Early Response and Long-Term Outcomes of Ruxolitinib Therapy in Myelofibrosis: Multicenter Retrospective Study in 10 Centers of the Russian Federation

EG Lomaia1, NT Siordiya1, OM Senderova2, OE Ochirova3, EB Zhalsanova3, AYu Furtovskaya1, GP Dimov4, MG Pozina4, OYu Li5, KB Trizna6, MA Mikhalev7, EV Sokurova8, AA Otmorskaya9, AS Khazieva10, VV Ust’yantseva11, YuD Rogovaya1, AYu Zaritskey1

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

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

3 NA Semashko Republican Clinical Hospital, 12 Pavlova str., Ulan-Ude, Russian Federation, 670031

4 Municipal Clinical Hospital No. 1, 16 Vorovskogo str., Chelyabinsk, Russian Federation, 454048

5 Sakhalin Regional Clinical Hospital, 430 Mira pr-t, Yuzhno-Sakhalinsk, Russian Federation, 693004

6 Tomsk Regional Clinical Hospital, 96 Ivana Chernykh str., Tomsk, Russian Federation, 634063

7 Krasnoyarsk Interdistrict Clinical Hospital No. 7, 4 Akademika Pavlova str., Krasnoyarsk, Russian Federation, 660003

8 Vladivostok Polyclinic No. 4, 5 Voropaeva str., Vladivostok, Russian Federation, 690000

9 Regional Clinical Hospital, 1 Lyapidevskogo str., Barnaul, Russian Federation, 656024

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

11 Railway Clinical Hospital, the Chelyabinsk Railway Station, 41 Tsvillinga str., Chelyabinsk, Russian Federation, 454000

For correspondence: Nadiya Tamazovna Siordiya, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; e-mail: siordian@list.ru

For citation: Lomaia EG, Siordiya NT, Senderova OM, et al. Early Response and Long-Term Outcomes of Ruxolitinib Therapy in Myelofibrosis: Multicenter Retrospective Study in 10 Centers of the Russian Federation. Clinical oncohematology. 2020;13(3):335–45 (In Russ).

DOI: 10.21320/2500-2139-2020-13-3-335-345


ABSTRACT

Aim. To assess the efficacy of targeted therapy with ruxolitinib in patients with myelofibrosis in real clinical practice in Russia. To determine the prognostic value of spleen reduction in the early stages of ruxolitinib treatment and its effect on overall survival.

Materials & Methods. The present retrospective study was based on the data of 10 centers of Russia. It included 56 myelofibrosis (primary or post-polycythemic and post-thrombocythemic) patients who received ruxolitinib. The median age of patients was 56 years (range 26–76 years). Most of them (59 %) were considered intermediate-1 risk according to DIPSS and had massive splenomegaly (80 %), and constitutional symptoms (86 %). The initial drug dose was 30 mg per day in 64 % of cases, and the level of thrombocytes was ≥ 200 × 109/L in 61 % of patients. The spleen size was evaluated by palpation.

Results. By the start of data collection most of patients (79 %) had been treated with ruxolitinib. In no case therapy was withdrawn for the reason of drug toxicity. On ruxolitinib constitutional symptoms were reversed in 70 %, 87 %, and 98 % of patients by months 1, 3 and 6, respectively. In 36 % and 46 % of patients by months 3 and 6, respectively, ≥ 50 % decrease in spleen size was observed. Overall, in 31 % and 27 % of cases the size of the spleen decreased by less than 25 % by months 3 and 6, respectively. The factors affecting the changes in spleen size have not been identified. The probability of overall survival by years 2 and 5 of follow-up was 97 % and almost 70 %, respectively. This parameter was significantly affected by the extent of spleen size reduction by month 3 of follow-up as well as by its initial size.

Conclusion. Ruxolitinib shows high efficacy for both decrease of general myelofibrosis symptoms and reduction in spleen size. The extent of spleen reduction is an important prognostic factor. In patients with insufficient spleen reduction an increase in drug dose is advisable. If it is not possible, alternative methods of treatment should be sought.

Keywords: myelofibrosis, ruxolitinib, spleen size changes, constitutional symptoms, overall survival.

Received: January 31, 2020

Accepted: May 15, 2020

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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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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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Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis

MV Barabanshchikova, EV Morozova, VV Baikov, IM Barkhatov, NN Mamaev, SN Bondarenko, AL Alyanskii, LS Zubarovskaya, BV Afanas’ev

R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Lyudmila Stepanovna Zubarovskaya, DSci, Professor, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)338-62-64; e-mail: zubarovskaya_ls@mail.ru

For citation: Barabanshchikova MV, Morozova EV, Baikov VV, et al. Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis. Clinical oncohematology. 2016;9(3):279-86 (In Russ).

DOI: 10.21320/2500-2139-2016-9-3-279-286


ABSTRACT

Background & Aims. At present, the allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment option with curative potential in patients with myelofibrosis (MF), especially in intermediate and high risk categories. The aim of the study is to perform a retrospective analysis of allo-HSCT outcomes in MF patients.

Materials & Methods. Outcomes of allo-HSCT in 11 intermediate-2 (= 3) and high (= 6) risk patients (based on Dynamic International Prognostic Scoring Scale, DIPSSplus) performed in the R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation over the period from 2005 till 2015 were analyzed in the study. Two more patients underwent allo-HSCT in MF blast phase. Two patients received ruxolitinib before allo-HSCT and 1 patient before and after allo-HSCT. Reduced intensity conditioning regimen was used in all cases.

Results. Primary engraftment was documented in 8 patients. 72 % of patients achieved complete hematological remission. Molecular remission and myelofibrosis regression were confirmed in 5 patients. 5 of 11 patients were still with remission and followed-up by the date of the paper submission. The overall two-year survival was 46 %.

Conclusion. Allo-HSCT is an effective treatment option for MF patients. Further trials are required to evaluate an optimal timing for allo-HSCT in MF patients and efficacy of Janus kinase (JAK) inhibitors as pre- and posttransplant therapy in MF.


Keywords: myelofibrosis, allo-HSCT, reduced intensity conditioning regimen, ruxolitinib.

Received: January 28, 2016

Accepted: March 22, 2016

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Extensive Combined Surgeries in Patients with Blood Diseases and Gastric Cancer

S.R. Karagyulyan, K.I. Danishyan, A.V. Grzhimolovskii, V.S. Shavlokhov, S.A. Shutov, M.A. Silaev, L.G. Kovaleva, O.M. Sorkina, A.Yu. Bulanov

Hematology Research Center of RF MH, Moscow, Russian Federation

For citation: Karagyulyan S.R., Danishyan K.I., Grzhimolovskii A.V., Shavlokhov V.S., Shutov S.A., Silaev M.A., Kovalyova L.G., Sorkina O.M., Bulanov A.Yu. Extensive Combined Surgeries in Patients with Blood Diseases and Gastric Cancer. Klin. onkogematol. 2014; 7(3): 335–42 (In Russ.).

ABSTRACT

The second tumor in patients with myelo- or lymphproliferative diseases is not rare. However, the state of patients’ hemostasis and severely enlarged spleen can become a contraindication for a surgical intervention in a general surgery unit. Four cases of a successful gastrectomy with expanded lymphodissection are presented in a 53 year old woman with subleukemic myelosis (primary myelofibrosis according to WHO classification) and giant splenomegaly (38 ´ 21 ´ 13 cm, spleen weight: 4500 g) and in a 68 year old man with diffuse large В-cell lymphoma and massive splenomegaly (22 ´ 12 ´ 8 cm, spleen weight: 2850 g). Intraoperative compensated blood loss in both cases was 3800 ml and 3740 ml, respectively. Two patients had mild hemophilia A. Specially designed transfusional and anaesthetic strategy was required in all cases because of hemostatic disorders.


Keywords: stomach cancer, surgical treatment, hemophilia, myelofibrosis, lymphoma.

Address correspondence to: max-blood@mail.ru

Accepted: May 28, 2014

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