The Effect of Anticoagulant Therapy on Survival and Outcome of Venous Thrombosis in Children, Teenagers, and Young Adults with Acute Lymphoblastic Leukemia Treated According to ALL-MB-2008 and ALL-MB-2015 Protocols

VV Dmitriev, NV Migal, OI Bydanov, NV Lipai, EV Dmitriev

Republican National Applied Research Center of Pediatric Oncology, Hematology and Immunology, 43 Frunzenskaya, Borovlyany, Minskii district, Republic of Belarus, 223053

For correspondence: Vyacheslav Vasil’evich Dmitriev, MD, PhD, 43 Frunzenskaya str., Borovlyany, Minskii district, Republic of Belarus, 223053; Tel.: +375(17)265-42-22; e-mail: dmitrievhaematol@mail.ru

For citation: Dmitriev VV, Migal NV, Bydanov OI, et al. The Effect of Anticoagulant Therapy on Survival and Outcome of Venous Thrombosis in Children, Teenagers, and Young Adults with Acute Lymphoblastic Leukemia Treated According to ALL-MB-2008 and ALL-MB-2015 Protocols. Clinical oncohematology. 2019;12(3):338–43 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-338-343


ABSTRACT

Aim. To assess the effect of anticoagulant therapy on survival and outcome of venous thrombosis in children, teenagers, and young adults with acute lymphoblastic leukemia (ALL).

Materials & Methods. Venous thrombosis was diagnosed in 42 out of 592 ALL patients treated according to ALL-MB-2008 and ALL-MB-2015 protocols from 2008 to 2017.

Results. A daily dose of 150–200 IU/kg low molecular weight heparin (LMWH) was administered to 30 patients. Duration of anticoagulant treatment was up to 1 month in 4 patients, 2–3 months in 8 patients, 4–6 months in 12 patients, and 7–12 months in 4 patients. To 2 patients anticoagulants were administered for more than 24 months. Complete recanalization of thrombosed vessel was achieved in 19 patients, partial recanalization was achieved in 6 patients, obliteration of predominantly internal jugular vein was found in 5 patients. During thrombocytopenia (100 to 35 × 109/L) 12 patients received reduced doses of LMWH for 1–4 weeks. In the period of chemotherapy-induced thrombocytopenia the daily LMWH dose was reduced in proportion to thrombocyte level. After thrombocyte recovery up to more than 100 × 109/L antithrombotic treatment was continued with LMWH daily dose of 150–200 anti-Xa IU/kg. The duration of anticoagulant treatment among 12 patients who received reduced doses of LMWH was up to 1 month in 3 patients, 2–3 months in 4 patients, 4–6 months in 3 patients, and 7–12 months in 2 patients. Complete recanalization of thrombosed vessel was achieved in 8 patients, partial recanalization was achieved in 2 patients, vein obliteration was found in 2 patients. No correlation between LMWH dosage and thrombosis outcome was observed (χ2 = 0.494; = 0.78). Maintenance (accompanying) therapy was completed in 38 out of 42 ALL patients with venous thrombosis. Event-free survival was 83 ± 8 %, that was similar to the one (81 ± 2 %) in patients without thrombosis (= 0.654).

Conclusion. Anticoagulant treatment of venous thrombosis complicating ALL in children, teenagers, and young adults did not yield a decrease of either overall or event-free survival. Reduction of LMWH doses in the period of chemotherapy-induced thrombocytopenia did not affect the outcome of venous thrombosis.

Keywords: venous thrombosis, coagulation, acute lymphoblastic leukemia, children, teenagers, young adults, anticoagulant therapy, low molecular weight heparin.

Received: October 30, 2018

Accepted: June 5, 2019

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REFERENCES

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Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Russian Multicenter Clinical Trial

SN Bondarenko1, EN Parovichnikova2, AA Maschan3, OYu Baranova4, TV Shelekhova5, VA Doronin6, VYa Mel’nichenko7, KD Kaplanov8, OS Uspenskaya9, AN Sokolov2, NV Myakova3, IS Moiseev1, IV Markova1, EI Darskaya1, AG Smirnova1, TA Bykova1, BI Ayubova1, IA Samorodova1, EV Babenko1, IM Barkhatov1, TL Gindina1, AD Kulagin1, BV Afanas’ev1

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

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

3 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117997

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

5 VI Razumovskii Saratov State Medical University, 112 Bol’shaya Kazach’ya str., Saratov, Russian Federation, 410012

6 Municipal Clinical Hospital No. 40, 7 Kasatkina str., Moscow, Russian Federation, 129301

7 NI Pirogov Russian National Medical Center of Surgery, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

8 Volgograd Regional Clinical Oncologic Dispensary, 78 Zemlyachki str., Volgograd, Russian Federation, 400138

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

For correspondence: Sergei Nikolaevich Bondarenko, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)338-62-72; e-mail: dr.sergeybondarenko@gmail.com

For citation: Bondarenko SN, Parovichnikova EN, Maschan AA, et al. Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Russian Multicenter Clinical Trial. Clinical oncohematology. 2019;12(2):145–53.

DOI: 10.21320/2500-2139-2019-12-2-145-153


ABSTRACT

Background. Recent advances in the treatment of relapsed/refractory acute lymphoblastic leukemia (R/R ALL) are attributed to the implementation of immunotherapy methods which include blinatumomab, the bispecific engager of a patient’s endogenous T-cells (Blincyto™, Amgen®) (BC).

Aim. To assess BC efficacy and toxicity in the treatment of R/R ALL patients with persistence of minimal tumor clone before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Materials & Methods. The trial included 66 B-ALL patients with CD19+ aged 18 to 72 years, 23 (35 %) of them with measurable minimal residual disease (MRD+) and 43 (65 %) with R/R ALL. In 18 (27 %) patients BC was administered after prior allo-HSCT.

Results. In the overall group 2-year overall survival (OS) and disease-free survival (DFS) in patients with response to BC treatment were 53 % and 38 % respectively. In the R/R ALL group complete remission (CR) was achieved in 29 (67 %) patients including 24 (83 %) patients with negative MRD. CR rate was higher in standard cytogenetic risk group (73 %) in comparison with high-risk group (59 %). In patients with more or less than 50 % blast cells in bone marrow CR rate was 85 % and 61 %, respectively. When BC was administered after prior allo-HSCT and without it CR rate was 80 % and 60 %, respectively. In R/R ALL patients with response to BC 2-year OS and DFS were 40 % and 26 %, respectively, in the MRD+ group of ALL patients they were 66 % and 51 %, respectively. Relapse rate was lower in the group with allo-HSCT than in the group without it, i.e. 21 % vs. 55 %. Adverse events of grade 3–4 were observed in 25 (38 %) patients. In 11 (16 %) patients BC therapy had to be discontinued, in 5 (7 %) patients it was terminated prior to the scheduled date.

Conclusion. BC efficacy is higher in the MRD+ group and in R/R ALL patients with smaller tumor mass. BC treatment after allo-HSCT yields remissions in most patients and can be combined with immune-adoptive therapy.

Keywords: acute lymphoblastic leukemia, targeted therapy, blinatumomab.

Received: August 22, 2018

Accepted: January 18, 2019

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REFERENCES

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  10. Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57–66. doi: 10.1016/s1470-2045(14)71170-2.

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Manufacturing of CD19 Specific CAR T-Cells and Evaluation of their Functional Activity in Vitro

AV Petukhov1, VA Markova2, DV Motorin1, AK Titov1, NS Belozerova2, PM Gershovich2, AV Karabel’skii2, RA Ivanov2, EK Zaikova1, EYu Smirnov2, PA Butylin1, AYu Zaritskey1

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

2 Biocad Biotechnology Company, 34-A Svyazi str., Strel’na, Saint Petersburg, Russian Federation, 198515

For correspondence: Andrei Yur’evich Zaritskey, MD PhD, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(812)702-68-28, Fax: +7(812)702-37-65; e-mail: zaritskey@gmail.com

For citation: Petukhov AV, Markova VA, Motorin DV, et al. Manufacturing of CD19 Specific CAR T-Cells and Evaluation of their Functional Activity in Vitro. Clinical oncohematology. 2018;11(1):1–9.

DOI: 10.21320/2500-2139-2018-11-1-1-9


ABSTRACT

Background. The most promising variant of adoptive immunotherapy of the B-line oncohematological diseases includes the use of cells with the chimeric antigen receptor (CAR T-cells), that showed extraordinary results in clinical studies.

Aim. To manufacture CAR T-cells for the clinical use and to study their cytotoxicity in vitro.

Methods. Human T-lymphocytes were transduced by the lentiviral vector containing anti-CD19-CAR, RIAD, and GFP genes. The T-cell transduction efficacy was assessed on the basis of GFP protein signal by flow cytometry. Propidium iodide was used to analyse the cell viability. Cytotoxic activity of the manufactured CAR T-cells was studied in the presence of the target cells being directly co-cultivated. Analysis of the number and viability of CAR T-cells and cytokine expression was performed by flow cytometry.

Results. The viability of the transduced T-cells and GFP expression reached 91.87 % and 50.87 % respectively. When cultured in the presence of IL-2 and recombinant CD19 (the target antigen), the amount of CAR-T after 120 h of the process was 1.4 times larger compared with the period of 48 h. In the cytotoxic test of co-cultivation CAR-T with the K562-CD19+ cells the percentage of CAR-T increased to 57 % and 84.5 % after 48 h and 120 h of exposure respectively. When cultured with the K562 cells (test line not expressing CD19) the number of CAR T-cells decreased to 36.2 % within 48 h while the number of K562 cells increased to 58.3 %. The viability of target cells in the experimental and control groups was 3.5 % and 36.74 % respectively. Comparison of IL-6 level in the control and experimental groups revealed that the differences are insignificant, as opposed to the level of other cytokines (IFN-γ, IL-2, TNF) which proved to be different in both groups.

Conclusion. The present work resulted in the production of anti-CD19 CAR T-cells with adequate viability. The in vitro model demonstrated their cytotoxicity. Manufacturing of CAR T-cells for clinical use is the first step of the development of adoptive immunotherapy in the Russian Federation.

Keywords: CAR T-cells, adoptive immunotherapy, acute lymphoblastic leukemia, non-Hodgkin’s lymphomas, lentiviral transduction, graft-versus-host reaction, сytokine release syndrome.

Received: September 15, 2017

Accepted: December 7, 2017

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Bortezomib Combination Therapy of Relapsed and Refractory Acute Lymphoblastic Leukemia in Children

NA Batmanova, MA Shervashidze, AV Popa, LYu Grivtsova, IN Serebryakova, GL Mentkevich

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

For correspondence: Natal’ya Andreevna Batmanova, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(925)321-26-42; e-mail: Batmanova_nataly@mail.ru

For citation: Batmanova NА, Shervashidze MА, Popa АV, et al. Bortezomib Combination Therapy of Relapsed and Refractory Acute Lymphoblastic Leukemia in Children. Clinical oncohematology. 2017;10(3):381–9 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-381-389


ABSTRACT

Background & Aims. Despite significant success in the treatment of acute lymphoblastic leukemia (ALL) in children, relapses and drug resistance to the standard therapy remain the main cause of treatment failure. The addition of bortezomib to the combination therapy of relapsed ALL to change the sensitivity of blast cells may be a perspective approach to cure patients. The aim was to evaluate the efficacy and toxicity of the anti-relapse ALL treatment protocols REZ BFM 95/96 without bortezomib and COG AALL07P1 with bortezomib in relapsed and refractory ALL in children.

Materials & Methods. The study included 54 children with a confirmed ALL of various localizations. From 1995 to 2011, ALL REZ BFM 95/96 treatment without bortezomib was administered to 26 patients. From 2011 to 2016, 28 children received COG AALL07P1 combination treatment with bortezomib.

Results. The immediate treatment efficacy significantly higher in patients treated with bortezomib (85.7 % vs 57.6 %) after induction chemotherapy with the ALL REZ BFM 95/96. The analysis of the long-term outcomes (disease-free, event-free, overall survival) showed no significant differences between the groups. The event-free survival of patients with isolated bone marrow relapses for a period of 2 years was 20.3 ± 17.5 %. The tolerability of the program was acceptable, complications developing during myelosuppression were not associated with the administration of bortezomib.

Conclusion. The intensification of induction chemotherapy in recurrent remission according to COG AALL07P1 protocol with the addition of bortezomib allowed to increase the number of complete remissions including MRD negative ones.

Keywords: acute lymphoblastic leukemia, refractoriness, relapses, bortezomib.

Received: February 24, 2017

Accepted: May 2, 2017

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REFERENCES

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Acute Lymphoblastic Leukemia with t(4;11)(q21;q23)/KMT2A-AFF1 Translocation: The Results of Allogeneic Hematopoietic Stem Cells Transplantation in Children and Adults

TL Gindina, NN Mamaev, OV Paina, AS Borovkova, PV Kozhokar’, OA Slesarchuk, YaV Gudozhnikova, EI Darskaya, AL Alyanskii, SN Bondarenko, LS Zubarovskaya, BV Afanas’ev

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

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: Gindina TL, Mamaev NN, Paina OV, et al. Acute Lymphoblastic Leukemia with t(4;11)(q21;q23)/KMT2A-AFF1 Translocation: The Results of Allogeneic Hematopoietic Stem Cells Transplantation in Children and Adults. Clinical oncohematology. 2017;10(3):342–50 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-342-350


ABSTRACT

Aim. The aim was to evaluate the results of the allogeneic hematopoietic stem cells transplantation (allo-HSCT) in children and adults with the most prognostically unfavorable acute lymphoblastic leukemia (ALL) with t(4;11)(q21;q23)/KMT2A-AFF1 translocation.

Methods. We examined 21 patients (12 females, 9 males) aged from 3 months to 48 years (median 18.9 years). The analysis of prognostic factors of overall (OS) and event-free survival (EFS) after allo-HSCT in patients of different age groups with various clinical, transplantation and cytogenetic characteristics was performed. Allo-HSCT from HLA-compatible related and unrelated donors, as well as haploidentical allo-HSCT were performed in 4, 9 and 8 patients of age groups < 1 year, 1–18 years, and >18 years, respectively. In 10 (48 %) patients, allo-HSCT was performed in the first remission, in 2 (10 %) patients in the second remission, and in 9 (43 %) patients during the disease relapse.

Results. In 8 (38 %) patients, the only chromosomal disorder was the translocation t(4;11)(q21;q23). Additional changes in chromosomes were found in 11 (52 %) patients. In 8 (38 %) of them, 3 or more chromosomal abnormalities in the karyotype were found. According to the results of a univariant analysis, the OS and EFS were significantly different in patients with allo-HSCT performed in the first remission and at other stages of ALL (in the second remission and in relapse: < 0.001 in both cases), as well as in patients with or without 3 or more cytogenetic disorders in the karyotype (p = 0.04 in both cases). The multivariant analysis showed that the only independent prognostic factor affecting the OS and EFS in ALL patients with t(4;11) was the allo-HSCT, including the haploidentical procedure, during the first complete hematological and molecular remission (p = 0.002 and p = 0.0004, respectively).

Conclusion. ALL with t(4;11)/KMT2A-AFF1 was as an absolute indication for allo-HSCT in first remission, including children of < 1 year age group. Satisfactory results can be obtained with the use of haploidentical transplantation from the parents. This approach eliminates the search in the registers completely HLA-compatible donor and facilitates the treatment procedure.

Keywords: acute lymphoblastic leukemia, t(4;11)/KMT2A-AFF1 translocation, allogeneic HSCT.

Received: January 17, 2017

Accepted: May 10, 2017

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REFERENCES

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  14. Motllo C, Ribera J-M, Morgades M, et al. Frequency and prognostic significance of t(v;11q23)/KMT2A rearrangements in adult patients with acute lymphoblastic leukemia treated with risk-adapted protocols. Leuk Lymphoma. 2017;58(1):145–52. doi: 10.1080/10428194.2016.1177182.
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Cytogenetic and Molecular Genetic Prognostic Factors of Acute Lymphoblastic Leukemias

AV Misyurin

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

For correspondence: Andrei Vital’evich Misyurin, PhD, 24 Kashirskoe sh., Moscow, Russian Federation, 115478; e-mail: and@genetechnology.ru

For citation: Misyurin AV. Cytogenetic and Molecular Genetic Prognostic Factors of Acute Lymphoblastic Leukemias. Clinical oncohematology. 2017;10(3):317–23 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-317-323


ABSTRACT

This review presents characteristic and reproducible chromosome rearrangements in acute lymphoblastic leukemia (ALL), which can be detected with a standard cytogenetic research (G-bands staining) or by FISH. More subtle genetic changes, inaccessible to the observation of cytogeneticists, are detected with the help of modern methods of molecular biological diagnosis. The prognostic value of cytogenetic and molecular genetic markers of ALL is shown in this article. A minimal set of clinically relevant molecular markers is presented, which it is advisable to investigate with ALL.

Keywords: acute lymphoblastic leukemia, chromosomal aberration, chimeric oncogene, gene expression, gene mutation.

Received: December 3, 2016

Accepted: March 8, 2017

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Bone Marrow Transplantation in Patients with Acute Lymphoblastic Leukemia with Extremely Poor Prognosis: Literature Review and Case Report

NN Subbotina, AV Popa, IS Dolgopolov, VK Boyarshinov, RI Pimenov, VV Dailidite, GL Mentkevich

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Natal’ya Nikolaevna Subbotina, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-45-08; e-mail: natik-23@yandex.ru

For citation: Subbotina N.N., Popa A.V., Dolgopolov I.S., Boyarshinov V.K., Pimenov R.I., Dailidite V.V., Mentkevich G.L. Bone Marrow Transplantation in Patients with Acute Lymphoblastic Leukemia with Extremely Poor Prognosis: Literature Review and Case Report. Klin. Onkogematol. 2015; 8(3): 331-6. (In Russ.)


ABSTRACT

The difference in the survival rate between patients receiving the chemotherapy alone and those receiving the chemotherapy with hematopoietic stem cell transplantation (HSCT) becomes more significant with the increased number of acute lymphoblastic leukemia (ALL) risk factors. Myeloablative conditioning regimens remain a gold standard before HSCT in children and young adults with ALL. The traditional TBI-CPM based conditioning regimen followed by HSCT from related HLA identical donor demonstrates the highest survival rates. The survival rate of patients with ALL relapses after allogeneic HSCT remains low. The second HSCT is the only possible therapeutic option that provides a longer survival rate for not more than 10–15 % of patients. Delayed relapses after the first HSCT and patient’s age less than 10 y.o. are statistically significant factors of a better prognosis. The article describes author’s own experience in the management of an ALL high-risk group patients who have undergone chemotherapy, 3 allogeneic related HSCT with involvement of several donors, as well as an additional transfusion of peripheral blood stem cells obtained from the second HLA matching donor. The patient remains under medical supervision in the N.N. Blokhin Russian Cancer Research Center by the date of composition of this paper (23 months after a haploidentical HSCT).


Keywords: acute lymphoblastic leukemia, extremely poor prognosis, hematopoietic stem cell transplantation, conditioning regimen.

Received: March 3, 2015

Accepted: June 3, 2015

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