acute lymphoblastic leukemia

Pharmacoeconomic Analysis of CAR-T Cell Therapy in Diffuse Large B-Cell Lymphoma and B-Lineage Acute Lymphoblastic Leukemias

AUTOIMMUNE THROMBOCYTOPENIA

IV Gribkova, AA Zavyalov

Research Institute of Healthcare and Medical Management, 9 Sharikopodshipnikovskaya ul., Moscow, Russian Federation, 115088

For correspondence: Irina Vladimirovna Gribkova, PhD in Biology, 9 Sharikopodshipnikovskaya ul., Moscow, Russian Federation, 115088; Tel.: +7(916)078-73-90; e-mail: igribkova@yandex.ru

For citation: Gribkova IV, Zavyalov AA. Pharmacoeconomic Analysis of CAR-T Cell Therapy in Diffuse Large B-Cell Lymphoma and B-Lineage Acute Lymphoblastic Leukemias. Clinical oncohematology. 2022;15(2):205–12. (In Russ).

DOI: 10.21320/2500-2139-2022-15-2-205-212

ABSTRACT

Genetically modified Т-lymphocytes with chimeric antigen receptors (CAR-T cells) represent a new treatment strategy in relapsed/refractory B-cell malignant neoplasms. In 2017–2018 two CAR-T cell drugs, tisagenlecleucel and axicabtagene ciloleucel, were approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for clinical use in patients with refractory acute lymphoblastic leukemia and relapsed/refractory B-cell lymphomas. Due to its high efficacy, CAR-T cell therapy is increasingly becoming an integral part of clinical practice. However, this method of chemotherapy is very expensive. The mean cost of tisagenlecleucel is $475,000 and that of axicabtagene ciloleucel is $373,000. It is worth noting that these are only the drug prices which exclude other therapy-related costs. In the studies of 2018–2020 groups of researchers attempted to estimate the CAR-T cell therapy-associated costs. The aim of the present review is to analyze these studies and to assess the total treatment cost and expense structure, as well as to discuss the factors underlying the increasing costs and to explore opportunities to improve availability of the CAR-T technology, on the whole. The results showed that the mean cost of tisagenlecleucel therapy in B-cell lymphoma was $515,150 and that of axicabtagene ciloleucel therapy was $503,955. The treatment cost in acute lymphoblastic leukemia was $580,459. The major factors affecting the total therapy cost were CAR-T cell drug prices, severity of adverse events, and high tumor load prior to CAR-T cell drug infusion. It is agreed that the main opportunities to rise affordability of the CAR-T cell therapy lie in reducing the drug prices (for example, by means of medical facility-based production at its own expense), further therapy improvement aimed at less toxicity, and its implementation at earlier stages of tumor disease.

Keywords: B-cell lymphoma, acute lymphoblastic leukemia, CAR-T cell therapy, chimeric antigen receptor, tisagenlecleucel, axicabtagene ciloleucel, costs, review.

Received: October 29, 2021

Accepted: February 15, 2022

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Protocol ALL-IC BFM 2002: Outcomes of Pediatric Acute Lymphoblastic Leukemia Treatment under Multi-Center Clinical Trial

AUTOIMMUNE THROMBOCYTOPENIA ,

TT Valiev1, MA Shervashidze1, IV Osipova2, TI Burlutskaya3, NA Popova4, NS Osmulskaya5, GA Aleskerova6, SL Sabantsev7, ZS Gordeeva7, VYu Smirnov8, OA Poberezhnaya8, SN Yuldasheva9, IA Babich10, NA Batmanova1, SR Varfolomeeva1

1 Research Institute of Pediatric Oncology and Hematology, NN Blokhin National Medical Cancer Research Center, 23 Kashirskoye sh., Moscow, Russian Federation, 115478

2 Pediatric Republican Clinical Hospital of Tatarstan, 140 Orenburgskii trakt, Kazan, Russian Federation, 420138

3 Pediatric Regional Clinical Hospital, 44 Gubkina ul., Belgorod, Russian Federation, 308036

4 Volgograd Regional Clinical Oncology Dispensary, 78 Zemlyachki ul., Volgograd, Russian Federation, 400138

5 Regional Pediatric Clinical Hospital, 77 Kuibysheva ul., Omsk, Russian Federation, 644001

6 Azerbaijan National Center for Oncology, 79b G. Zardabi ul., Baku, Azerbaijan, AZ1011

7 LI Sokolova Ioshkar-Ola Pediatric Municipal Hospital, 104 Volkova ul., Ioshkar-Ola, Russian Federation, 424004

8 Kaluga Regional Clinical Pediatric Hospital, 1 Vishnevskogo ul., Kaluga, Russian Federation, 248007

9 VK Gusak Institute of Emergency and Reconstructive surgery, 47 Leninskii pr-t, Donetsk, Donetsk People’s Republic, 83003

10 Regional Pediatric Hospital, 311 Lenina ul., Yuzhno-Sakhalinsk, Russian Federation, 693006

For correspondence: Prof. Timur Teimurazovich Valiev, MD, PhD, 23 Kashirskoye sh., Moscow, Russian Federation, 115478; e-mail: timurvaliev@mail.ru

For citation: Valiev TT, Shervashidze MA, Osipova IV, et al. Protocol ALL-IC BFM 2002: Outcomes of Pediatric Acute Lymphoblastic Leukemia Treatment under Multi-Center Clinical Trial. Clinical oncohematology. 2022;15(2):119–29. (In Russ).

DOI: 10.21320/2500-2139-2022-15-2-119-129

ABSTRACT

Background. Programs of pediatric acute lymphoblastic leukemia (ALL) treatment, developed by the BFM (Berlin-Frankfurt-Munster) Group in 2002, remain one the most effective in the world. Long-term (10–15 years) overall survival in ALL children is above 90 %. Great progress in ALL treatment provided ground for including the ALL-IC BFM 2002 protocol into the Clinical Guidelines in 2020 (ID: 529).

Aim. To present the outcomes of ALL treatment in children according to ALL-IC BFM 2002 under the multi-center clinical trial.

Materials & Methods. From 01.11.2003 to 12.10.2021 the multi-center retrospective-prospective trial included 433 patients with newly diagnosed ALL, aged between 3 months and 21 years. The patients were aged from 0 to 12 (n = 344), from 12 to 18 (n = 70), and older than 12 years (n = 19). All of them were treated with ALL-IC BFM 2002. Overall (OS), disease-free (DFS), and event-free (EFS) survivals were estimated as of 01.12.2021.

Results. In the vast majority of patients (97.9 %, n = 424) complete clinical hematological remission was reached by Day 33 of the ALL-IC BFM 2002 treatment. The 10-year OS was 91.8 ± 1.5 %, DFS was 87.4 ± 1.8 %, and EFS was 84.1 ± 1.9 %. The 10-year OS in the groups of standard- and intermediate-risk patients was 92.8 ± 1.7 % and 94.6 ± 2.6 %, respectively, whereas in high-risk ALL relapse patients it was 71.1 ± 11.1 %.

Conclusion. The ALL-IC BFM 2002 protocol for treating pediatric ALL is reproducible in federal and regional clinics. The outcomes of the ALL-IC BFM 2002 treatment appeared to be impressive. They are comparable to those achieved in leading European and American clinics. To improve survival of high-risk patients, additional stratifying criteria are required, one of which should be the assessment of minimal residual disease (MRD). MRD detection became a basis for prognostic risk stratification under ALL-IC BFM 2009, the results of which will be presented in 2022–2023.

Keywords: acute lymphoblastic leukemia, treatment, ALL-IC BFM 2002, children.

Received: January 17, 2022

Accepted: March 25, 2022

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Use of Blinatumomab in Acute Lymphoblastic Leukemia in Municipal Healthcare: A Case Report

AUTOIMMUNE THROMBOCYTOPENIA , ,

VA Shuvaev1,2, OV Ushakova1, EI Mullo1, TV Tolstykh1, NZ Triputen1

1 VV Veresaev Municipal Clinical Hospital, 10 Lobnenskaya str., Moscow, Russian Federation, 127644

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

For correspondence: Vasilii Anatolevich Shuvaev, MD, PhD, 10 Lobnenskaya str., Moscow, Russian Federation, 127644; e-mail: shuvaev77@mail.ru

For citation: Shuvaev VA, Ushakova OV, Mullo EI, et al. Use of Blinatumomab in Acute Lymphoblastic Leukemia in Municipal Healthcare: A Case Report. Clinical oncohematology. 2021;14(2):198–203. (In Russ).

DOI: 10.21320/2500-2139-2021-14-2-198-203

ABSTRACT

Acute lymphoblastic leukemia is one of the groups of most challenging malignant neoplasms of hematopoietic tissue. Despite the success in achieving remission induction in primary patients, later, most of them develop disease relapses. Overall and disease-free survivals have to be improved, which cannot be achieved solely with chemotherapy intensification. The new target drugs and cell technologies improve the treatment options for the resistant forms and relapses of acute lymphoblastic leukemia. The effective use of new drugs presupposes their timely assignment which can be ensured by their availability in routine clinical practice. The provided case report describes the successful use of bispecific antibody blinatumomab for treating an early relapse of acute lymphoblastic leukemia in the clinical practice within the municipal healthcare system.

Keywords: acute lymphoblastic leukemia, clinical practice, target therapy, blinatumomab.

Received: September 22, 2020

Accepted: February 3, 2021

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  9. BLINCYTO® (blinatumomab) for injection, for intravenous use. Initial U.S. approval: 2014. Available from: https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/blincyto/blincyto_pi_hcp_english.pdf. (accessed 21.09.2020).
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  11. Martinelli G, Boissel N, Chevallier P, et al. Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. J Clin Oncol. 2017;35(16):1795–802. doi: 10.1200/jco.2016.69.3531.
  12. von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase 1/2 Study in Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Receiving Blinatumomab Treatment. Blood. 2014;124(21):2292. doi: 10.1182/blood.V124.21.2292.2292.
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  14. Topp MS, Gokbuget N, Zugmaier G, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32(36):4134–40. doi: 10.1200/jco.2014.56.3247.
  15. 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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  20. Geyer MB, Hsu M, Devlin SM, et al. Overall survival among older US adults with ALL remains low despite modest improvement since 1980: SEER analysis. Blood. 2017;129(13):1878–81. doi: 10.1182/blood-2016-11-749507.
  21. Бондаренко С.Н., Паровичникова Е.Н., Масчан А.А. и др. Блинатумомаб в терапии острого лимфобластного лейкоза: Российское многоцентровое исследование. Клиническая онкогематология. 2019;12(2):145–53. doi: 10.21320/2500-2139-2019-12-2-145-153.
    [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. (In Russ)]
  22. Markova IV, Bondarenko SN, Paina OV, et al. Features of response to blinatumomab and inotuzumab ozogamicin therapy in patients with relapse/refractory B-cells acute lymphoblastic leukemia in real clinical practice. Cell Ther Transplant. 2020;9(1):47–52. doi: 10.18620/ctt-1866-8836-2020-9-1-47-52.

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

COMPLICATIONS OF ANTITUMOR TREATMENT , , , , , , ,

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; p = 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 (p = 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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    [Zharkov PA, Rumyantsev AG, Novichkova GA. Venous thromboembolism in children with cancer. Russian Journal of Pediatric Hematology and Oncology. 2015;2(1):66–74. doi: 10.17650/2311-1267-2015-1-66-74. (In Russ)]

  2. Raetz EA, Salzer WL. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2010;32(7):554–63. doi: 10.1097/mph.0b013e3181e6f003.

  3. Payne JH, Vora AJ. Thrombosis and acute lymphoblastic leukemia. Br J Haematol. 2007;138(4):430–45. doi: 10.1111/j.1365-2141.2007.06677.x.

  4. Athale UH, Laverdiere C, Nayiager T, et al. Evaluation for inherited and acquired prothrombotic defects predisposing to symptomatic thromboembolism in children with acute lymphoblastic leukemia: a protocol for a prospective, observational, cohort study. BMC Cancer. 2017;17(1):313. doi: 10.1186/s12885-017-3306-5.

  5. Tuckuviene R, Ranta S, Albertsen BK, et al. Prospective study of thromboembolism in 1038 children with acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology (NOPHO) study. J Thromb Haemost. 2016;14(3):485–94. doi: 10.1111/jth.13236.

  6. Caruso V, Iacoviello L, Di Castelnuovo A, et al. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood, 2006;108(7):2216–22. doi: 10.1182/blood-2006-04-015511.

  7. Mitchell L, Lambers M, Flege S, et al. Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study. 2010;115(24):4999–5004. doi: 10.1182/blood-2010-01-263012.

  8. Appel IM, Hop WCJ, van Kessel-Bakvis C, et al. L-Asparaginase and the effect of age on coagulation and fibrinolysis in childhood acute lymphoblastic leukemia. Thromb Haemost. 2008;100(08):330–7. doi: 10.1160/th07-10-0620.

  9. Kearon С, Akl E, Ornelas J, et al. Antithrombotic Therapy for VTE Disease. CHEST Guideline and Expert Panel Report. CHEST. 2016;149 (2):315–52. doi: 10.1016/j.chest.2015.11.026.

  10. Carrier M, Khorana AA, Zwicker JI, et al. Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. J Thromb Haemost. 2013;11(9):1760–5. doi: 10.1111/jth.12338.

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  13. Babilonia KM, Golightly LK, Gutman JA, et al. Antithrombotic Therapy in Patients With Thrombocytopenic Cancer: Outcomes Associated With Reduced-Dose, Low-Molecular-Weight Heparin During Hospitalization. Clin Appl Thromb Hemost. 2014;20(8):799–806. doi: 10.1177/1076029614543140.

  14. Dmitriev Nadroparin and dalteparin pharmacokinetics in thromboses complicated the treatment of children with oncological diseases. The Book of Abstracts The Congress on Open Issues in Thrombosis and Hemostasis 2018 jointly with the 9th Russian Conference on Clinical Hemostasiology and Hemorheology, Saint Petersburg, Russia October 4–6, 2018. pp 60.

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

LYMPHOID TUMORS ,

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

  1. Gokbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. 2012;120(10):2032–41. doi: 10.1182/blood-2011-12-399287.

  2. Faderl S, O’Brien S, Pui C-H, et al. Adult Acute Lymphoblastic Leukemia. Cancer. 2010;116(5):1165–76. doi: 10.1002/cncr.24862.

  3. Gokbuget N, Dombret H, Ribera J-M, et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractor y acute lymphoblastic leukemia. Haematologica. 2016;101(12):1524–33. doi: 10.3324/haematol.2016.144311.

  4. Pavlu J, Labopin M, Zoellner AK, et al. Allogeneic Hematopoietic Cell Transplantation for Primary Refractory Acute Lymphoblastic Leukemia: A Report From the Acute Leukemia Working Party of the EBMT. Cancer. 2017;123(11):1965–70. doi: 10.1002/cncr.30604.

  5. Bondarenko SN, Moiseev IS, Slesarchuk OA, et al. Allogeneic hematopoietic stem cell transplantation in children and adults with acute lymphoblastic leukemia. Cellular Therapy and Transplantation. 2016;5(2):12–20. doi: 10.18620/1866-8836-2016-5-2-12-20.

  6. Паровичникова Е.Н., Соколов А.Н., Троицкая В.В. и др. Острые Ph-негативные лимфобластные лейкозы взрослых: факторы риска при использовании протокола ОЛЛ-2009. Терапевтический архив. 2016;88(7):15–24.

    [Parovichnikova EN, Sokolov AN, Troitskaya VV, et al. Acute Ph-negative lymphoblastic leukemias in adults: Risk factors in the use of the ALL-2009 protocol. Terapevticheskii arkhiv. 2016;88(7):15–24. (In Russ)]

  7. Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest. 2007;117(5):1137–46. doi: 10.1172/jci31405.

  8. Biagi E, Marin V, Attianese GM, et al. Chimeric T-cell receptors: new challenges for targeted immunotherapy in hematologic malignancies. Haematologica. 2007;92(3):381–8. doi: 10.3324/haematol.10873.

  9. Klinger M, Brandl C, Zugmaier G, et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell–engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood. 2012;119(26):6226–33. doi: 10.1182/blood-2012-01-400515.

  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.

  11. Gokbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522–31. doi: 10.1182/blood-2017-08-798322.

  12. Kantarjian H, Stein AS, Gokbuget N, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017;376(9):836–47. doi: 10.1056/NEJMoa1609783.

  13. Zugmaier G, Gokbuget N, Klinger M, et al. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015;126(24):2578–84. doi: 10.1182/blood-2015-06-649111.

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

EXPERIMENTAL STUDIES , , , , , ,

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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REFERENCES

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

LYMPHOID TUMORS , ,

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

BONE MARROW TRANSPLANTATION , ,

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: p < 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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Cytogenetic and Molecular Genetic Prognostic Factors of Acute Lymphoblastic Leukemias

REVIEWS , , , ,

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

BONE MARROW TRANSPLANTATION , , ,

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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