stem cell transplantation in chronic myeloid leukemia

BONE MARROW TRANSPLANTATION , , ,

A.V. Gorbunova, T.L. Gindina, E V. Morozova, I.M. Barkhatov, N.N. Mamayev, and B.V. Afanasyev

R.M. Gorbacheva Institute of Pediatric Oncology, Hematology and Transplantology, I.P. Pavlov State Medical University, Saint Petersburg, Russian Federation

ABSTRACT

Point mutations in the BCR-ABL kinase domain, BCR-ABL and EVI1 gene expression alterations, and additional chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia are strongly associated with resistance to tyrosine kinase inhibitors (TKIs) and disease progression, but their effect on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is uncertain. This retrospective study included 35 CML patients with resistance to TKI therapy who received a related or unrelated HSCT. Additional chromosomal aberrations were associated with the decreased rate of the complete molecular response (CMR) after allo-HSCT. EVI1 expression level was associated with a decreased disease-free survival (DFS). BCR-ABL kinase domain mutations showed no influence on CMR, OS, and DFS in this patient cohort. 9 out of 10 patients with T315I mutation achieved CMR. EVI1-directed stratification of patients during the post-transplantation period may improve outcome of HSCT.

Keywords: chronic myeloid leukemia, CML, allogeneic hematopoietic stem cells transplantation, allo-HSCT, BCR-ABL, EVI1.

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Genfatinib® therapy for chronic-phase chronic myeloid leukemia in routine clinical practice

CLINICAL PRESENTATION, DIAGNOSIS, AND MANAGEMENT OF MYELOID MALIGNANCIES , , ,

T.V. Chagorova1, V.V. Yablokova2, P.A. Borkina3, and N.A. Pryanikova3

1 Regional Oncology Clinic, Penza, Russian Federation

2 Yaroslavl Regional Clinical Hospital, Yaroslavl, Russian Federation

3 Moscow Representative Office of GENFA LTD (United Kingdom), Moscow, Russian Federation

ABSTRACT

The article describes the outcomes of Genfatinib® therapy in routine clinical practice at the Regional Oncology Clinic (Penza) and Yaroslavl Regional Clinical Hospital (Yaroslavl). 62 patients with chronic myeloid leukemia (chronic phase) were treated at the above institutions from April 2012 to April 2013. The patients were assigned into the following groups: the first treatment group, where Genfatinib® was prescribed as an initial therapy at the time of diagnosis of chronic-phase chronic myeloid leukemia; the second group, where Genfatinib® was prescribed after the initial therapy with Gleevek®. The main objectives were assessment of the Genfatinib® efficacy (rates of complete or partial clinico-hematological, cytogenetic, and molecular responses), toxicity, and safety. It was shown that Genfatinib® used after previous therapy with Gleevek® caused no negative influence of the rates of clinico-hematological, cytogenetic, and molecular responses. In the patients who received Genfatinib® as an initial therapy, the complete clinico-hematological and cytogenetic and molecular responses were achieved by 3–5 and 3–6 months of treatment, respectively. The spectrum of adverse events observed with Genfatinib® therapy was similar to the one of Gleevek®.

Keywords: chronic myeloid leukemia, chronic phase, Genfatinib®, efficacy, safety.

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Refernces

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Association between HLA-DRB1 alleles and response to imatinib in chronic myeloid leukemia

LYMPHOID TUMORS ,

E.G. Ovsyannikova1, I.L. Davydkin2, E.A. Popov1, L.V. Zaklyakova1, and B.N. Levitan1

1 Astrakhan State Medical Academy, RF Ministry of Health, Astrakhan, Russian Federation

2 Research Institute of Hematology, Transfusiology, and Intensive Care, Samara State Medical University, RF Ministry of Health, Samara, Russian Federation

ABSTRACT

The article presents analysis of association between the HLA-DRB1 gene alleles and the response to imatinib in the patients with Ph-positive chronic myeloid leukemia (Ph+ CML). HLA class II alleles, DRB1 locus, were determined using PCR-SSP. The predictors of optimal response to imatinib in 3 to 18-months treatment of CML are HLA-DRB1*16(02), HLA-DRB1*17(03), and HLA-DRB1*08 specificities. Immunogenetic markers of imatinib treatment failure are HLA-DRB1*11(05), HLA-DRB1*12(05), and HLA-DRB1*14(06) alleles. The results obtained can be used for the development of individual long-term prognosis for chronic myeloid leukemia and optimization of the treatment choice.

Keywords: chronic myeloid leukemia, HLA-DRB1, imatinib, prognosis.

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Quality of life and symptom profile in patients with chronic myeloid leukemia receiving dasatinib as а second-line therapy due to intolerance or resistance to imatinib

CLINICAL PRESENTATION, DIAGNOSIS, AND MANAGEMENT OF MYELOID MALIGNANCIES , , ,

Ionova1,2, D. Fedorenko1,2, T. Nikitina1, and K. Kurbatova1

1 N.I. Pirogov National Medico-surgical Center, Moscow, Russian Federation

2 International Center for Quality of Life Studies, Saint-Petersburg, Russian Federation

ABSTRACT

The article is focused on preliminary results of the observational study “Quality of life and symptom profile in imatinib-resistant or intolerant patients with chronic myeloid leukemia during disease-modifying treatment” (2011–2012). 56 imatinib-resistant or intolerant patients with chronic myeloid leukemia in chronic phase were included in the preliminary analysis. It was shown that prior to treatment with dasatinib more than one third of patients had severe or critical quality of life deterioration. Patients treated with standard doses of imatinib during the first-line treatment reported better quality of life than patients treated with high doses of imatinib. After 12 months of treatment with dasatinib, the majority of patients showed complete or partial cytogenetic response (62 %); most of the patients with complete cytogenetic response were treated with standard doses of imatinib during the first-line treatment (19 % vs 8 %). During treatment with dasatinib, stabilization of quality of life parameters was recorded with a slight trend towards improved vitality, mental health, and pain scales. In the majority of patients (68 %), the treatment response as improved or stabilized quality of life was observed. During treatment with dasatinib, severity of the most frequent disease- or treatment-specific symptoms decreased. In this observational study, it was shown that dasatinib therapy in the real-world practice is effective both in terms of clinical parameters and patient-reported outcomes, and characterized by good tolerability.

Keywords: quality of life, symptom profile, chronic myeloid leukemia, dasatinib.

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  21. Bevans M.F., Mitchell S.A., Barrett A.J. et al. Function, Adjustment, Quality of Life and Symptoms (FAQS) in Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Survivors: A Study Protocol. Health and Quality of Life Outcomes 2011; 9: 24. doi: 10.1186/1477-7525-9-24.

The problem of adherence to therapy in chronic myeloid leukemia: understanding the patient and making a decision

CLINICAL PRESENTATION, DIAGNOSIS, AND MANAGEMENT OF MYELOID MALIGNANCIES , ,

E.Yu. Chelysheva1, A.V. Galaktionova2, and A.G. Turkina1

1 Hematology Research Center, RF Ministry of Health, Moscow, Russian Federation

2 ANO “CO-operation project”, Moscow, Russian Federation

ABSTRACT

This article prepared by hematologists and the psychologist raises the problem of adherence to therapy in chronic myeloid leukemia. Poor adherence to therapy can worsen treatment outcomes. Patients who take less than 90 % of prescribed imatinib have lower chances to achieve clinically significant deep remission. It is shown that adherence rates decrease over time. Methods for measurement of adherence have limitations and do not always reflect an actual situation. It is noted that long-term treatment using medication in a form of tablets has its peculiarities associated with the necessity of a patient’s clear understanding of treatment goals, appropriate information on therapy aspects, and correction of side effects. The data on tyrosine kinase inhibitors regimens in chronic myeloid leukemia are included. The causes of poor adherence to therapy related to a particular mode of treatment and psychological status of the patient are described. Practical recommendations on adherence improvement are given.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, adherence to therapy

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REFERENCES

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Cardiovascular complications of chronic myeloid leukemia treated with tyrosine kinase inhibitors

COMPLICATIONS OF ANTITUMOR TREATMENT , , ,

G.E. Gendlin, L.M. Makeeva, E.I. Emelina, K.V. Shuikova, G.I. Storozhakov

 FGEI HPE RNRMU named after N.I. Pirogov of Russian MoH, Moscow, Russian Federation

ABSTRACT

The achieved nowadays success in oncohematology patients’ treatment is primarily associated with the development of targeted therapy, including invention of specific tyrosine kinase inhibitors for chronic myeloid leukemia treatment (imatinib, nilotinib and dasatinib,). However, along with the high efficacy, these medicines have certain toxicities. Cardiovascular complications of tyrosine kinase inhibitors therapy of chronic myeloid leukemia are described in this review article. Taking onto consideration the fact that therapy with these medicines can cause rear but serious side effects. It is necessary to consider the probability of cardiotoxicity, arterial occlusion of various diameter and pulmonary hypertension development before prescription. In order to minimize side effects patients examination is recommended before treatment initiation for recognition of initial cardiovascular diseases, as well as thorough control of cardiovascular condition throughout the treatment.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, cardiac toxicity, targeted therapy

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