non-Hodgkin’s lymphomas

Carmustine in the Therapy of B-Cell Lymphomas

AUTOIMMUNE THROMBOCYTOPENIA , , ,

DA Koroleva, EE Zvonkov

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

For correspondence: Daria Aleksandrovna Koroleva, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-44-72; e-mail: koroleva_12-12@mail.ru

For citation: Koroleva DA, Zvonkov EE. Carmustine in the Therapy of B-Cell Lymphomas. 2021;14(4):496–502. (In Russ).

DOI: 10.21320/2500-2139-2021-14-4-496-502

ABSTRACT

Aim. To analyze the efficacy and toxicity of different high-dose chemotherapy protocols for the purpose of determining the optimal conditioning regimen with autologous hematopoietic stem cell transplantation (auto-HSCT).

Materials & Methods. The present review provides the analysis of some comparative retrospective studies. The evidence-based analysis proceeded in two stages consisting of a search and then primary processing of available literature. The PubMed database was searched for publications for the period 2004–2020.

Results. In relapsed and refractory non-Hodgkin’s lymphomas as well as in Hodgkin’s lymphoma, the literature analysis demonstrated satisfactory efficacy of carmustine as part of BEAM conditioning. With the use of the BEAM conditioning regimen with subsequent auto-HSCT, up to 50 % of complete remissions were achieved in patients with non-Hodgkin’s lymphomas and up to 70 % in patients with Hodgkin’s lymphoma. Comparative studies show that despite concerns about severe toxicity, the use of carmustine was not associated with an increase in the incidence of adverse events. Lung and liver toxicity proved to be comparable with that of being observed while using alternative programs of high-dose chemotherapy and corresponded to 9 % and 6 % on LEAM and BEAM regimens, respectively. Besides, carmustine feasibility in primary diffuse large B-cell CNS lymphoma was considered and analyzed in the context of the lack of thiotepa.

Conclusion. High efficacy of carmustine as part of BEAM conditioning with subsequent auto-HSCT was proved in extremely unfavorable patients with relapsed and refractory non-Hodgkin’s lymphomas and Hodgkin’s lymphoma with an acceptable toxicity profile. The study of carmustine in the therapy of primary CNS lymphoma seems to be аn important area of clinical studies aimed at developing rational treatment options.

Keywords: carmustine, non-Hodgkin’s lymphomas, Hodgkin’s lymphoma, auto-HSCT, lomustine, thiotepa, primary diffuse large B-cell CNS lymphoma.

Received: July 15, 2021

Accepted: September 10, 2021

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REFERENCES

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Stable Chronology of Granulopoiesis under R(G)-DHAP Immunochemotherapy-Induced Cytotoxic Stress in Non-Hodgkin’s Lymphomas

AUTOIMMUNE THROMBOCYTOPENIA , , , ,

In memory of Academician A.I. Vorob’ev,
Russian Academy of Medical Sciences and Russian Academy of Sciences

KA Sychevskaya, SK Kravchenko, FE Babaeva, AE Misyurina, AM Kremenetskaya, AI Vorob’ev

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

For correspondence: Kseniya Andreevna Sychevskaya, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(910)409-79-44; e-mail: sychevskaya-ka@yandex.ru

For citation: Sychevskaya KA, Kravchenko SK, Babaeva FE, et al. Stable Chronology of Granulopoiesis under R(G)-DHAP Immunochemotherapy-Induced Cytotoxic Stress in Non-Hodgkin’s Lymphomas. Clinical oncohematology. 2021;14(2):204–19. (In Russ).

DOI: 10.21320/2500-2139-2021-14-2-204-219

ABSTRACT

Background. Chronology of granulopoiesis based on periodic hematopoiesis model has been thoroughly studied. However, the pattern of influence of chemotherapy- and immunotherapy-induced cytotoxic stress on the development rhythm of a stem cell requires further investigation. The interaction of antitumor drugs with normal hematopoietic cells is relevant for assessing the intensity of chemotherapy adverse events. Besides, there is a demand for studying hematopoiesis under cytotoxic stress to predict immunological reactivity as a condition for efficacy of immunotherapeutic agents, the effect of which is based on cell immunity.

Aim. To study the chronological pattern of leukocyte count dynamics after R(G)-DHAP immunochemotherapy in non-Hodgkin’s lymphomas.

Materials & Methods. The dynamics of leukocyte count changes after R(G)-DHAP immunochemotherapy was analyzed using the data of 39 treatment courses in 19 non-Hodgkin’s lymphomas patients. After 18 out of 39 cycles of treatment granulocyte colony-stimulating factor (G-CSF) was administered to prevent granulocytopenia, in other cases the previously planned hematopoietic stem cell mobilization was performed according to the accepted protocol.

Results. Time to activation of spontaneous granulopoiesis depends neither on G-CSF stimulation, nor on the total dose of growth-stimulating factor and corresponds on average to Day 10 or Day 11 of the break from the last day of immunochemotherapy. The tendency of shorter agranulocytosis duration on prophylactic use of G-CSF is associated with transient hyperleukocytosis at an early stage after completing immunochemotherapy. Regimens with platinum-based drugs, like R(G)-DHAP, are suggested to be combined with immunochemotherapeutic agents in patients with the failure of first-line chemotherapy. The time interval preceding myelopoiesis activation within the first days of the break between the courses is likely to contribute to the initiation of treatment with immunotherapeutic drugs after second-line chemotherapy.

Conclusion. The determination of granulopoiesis dynamics under R(G)-DHAP immunochemotherapy-induced cytotoxic stress enables to plan the optimum G-CSF regimen and to predict the optimum timing of immune antitumor effect combined with chemotherapy.

Keywords: periodic hematopoiesis, mathematical hematopoiesis model, non-Hodgkin’s lymphomas, chemotherapy, immunotherapy, G-CSF, antitumor immunity, R(G)-DHAP.

Received: November 15, 2020

Accepted: February 25, 2021

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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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Prognostic Significance of Thymidine Kinase-1 versus β2-Microglobulin and Lactate Dehydrogenase in Lymphoproliferative Diseases

LYMPHOID TUMORS , , , ,

N.K. Parilova1, N.S. Sergeeva1,2, N.V. Marshutina1, N.G. Tyurina1, I.S. Meisner2

1 P.A. Hertzen Moscow Cancer Research Institute, a branch of the National Medical Research Radiological Center under the Ministry of Health of the Russian Federation, 3 Botkinskii pr-d, Moscow, Russia 125284

2 N.I. Pirogov Russian National Research Medical University under the Ministry of Health of the Russian Federation, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

For correspondence: Natal’ya Konstantinovna Parilova, junior researcher, 3 2nd Botkinskii pr-d, Moscow, Russia, 125284; Tel.: + 7(495)945-74-15; e-mail: parilochka@mail.ru.

For citation: Parilova NK, Sergeeva NS, Marshutina NV, et al. Prognostic Significance of Thymidine Kinase-1 versus b2-Microglobulin and Lactate Dehydrogenase in Lymphoproliferative Diseases. Clinical oncohematology. 2016;9(1):6–12 (In Russ).

DOI: 10.21320/2500-2139-2016-9-1-6-12

ABSTRACT

Background & Aims. Lactate dehydrogenase (LDH) and b2-microglobulin (b2-MG) are usually detected as serological tumor markers (TM) in malignant lymphoproliferative diseases (LPD); however, their use in monitoring of chemotherapy (CT) is limited due to their low sensitivity and specificity. The aim of this paper is to evaluate the prognostic value of baseline levels of thymidine kinase-1 (TK-1) versus b2-MG and LDH in patients with non-Hodgkin’s lymphomas (NHL) and Hodgkin’s lymphoma (HL) and to assess their clinical significance of changes in these parameters during CT as criteria of its effectiveness.

Methods. TK-1, b2-MG and LDH levels were evaluated in 61 NHL patients and 34 HL patients at baseline and after each subsequent CT cycle. The average age of patients enrolled in the study was 42.5 years (range 18–77 years). Of them 45 were men and 50 were women. Marker levels were determined in serum using the following tests: enzyme-linked immunosorbent assay (ELISA) for TK-1, immunoturbidimetry for b2-MG, and biochemical method for LDH. Discriminatory levels specified by test-system manufacturers were used in calculations: 50 DU/l for TK-1, 800–2400 mg/l for b2-MG, and 225–450 U/l for LDH.

Results. The study demonstrated that lower baseline levels of all three TM were associated with higher probability of complete or partial remission, and the statistical difference was higher. Baseline levels of TK-1 < 150 DU/l and b2-MG < 2200 mg/l may serve as prognostic factors of higher probability of achievement of complete or partial remission.

Conclusion. 4-fold increase in TK-1 serum activity from baseline after the 1st course of CT can predict the effectiveness of antitumor therapy. At the same time, no significant associations between b2-MG and LDH serum levels changes during the treatment and efficacy of the treatment were found.

Keywords: thymidine kinase-1, b2-microglobulin, lactate dehydrogenase, Hodgkin’s lymphoma, non-Hodgkin’s lymphomas.

Received: June 17, 2015

Accepted: November 3, 2015

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REFERENCES

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  10. Парилова Н.К., Сергеева Н.С., Тюрина Н.Г. и др. Сывороточные уровни тимидинкиназы-1 (ТК-1) у больных с лимфопролиферативными заболеваниями. Онкология. Журнал им. П.А. Герцена. 2012;1:33–8.
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Modern Aspects of Diagnosis and Treatment of Complicated Forms of Non-Hodgkin’s Lymphomas of Small and Large Intestine

LYMPHOID TUMORS , , , ,

OA Malikhova, AO Tumanyan, VA Shalenkov, AG Malikhov, YuP Kuvshinov, GV Ungiadze

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

For correspondence: Ol’ga Aleksandrovna Malikhova, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-43-27; e-mail: malikhova@inbox.ru

For citation: Malikhova OA, Tumanyan AO, Shalenkov VA, et al. Modern Aspects of Diagnosis and Treatment of Complicated Forms of Non-Hodgkin’s Lymphomas of Small and Large Intestine. Clinical oncohematology. 2015;8(2):129–35 (In Russ).

ABSTRACT

Background & Aims. Lymphomas constitute 5 to 10 % of gastrointestinal tumors and most of them are non-Hodgkin’s lymphomas (NHLs). They constitute 30–45 % of all extranodal NHLs. Primary involvement of the gastrointestinal tract is observed in 2/3 of patients. The objective of this study is to determine clinical and morphological features and treatment outcomes of complicated forms of NHLs of the small and large intestine.

Methods. NHLs of the small and large intestine were studied in 189 patients treated in the N.N. Blokhin Russian Cancer Research Center within the period of 1985–2010. Large intestine involvement was observed in 64 patients and small intestine involvement in 125 patients.

Results. Surgical interventions for ileus, bleeding or perforation of a hollow organ were performed in 92 patients with primary or secondary involvement of the small and large intestine (48.7 %). The intestine involvement was primary in 58.9 % of cases and secondary in 41.0 % of cases.

Conclusion. Complications of gastrointestinal NHLs deteriorate the overall survival rate. Patients with small or large intestine involvement require a special approach to diagnosis and treatment because of a high risk of surgical complications.

Keywords: lymphoma, small intestine, large intestine, oncohematology, non-Hodgkin’s lymphomas.

Received: January 30, 2014

Accepted: February 12, 2015

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