Клинический случай

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Introduction

Haploidentical HSCT is the established option for high-risk acute lymphoblastic leukemia in absence of HLA-identical donors [1]. However, relapse after haplo-HSCT has limited options for cure [2]. Second transplantation could be effective in patients that achieved remission [3]. The currently available immunotherapies, e.g., blinatumomab, a bispecific T-cells engager (BITE) antibody, or conjugate antibody inotuzumab ozogamicin have provided curative strategy in some patients to achieve remission before second haplo-HSCT with acceptable toxicity. Blinatumomab and inotuzumab ozogamicin demonstrate comparable CR rates, with a trend for blinatumomab administration in the setting of low-level residual disease, or lower marrow blast percentages without CNS involvement. Inotuzumab ozogamicin is effective regardless of blast counts [4, 5]. Despite these encouraging results, patients refractory to immunotherapy have poor prognosis [6].

Case description

Figure 1. Blood lymphocyte counts: time course following 1^st and 2^nd transplant (for details see text)

A young man aged 15 years old was diagnosed with B-ALL, isolated marrow involvement, in September, 2015. Cytogenetic test revealed 53XY, no molecular abnormalities found. The patient was treated according to the National ALL-MB2015 protocol, and morphological remission was reached after first induction cycle. The protocol was completed in December 2017. BM relapse with the same karyotype was documented 8 months later, in August 2018. The treatment proceeded by ALL-REZ-BFM-2002 protocol. Second morphologic remission was achieved after the first cycle. In December 2018, the patient was referred to the transplant center, and multicolor flow cytometry of leukocytes showed minimal residual disease at 1.8%. HLA-identical donor search was unsuccessful, and, therefore, allo-HSCT from haploidentical father was performed 11.12.2018. Myeloablative conditioning regimen included Fludarabine, Treosulfan and Tiotepa. GvHD prophylaxis was performed with ex vivo TCR αβ depletion. Engraftment with complete donorchimerism and MRD negativity was reached at day+11. However, lymphopenia of moderate to severe grade persisted over this period (Fig. 1).

In May 2019, bone marrow (BM) examination has revealed 64% of blasts with CD45dim/CD19+/CD10+/CD34+/CD38-/CD22+/
CD20- phenotype. The indexes of cerebrospinal fluid were normal, no extramedullar lesions were found. Blinatumomab was administered as a prolonged 4-week infusion after a pre-phase with cyclophosphamide treatment at a dose of 200 mg/kg. The therapy was well tolerated, in absence of non-hematologic toxicity. BM examination revealed 89% of blasts with CD45dim/CD19+/CD10+/CD34-/CD38+/CD22+/CD20- phenotype ten days later. Inotuzumab ozogamicin was administered at the doses of 1.8, 0.8 and 0.5 mg/m² weekly. Inotuzumab treatment was well tolerated, without non-hematologic toxicity, thrombocytopenia grade 2 and neutropenia grade 4 proved to be reversible. Complete BM remission was achieved, and MRD was negative.

Allogeneic stem cell transplantation from haploidentical mother was performed 05.09.2019., four weeks after finishing Inotuzumab therapy. Conditioning regimen with reduced toxicity included Fludarabine and Busulfan 10 mg/kg. GvHD prophylaxis was performed with posttransplant cyclophosphamide, tacrolimus, mycophenolate mofetil. Engraftment was documented on the day+23, with complete donor chimerism and MRD negativity. No signs of sinusoidal occlusive syndrome were observed, and no acute GvHD occurred. Tacrolimus was discontinued by D+100. After 9 months of follow up, the patient is in complete MRD-negative remission with mild cGvHD, without any systemic medications.

Discussion

Haploidentical hematopoietic stem cell transplantation with ex vivo TCR αβ depletion is a novel approach aimed to reduce graft failure, graft-versus-host disease (GvHD) rate, and non-relapse mortality (NRM) in patients lacking HLA-indentical donor. However, high relapse rate and delayed immune reconstitution remain the principal disadvantages of this method [7]. Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to link T cells and CD19-positive B cells, which allows the patient’s endogenous T cells to recognize and eliminate CD19-positive ALL blasts [8]. Blinotumomab is highly effective in R/R ALL patients with 69% of complete remission (CR), or with incomplete hematologic recovery achieved even after alloHSCT [4, 9-10]. Jabbour et al. reported 68 patients with R/R B-cell ALL with blinatumomab failure, 38 (56%) of them was initially refractory to this treatment [11]. The mechanism of refractory disease is not clear. Among the blinatumomab-refractory patients, only one patient lost CD19 expression, and a decrease in CD19 expression was found in two cases. Among the relapsed patients who initially responded, four patients have lost CD19 expression. After blinatumomab failure, the overall response rate to inotuzumab ozogamicin was 77% (10/13).

Another mechanism of resistance may be a lineage switch after blinatumomab treatment reported in several cases [12, 13]. Functional immune system is also required for benefit of blinatumomab [14]. The possible reason of blinatumomab failure in our case was low absolute lymphocyte count was 0.9×10⁹, with 35% of CD3+ cells that are required for blinatumomab action (Fig. 1). Along with quantitative abnormalities, the repertoire of T-cells is significantly skewed after TCR αβ depletion, than after conventional prophylaxis [15]. Inotuzumab ozogamicin is a monoclonal antibody conjugated to cytotoxic agent, it works regardless tumor burden [16]. It doesn’t require lymphocytes to mediate its pharmacological activity. Further accumulation of clinical data should facilitate better decision-making for different modes of immunotherapy in R/R B-cell ALL.

Conflict of interest

None declared.

References

Santoro N, Ruggeri A, Labopin M, Bacigalupo A, Ciceri F, Gülbaş Z, Huang H, Afanasyev B, Arcese W et al. Unmanipulated haploidentical stem cell transplantation in adults with acute lymphoblastic leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT. Journal of Hematology & Oncology. 2017; 10:113.
Gökbuget N, Dombret H, Ribera JM, Fielding AK, Advani A, Bassan R, Chia V, Doubek M, Giebel S, Hoelzer D et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2016;101(12):1524-1533.
Kozhokar P, Paina O, Frolova A, Rakhmanova Zh, Borovkova A, Semenova E, Osipova A, Ekushov K, Ovechkina V, Babenko E, Vitrishchak A, Smirnov B et al. Efficiency of second allogeneic HSCT in the children with acute leukemias with relapses after first transplantation. Cell Ther Transplant. 2019; 8(4): 33-40.
Kantarjian H, Stein A, Gökbuget N, Fielding A, Schuh A, Ribera JM, Wei A, Dombret H, Foà R, Bassan R et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017; 376(9): 836-847.
Kantarjian H, De Angelo D, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien S, Jabbour E, Wang T, Liang et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATEstudy. Cancer. 2019;125(14): 2474-2487.
Jabbour E, O'Brien S, Ravandi F, Kantarjian H. Monoclonal antibodies in acute lymphoblastic leukemia. Blood. 2015;125(26):4010-4016.
Locatelli F, Merli P, Pagliara D, Li Pira G, Falco M, Pende D, Rondelli R, Lucarelli B, Brescia L, Masetti R et al. Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion. Blood. 2017;130:677-685.
Kantarjian H, Stein A, Gökbuget N, Fielding A, Schuh A, Ribera J, Wei A, Dombret H, Foà R, Bassan R. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017;376:836-847.
Stein AS, Kantarjian H, Gökbuget N, Bargou R, Litzow MR, Rambaldi A, Ribera J-M, Zhang A, Zimmerman Z, Zugmaier G, Topp MS et al. Blinatumomab for acute lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019; 25(8):1498-1504.
Bondarenko S, Parovichnikova E, Maschan A, Baranova O, Shelekhovas T, Doronin V, Mel'nichenko V, Kaplanov K, Uspenskaya O, Sokolov A et al. Blinatumomab in the treatment of acute lymphoblastic leukemia: Russian Multicenter Clinical Trial. Clinical Oncohematology. 2019;12(2):145-153 (In Russian).
Jabbour E, Düll J, Yilmaz M, Khoury J, Ravandi F, Jain N, Einsele H, Garcia-Manero G, Konopleva M, Short N et al. Outcome of patients with relapsed/refractory acute lymphoblastic leukemia after blinatumomab failure: no change in the level of CD19 expression. Am J Hematol. 2018; 93:371-374.
Rayes A, McMasters R, O'Brien M. Lineage switch in MLL-rearranged infant leukemia following CD19-directed therapy. Pediatr Blood Cancer. 2016; 63(6):1113-1115.
Duffner U, Abdel-Mageed A, Younge J, Tornga C, Scott K, J Staddon J, Elliott K, Stumph J, Kidd P et al. The possible perils of targeted therapy. Leukemia. 2016;30(7):1619-1621.
Schultz L, Gardner R. Mechanisms of and approaches to overcoming resistance to immunotherapy. Hematology Am Soc Hematol Educ Program. 2019 (1): 226-232.
Zvyagin IV, Mamedov IZ, Tatarinova OV, Shugay M, Sycheva AL, Kasatskaya SA, Lebedev YB, Chudakov DM, Tatarinova OV, Kurnikova EE et al. Tracking T-cell immune reconstitution after TCRαβ/CD19-depleted hematopoietic cells transplantation in children. Leukemia. 2017; 31(5):1145‐1153.
Markova IV, Bondarenko SN, Paina OV, Aubova BI, Kozhokar PV, Frolova AS, Barkhatov IM, Babenko EV, Alyanskii AA, Ekushov KA, Gindina TL, Semenova EV, Moiseev IS, Zubarovskaya LS, Afanasyev BV. 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. 2019; 9(1):47-52.

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Introduction

Case description

Figure 1. Blood lymphocyte counts: time course following 1^st and 2^nd transplant (for details see text)

Discussion

Conflict of interest

None declared.

References

Santoro N, Ruggeri A, Labopin M, Bacigalupo A, Ciceri F, Gülbaş Z, Huang H, Afanasyev B, Arcese W et al. Unmanipulated haploidentical stem cell transplantation in adults with acute lymphoblastic leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT. Journal of Hematology & Oncology. 2017; 10:113.
Gökbuget N, Dombret H, Ribera JM, Fielding AK, Advani A, Bassan R, Chia V, Doubek M, Giebel S, Hoelzer D et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2016;101(12):1524-1533.
Kozhokar P, Paina O, Frolova A, Rakhmanova Zh, Borovkova A, Semenova E, Osipova A, Ekushov K, Ovechkina V, Babenko E, Vitrishchak A, Smirnov B et al. Efficiency of second allogeneic HSCT in the children with acute leukemias with relapses after first transplantation. Cell Ther Transplant. 2019; 8(4): 33-40.
Kantarjian H, Stein A, Gökbuget N, Fielding A, Schuh A, Ribera JM, Wei A, Dombret H, Foà R, Bassan R et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017; 376(9): 836-847.
Kantarjian H, De Angelo D, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien S, Jabbour E, Wang T, Liang et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATEstudy. Cancer. 2019;125(14): 2474-2487.
Jabbour E, O'Brien S, Ravandi F, Kantarjian H. Monoclonal antibodies in acute lymphoblastic leukemia. Blood. 2015;125(26):4010-4016.
Locatelli F, Merli P, Pagliara D, Li Pira G, Falco M, Pende D, Rondelli R, Lucarelli B, Brescia L, Masetti R et al. Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion. Blood. 2017;130:677-685.
Kantarjian H, Stein A, Gökbuget N, Fielding A, Schuh A, Ribera J, Wei A, Dombret H, Foà R, Bassan R. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017;376:836-847.
Stein AS, Kantarjian H, Gökbuget N, Bargou R, Litzow MR, Rambaldi A, Ribera J-M, Zhang A, Zimmerman Z, Zugmaier G, Topp MS et al. Blinatumomab for acute lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019; 25(8):1498-1504.
Bondarenko S, Parovichnikova E, Maschan A, Baranova O, Shelekhovas T, Doronin V, Mel'nichenko V, Kaplanov K, Uspenskaya O, Sokolov A et al. Blinatumomab in the treatment of acute lymphoblastic leukemia: Russian Multicenter Clinical Trial. Clinical Oncohematology. 2019;12(2):145-153 (In Russian).
Jabbour E, Düll J, Yilmaz M, Khoury J, Ravandi F, Jain N, Einsele H, Garcia-Manero G, Konopleva M, Short N et al. Outcome of patients with relapsed/refractory acute lymphoblastic leukemia after blinatumomab failure: no change in the level of CD19 expression. Am J Hematol. 2018; 93:371-374.
Rayes A, McMasters R, O'Brien M. Lineage switch in MLL-rearranged infant leukemia following CD19-directed therapy. Pediatr Blood Cancer. 2016; 63(6):1113-1115.
Duffner U, Abdel-Mageed A, Younge J, Tornga C, Scott K, J Staddon J, Elliott K, Stumph J, Kidd P et al. The possible perils of targeted therapy. Leukemia. 2016;30(7):1619-1621.
Schultz L, Gardner R. Mechanisms of and approaches to overcoming resistance to immunotherapy. Hematology Am Soc Hematol Educ Program. 2019 (1): 226-232.
Zvyagin IV, Mamedov IZ, Tatarinova OV, Shugay M, Sycheva AL, Kasatskaya SA, Lebedev YB, Chudakov DM, Tatarinova OV, Kurnikova EE et al. Tracking T-cell immune reconstitution after TCRαβ/CD19-depleted hematopoietic cells transplantation in children. Leukemia. 2017; 31(5):1145‐1153.
Markova IV, Bondarenko SN, Paina OV, Aubova BI, Kozhokar PV, Frolova AS, Barkhatov IM, Babenko EV, Alyanskii AA, Ekushov KA, Gindina TL, Semenova EV, Moiseev IS, Zubarovskaya LS, Afanasyev BV. 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. 2019; 9(1):47-52.

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Однако прогноз пациентов, рефрактерных к блинотумумабу, неутешителен. В этом случае назначение инотузумаба озогамицина является одной из терапевтических опций. В статье представлено описание клинического случая лечения костномозгового рецидива В-ОЛЛ после гаплоидентичной алло-ТГСК у молодого мужчины. После курса терапии Блинатумомабом ремиссия не была достигнута и пациенту был назначен инотузумаба озогамицин. После одного курса терапии была получена морфологическая ремиссия без признаков минимальной остаточной болезни. Пациенту была выполнена вторая алло-ТГСК от другого гаплоидентичного донора. <h3>Заключение</h3> Представленный клинический случай демонстрирует успешный исход терапии инотузумаба озогамицином после рефрактерности к блинотумомабу при возникновении рецидива после алло-ТГСК. <h2>Ключевые слова</h2> Трансплантация гемопоэтических стволовых клеток, аллогенная, острый лимфобластный лейкоз, блинотумомаб, инотузумаб озогамицин, резистентный рецидив.</p." 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string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26518" ["VALUE"]=> array(2) { ["TEXT"]=> string(449) "Сергей Н. Бондаренко, Анна Г. Смирнова, Иван С. Моисеев, Белла И. Аюбова, Елена В. Бабенко, Ильдар М. Бархатов, Татьяна Л. Гиндина, Инна В. Маркова, Александр Д. Кулагин, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(415) "

Сергей Н. Бондаренко, Анна Г. Смирнова, Иван С. Моисеев, Белла И. Аюбова, Елена В. Бабенко, Ильдар М. Бархатов, Татьяна Л. Гиндина, Инна В. Маркова, Александр Д. Кулагин, Борис В. Афанасьев

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26520" ["VALUE"]=> array(2) { ["TEXT"]=> string(2762) "Блинатумомаб, биспецифичное моноклональное антитело, активирующее Т-клетки пациента при связывании CD3 на поверхности Т-клеток и CD19 на поверхности В-лимфобластов, высоко эффективен при лечении резистентных В-клеточных острых лимфобластных лейкозов (В-ОЛЛ) в том числе при возникновении рецидива после аллогеннной трансплантации гемопоэтических стволовых клеток крови (алло-ТГСК). Однако прогноз пациентов, рефрактерных к блинотумумабу, неутешителен. В этом случае назначение инотузумаба озогамицина является одной из терапевтических опций. В статье представлено описание клинического случая лечения костномозгового рецидива В-ОЛЛ после гаплоидентичной алло-ТГСК у молодого мужчины. После курса терапии Блинатумомабом ремиссия не была достигнута и пациенту был назначен инотузумаба озогамицин. После одного курса терапии была получена морфологическая ремиссия без признаков минимальной остаточной болезни. Пациенту была выполнена вторая алло-ТГСК от другого гаплоидентичного донора. <h3>Заключение</h3> Представленный клинический случай демонстрирует успешный исход терапии инотузумаба озогамицином после рефрактерности к блинотумомабу при возникновении рецидива после алло-ТГСК. <h2>Ключевые слова</h2> Трансплантация гемопоэтических стволовых клеток, аллогенная, острый лимфобластный лейкоз, блинотумомаб, инотузумаб озогамицин, резистентный рецидив.</p." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2653) "

Блинатумомаб, биспецифичное моноклональное антитело, активирующее Т-клетки пациента при связывании CD3 на поверхности Т-клеток и CD19 на поверхности В-лимфобластов, высоко эффективен при лечении резистентных В-клеточных острых лимфобластных лейкозов (В-ОЛЛ) в том числе при возникновении рецидива после аллогеннной трансплантации гемопоэтических стволовых клеток крови (алло-ТГСК). Однако прогноз пациентов, рефрактерных к блинотумумабу, неутешителен. В этом случае назначение инотузумаба озогамицина является одной из терапевтических опций.

В статье представлено описание клинического случая лечения костномозгового рецидива В-ОЛЛ после гаплоидентичной алло-ТГСК у молодого мужчины. После курса терапии Блинатумомабом ремиссия не была достигнута и пациенту был назначен инотузумаба озогамицин. После одного курса терапии была получена морфологическая ремиссия без признаков минимальной остаточной болезни. Пациенту была выполнена вторая алло-ТГСК от другого гаплоидентичного донора.

Заключение

Представленный клинический случай демонстрирует успешный исход терапии инотузумаба озогамицином после рефрактерности к блинотумомабу при возникновении рецидива после алло-ТГСК.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, аллогенная, острый лимфобластный лейкоз, блинотумомаб, инотузумаб озогамицин, резистентный рецидив. string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26521" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-2-67-70" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-2-67-70" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26524" ["VALUE"]=> array(2) { ["TEXT"]=> string(328) "Sergey N. Bondarenko, Anna G. Smirnova, Ivan S. Moiseev, Bella I. Ayubova, Elena V. Babenko, Ildar M. Barkhatov, Tatiana L. Gindina, Inna V. Markova, Alexander D. Kulagin, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(282) "

Sergey N. Bondarenko, Anna G. Smirnova, Ivan S. Moiseev, Bella I. Ayubova, Elena V. Babenko,
Ildar M. Barkhatov, Tatiana L. Gindina, Inna V. Markova, Alexander D. Kulagin,
Boris V. Afanasyev

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26525" ["VALUE"]=> array(2) { ["TEXT"]=> string(495) "RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia Correspondence Dr. Sergey N. Bondarenko, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia Phone: +7 (812) 338 62372 E-mail: dr.sergeybondarenko@gmail.com" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(435) "

RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia

Correspondence
Dr. Sergey N. Bondarenko, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (812) 338 62372
E-mail: dr.sergeybondarenko@gmail.com

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Blinatumomab, a bispecific T-cell engaging CD3-CD19 antibody, is highly effective in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, patients who failed with Blina have a dismal outcome. Inotuzumab ozogamicin is one of the therapeutic options after blinatumomab failure. We report a young man who exhibited bone marrow (BM) relapse of B-ALL following haploidentical stem cell transplantation (haplo-HSCT). Remission was not achieved after Blinotumomab treatment, thus Inotuzumab was administered. A complete remission with no signs of minimal residual disease was achieved after a single cycle of Inotuzumab. The second haplo-HSCT from another donor was successful.

Conclusion

The present case demonstrate an opportunity of successful inotuzumab therapy after failure of allo-HSCT and blinotumomab treatment.

Keywords

Hematopoietic stem cell transplantation, allogeneic, acute lymphoblastic leukemia, Blinotumomab, Inotuzumab ozogamicin, relapsed/refractory.

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Bondarenko, Anna G. Smirnova, Ivan S. Moiseev, Bella I. Ayubova, Elena V. Babenko, Ildar M. Barkhatov, Tatiana L. Gindina, Inna V. Markova, Alexander D. Kulagin, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(282) "

Sergey N. Bondarenko, Anna G. Smirnova, Ivan S. Moiseev, Bella I. Ayubova, Elena V. Babenko,
Ildar M. Barkhatov, Tatiana L. Gindina, Inna V. Markova, Alexander D. Kulagin,
Boris V. Afanasyev

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Conclusion

The present case demonstrate an opportunity of successful inotuzumab therapy after failure of allo-HSCT and blinotumomab treatment.

Keywords

Hematopoietic stem cell transplantation, allogeneic, acute lymphoblastic leukemia, Blinotumomab, Inotuzumab ozogamicin, relapsed/refractory.

Conclusion

The present case demonstrate an opportunity of successful inotuzumab therapy after failure of allo-HSCT and blinotumomab treatment.

Keywords

Hematopoietic stem cell transplantation, allogeneic, acute lymphoblastic leukemia, Blinotumomab, Inotuzumab ozogamicin, relapsed/refractory.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia

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Заключение

Ключевые слова

Заключение

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, аллогенная, острый лимфобластный лейкоз, блинотумомаб, инотузумаб озогамицин, резистентный рецидив. array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26519" ["VALUE"]=> array(2) { ["TEXT"]=> string(367) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(355) "

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Introduction

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. However, while only 7-8% of children with cancer are diagnosed with NB, it is responsible for about 10% of cancer-related deaths in this population [1]. As more as 50% of high-risk group patients still develop a relapse in spite of highly intensive complex therapy used [2]. The patient’s age (>18 months), along with biological characteristics (MYCN amplification, 1p deletion, tumor DNA ploidy) and disease stage, is among the factors used to determine a risk group, to which the patient belongs [3]. Also, the age over 5 years at diagnosis is one of the factors used to determine an ‘ultra-high’ risk subgroup among high-risk patients [4]. Although less than 25% of high-risk patients are older than 5 years [4], and only 3% are older than 10 years [5], this group makes a significant input into overall NB-associated mortality [6]. The "adolescent" and "adult" NB cases seem to be different in their biological characteristics from younger cohorts since very few patients have MYCN-driven high-risk tumor [5], though having other biological factors at play [7]. These tumors are often characterized by aggressive local growth with relatively few distant metastases. As they are often resistant to standard chemotherapy regimens, local control measures and other systemic options, such as immunotherapy, play a significant role [8]. The allogeneic hematopoietic stem cell transplantation from haploidentical donor (haplo-HSCT) is an effective option for primary refractory and relapsed NB patients [9] which also may be used as a ‘platform’ for further immunotherapy [10].

Here we report the results of combined treatment including a haplo-HSCT with subsequent immunotherapy in a 12-year old girl with primary refractory NB.

Case presentation

Figure 1. The therapy flow-chart

In January 2016, a 12-year-old girl was diagnosed with non MYCN-amplified metastatic NB. At the time of diagnosis the patient had pain, fever. The chest and abdominal CT have shown a large paravertebral tumor invading the spinal canal at Th10-L4 level, an abdominal lesion 247×158 mm in size growing into the psoas muscle. The urethral compression and tumor invasion into left hilum led to left-sided hydronephrosis. There were also lytic lesions in Th3-4 and L3 vertebrae. The paravertebral lesion biopsy was performed and tumor morphology corresponded to undifferentiated neuroblastoma. No MYCN amplification was revealed, 1p or 11q chromosome deletions were subsequently found. The serum NSE was 380 ng/ml, LDH 1520 U/l. The tumor was ¹²³I-metaiodobenzylguanidine (MIBG)-positive with vivid tracer accumulation in thoracic and abdominal lesions, Th3-4 and L1-4 vertebrae. The therapy according to modified GPOH NB2004 protocol for high-risk patients (6 alternating N5/N6 cycles) was started (Fig. 1). No response was achieved by CT/MRI or MIBG scan. Subsequently, additional 3 topotecan-containing N8 cycles were performed, resulting in only disease stabilization. The surgical intervention was performed, but no local control was achieved, as only partial resection was possible. As the patient was not a candidate for autologous hemopoietic stem transplantation (auto-HSCT) as a poor mobilizer and there was a negative post-surgery dynamics with abdominal tumor growing to 175×131 mm, three additional RIST (rapamycin, irinotecan, sprycel, temozolomide) cycles were performed achieving again just disease stabilization.

As none other clinical options were available, the haplo-HSCT from KIR-incompatible brother was performed as salvage therapy. Reduced-intensity conditioning regimen (fludarabine 150 mg/m², melphalan 140 mg/m²) was used. The transplant was modified via CliniMACS device (Miltenyi Biotec, Bergisch Gladbach, Germany) to deplete T-cell receptor alpha/beta positive (TCRαβ(+)) and CD19 positive (CD19(+)) cells from initial apheresis products. The basic immunosuppression consisted of mycophenolate mofetil from D-1 to D+60 as the patient received a modified transplant. Engraftment was registered on D+12. The early post-transplant period was complicated by Gr2 skin, Gr3 gut and Gr1 hepatic acute graft-versus-host disease (aGvHD) with good response to steroids and extracorporeal photopheresis (ECP). After aGvHD signs emergence, tacrolimus was added on D+16. Also, asymptomatic infection with hepatitis C virus was found with negative status achieved with subsequent specific therapy. Later on, moderate chronic GvHD was observed (skin involvement in 20% of BSA with superficial sclerosis). The patient responded to ECP and topical tacrolimus with complete regress of cGvHD signs.

Figure 2. 123I-MIBG scans prior to haplo-HSCT (A.), after anti-GD2 therapy (B.), and after 3 courses of anti-PD1 therapy (C.)

Disease restaging on D+120 have shown a good positive dynamics by MIBG scanning (see Fig. 2), although CT scan did not show any evident dynamics, and there was still a bulky abdominal and paravertebral tumor. The FDG-PET scan have shown hypermetabolic (Deauville score of 4 or 5) areas corresponding to I-MIBG positive lesions. No positive dynamics was seen during subsequent restaging on D+180. Therefore, the patient was given post-transplant immunotherapy with two courses of ch14.18/CHO (Dinutuximab beta, a GD2-targeted antibody). During each course, the drug was given at 10 mg/m2 for 10 days without parallel IL-2 infusions due to the risk of GvHD. On standard supportive therapy only mild and controllable pain was observed. Further on, 4 cycles of differentiating therapy (isotretinoin 160 mg/m² for 14 days with 14 days break) were administered. The subsequent restaging has shown positive dynamics by I-MIBG and FDG-PET scan (see Figs. 1, 2).

As the patient had no signs of GvHD at restaging and there was still a bulky metabolically active tumor, she was scheduled for additional therapy by PD-1 inhibitor nivolumab. A total of 6 nivolumab infusions were performed with starting dose of 0.5 mg/kg and subsequent doses of 1 mg/kg due to the history of GvHD. No immune complications were seen. The restaging on D+390 have shown positive dynamics on I-MIBG scan with more intensive hypermetabolic lesions on FDG-PET scan. The diagnostic tumor biopsy has shown the lesion to consist of large polymorphic cells with signs of gangliocytic differentiation. The patient received 3 additional nivolumab injections with subsequent external beam radiation therapy. The latter involved abdominal tumor (total dose of 37 Gy by 2 Gy fractions; see Fig. 3) and paravertebral lesions irradiated with stereotactic technique (up to total dose of 30 Gy by 6 Gy fractions; see Fig. 3).

Figure 3. Radiation fields for abdominal (A.) and thoracic (B., C.) residual tumor components

The subsequent restaging has shown good positive dynamics by both I-MIBG and PET scans. The patient received 6 more cycles of nivolumab at 1 mg/kg followed by differentiating therapy (3 cycles, ceased due to skin toxicity). On subsequent restaging there was a positive dynamics by MIBG scam, while FDG-avid lesions were more intensive. After another 6 cycles of nivolumab there are no I-MIBG positive lesions with only residual metabolic activity by FDG-PET scan. No further therapy was given. The patient is currently under observation 3.5 years after haplo-HSCT. No therapy was given for the last 10 months.

Discussion

Although about 20% patients with high-risk NB develop primary resistance [11], there is still no consensus on optimal therapy in this group and many patients receive treatment within clinical trials. Among these, the 4-year event-free survival (EFS) in Phase I-II COG cohort was only 6% with median time to disease progression of 58 days and 15% 4-year overall survival (OS) [12]. The meta-analysis of ITCC/SIOPEN trials data on second-line chemotherapy effectiveness in primary resistant and relapsed NB patients yields slightly better results with median EFS of 12.5 ± 6.8 months and median OS of 27.9 ± 20.2 in primary refractory cohort [13]. However, in our case, the life expectancy was much lower due to a number of highly unfavorable prognostic factors. Beside the age at diagnosis of more than 5 years, highly aggressive disease course with distant bone metastases and high initial LDH levels, which are all adverse factors according to risk score by Ladenstein R. et al. [4], there was also no response to first and second-line therapy. While our patient was ineligible for auto-HSCT, in our experience the outcomes in primary resistant patients are dismal even if they respond to 2^nd- or 3^rd-line therapy [14]. The patient described had no response to topotecan-containing N8 therapy and RIST regimen. The latter is effective in some primary resistant cases [15], but not in the case described. Also, the surgical local control, which is extremely important in older patients [8], was unachievable, due to location and extent of the tumor.

The haplo-HSCT is one of the options available as consolidation for patients with primary resistant and relapsed NB. Thus, 5-year EFS and OS in patients receiving CD3 and CD19-depleted graft were 19% and 23%, accordingly [9]. However, the tumor load prior to haplo-HSCT was one of the most important prognostic factors with overall prognosis still being very poor for patients with significant residual disease. In older patients, however, surgical local control seems to play a decisive role [8], radiation therapy is also effective in most high-risk NB patients with post-surgical residual tumor. While COG ANBL0532 study failed to demonstrate the advantage for dose escalation strategy [16], there is still data suggesting its benefit in patients with gross residual disease [17]. In case described, the total doses of 37 Gy and 30 Gy were applied to abdominal and thoracic lesions, accordingly, having been higher than routine dosage used in such cases. However, due to the volume of I-MIBG and FDG-PET positive lesions and history of bone involvement, some additional systemic therapy was viewed as a feasible option.

An anti-GD2 antibody dinutuximab beta is effective as maintenance therapy in high-risk NB patients [18]. It also displayed limited activity as single agent in primary refractory and relapsed patients [19]. It is more effective in combination with irinotecan and temozolomide (1-year EFS of 67.9%), although the majority of responders later had some kind of consolidation therapy [20]. This form of immunotherapy also seems to be synergistic with haplo-HSCT. In the cohort of 56 patients with 1^st or ≥2^nd metastatic relapse complete response was seen in 41% of patients with measurable tumor burden and 3-year OS and EFS were 58% and 45%, respectively [10]. However, disease status prior to HSCT was still a major prognostic factor with 3-year EFS in patients with stabilization being only 11%. Therefore, while we achieved good response by I-MIBG scan in our patient, we still considered her a candidate for additional immunotherapy.

Immune checkpoint inhibitors are surprisingly effective in some adults with solid tumors [21], but their use in pediatric cancer patients is much more limited due to fundamental differences in tumor biology between children and adults [22]. Two large pediatric PD-1 inhibitors trials have yielded disappointing results. In KEYNOTE-051 trial, in which a total of 11 NB patients were enrolled, some positive dynamics by I-MIBG scan was achieved only in one patient [23]. In ADVL1412 trial no objective responses were seen in 22 NB patients [24]. However, the latter included mostly patients without PD-L1 expression (1 of 15 samples studied) and some prolonged (6-30 months) disease stabilizations were seen in 4 of 12 patients without large lesions measurable by RECIST. In case reviewed there were some factors in favor of anti-PD1 agents. First, the different disease mechanisms in older patients suggests better neo-antigen expression compared to younger ones [8]. Also, the patient had history of anti-GD2 therapy, which is able to induce PD ligands expression in preclinical models [25]. There are also two case reports demonstrating the synergism of anti-GD2 and anti-PD1 therapy [26]. The PD-1 blocking strategy also seems to be synergistic with allogeneic transplant [27], although the risk of life-threatening GvHD is the main concern in these patients [28]. Although we have generally positive experience in post-transplant use of nivolumab in our clinic [29], we still started from smaller nivolumab doses as this approach proved its effectiveness in lymphoma patients [30].

Although our patient still has gross measurable disease by CT/MR imaging, the residual tumor is not accumulating MIBG and shows a marked decrease in glucose metabolism. In some auto-HSCT recipients the MIBG-positive lesion with gradually decreasing MIBG accumulation may be a sign of tumor differentiation [31]. We also had a similar experience in haplo-HSCT recipient, who now maintains a response for more than 100 months post-transplant [32].

Conclusion

A combination of haplo-HSCT with post-transplant anti-GD2 antibody and nivolumab led to a long-term response in an adolescent with primary resistant NB in spite of a large residual tumor mass.

Acknowledgements

We are much appreciated to Dr. Andrew P. Litvinov for supporting MIBG images and to Dr. Elena Babenko for performing the MACS selection.

Conflict of interests

None declared.

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Moreno L, Rubie H, Varo A, Le Deley MC, Amoroso L, Chevance A et al. Outcome of children with relapsed or refractory neuroblastoma: A meta‐analysis of ITCC/SIOPEN European phase II clinical trials. Pediatr Blood Cancer 2017; 64(1): 25-31.
Kazantsev IV, Gevorgyan AG, Yukhta TV, Tolkunova PS, Kozlov AV, Andreeva TV et al. High-dose chemotherapy with autologous hematopoietic stem cell transplantation in high-risk neuroblastoma patients: R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg experience. Russian Journal of Pediatric Hematology and Oncology. 2018; 5(4): 11-20. (In Russian).
Indolfi P, Corbacioglu S, Perrotta S, Rossi F, Marte A, Pota E et al. Targeted molecular therapy (modified RIST regimen) in relapsed high risk stage IV neuroblastoma: two cases report. Theory Clin Pract Pediatr. 2018; 2(1): 1-3.
Liu KX, Naranjo A, Zhang FF, Dubois SG, Braunstein SE, Voss SD et al. Role of radiotherapy dose-escalation for high-risk neuroblastoma with post-surgical primary site gross residual disease: A report from the COG ANBL0532 Study. Int J Radiat Oncol Biol Phys. 2019; 105(1s): S3.
Casey DL, Kushner BH, Cheung NKV, Modak S, LaQuaglia MP, Wolden SL. Dose-escalation is needed for gross disease in high-risk neuroblastoma. Pediatr Blood Cancer. 2018; 65(7): e27009.
Ladenstein R, Pötschger U, Valteau-Couanet D, Luksch R, Castel V, Ash S et al. Investigations of the role of dinutuximab beta-based immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1). Cancers. 2020; 12(2): 309.
Mueller I, Ehlert K, Endres S, Pill L, Siebert N, Kietz S et al. Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO. MAbs 2018; 10(1): 55-61.
Mody R, Yu AL, Naranjo A, Zhang FF, London WB, Shulkin BL et al. Irinotecan, temozolomide, and dinutuximab with GM-CSF in children with refractory or relapsed neuroblastoma: A report from the Children's Oncology Group. J Clin Oncol. 2020: JCO2000203. [Epub ahead of print].
Herrscher H, Robert C. Immune checkpoint inhibitors in the metastatic, neoadjuvant, and adjuvant settings. Curr Opin Oncol. 2020; 32(2): 106-113.
Gröbner SN, Worst BC, Weischenfeldt J, Buchhalter I. Kleinheinz K, Rudneva VA et al. The landscape of genomic alterations across childhood cancers. Nature 2018; 555(7696): 321-327.
Geoerger B, Kang HG, Yalon-Oren M, Marshall LV, Vezina C, Pappo A et al. Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): Interim analysis of an open-label, single-arm, Phase 1-2 trial. Lancet Oncol. 2020;21(1): 121-133.
Davis KL, Fox E, Merchant MS, Reid JM, Kudgus RA, Xiaowei L et al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): A multicentre, open-label, single-arm, Phase 1-2 trial. Lancet Oncol. 2020;21(4): 541-550.
Ehlert K, Hansjuergens I, Zinke A, Sylke O, Siebert N, Henze G et al. Nivolumab and dinutuximab beta in two patients with refractory neuroblastoma. J Immunother Cancer. 2020;8(1): e000540.
Siebert N, Zumpe M, Jüttner M, Troschke-Meurer S, Lode HN. PD-1 blockade augments anti-neuroblastoma immune response induced by anti-GD2 antibody ch14.18/CHO. Oncoimmunology. 2017; 6(10): e1343775.
Soiffer RJ. Checkpoint inhibition to prevent or treat relapse in allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2019;54(Suppl 2):798-802.
Ijaz A, Khan AY, Malik SU, Faridi W, Fraz MA, Usman M et al. Significant risk of graft-versus-host disease with exposure to checkpoint inhibitors before and after allogeneic transplantation. Biol Blood Marrow Transplant 2019; 25(1): 94-99.
Lepik KV, Kozlov AV, Borzenkova ES, Popova MO, Moiseev IS, Darskaya EI. Safety and efficacy of nivolumab applied at different dosage in the patients with relapsing Hodgkin lymphoma after allogeneic hematopoietic stem cell transplantation. Cell Ther Transplant. 2018; 7(2): 28-35.
Fedorova LV, Lepik KV, Mikhailova NB, Kondakova EV, Zalyalov YuR, Beynarovich AV et al. Interim analysis of effectiveness and safety of Nivolumab 40 mg in relapsed/refractory Hodgkin lymphoma. Cell Ther Transplant. 2018; 7(3): 53-54.
Okamoto Y, Kodama Y, Nishikawa T, Rindiarti A, Tanabe T, Nakagawa S et al. Persistent positive metaiodobenzyl- guanidine scans after autologous peripheral blood stem cell transplantation may indicate maturation of stage 4 neuroblastoma. Pediatr Hematol Oncol. 2017;34(3):157-164.
Tolkunova PS, Kazantsev IV, Gevorgyan AG, Youkhta TV, Kozlov AV, Morozova EV et al. Long-term disease stabilization in a patient with relapsed neuroblastoma after allogeneic hematopoietic stem cell transplantation. Clinical case and literature review. Russian Journal of Pediatric Hematology and Oncology. 2018; 5(1): 68-72. (In Russian).

" ["~DETAIL_TEXT"]=> string(22844) "

Introduction

Here we report the results of combined treatment including a haplo-HSCT with subsequent immunotherapy in a 12-year old girl with primary refractory NB.

Case presentation

Figure 1. The therapy flow-chart

Figure 2. 123I-MIBG scans prior to haplo-HSCT (A.), after anti-GD2 therapy (B.), and after 3 courses of anti-PD1 therapy (C.)

Figure 3. Radiation fields for abdominal (A.) and thoracic (B., C.) residual tumor components

Discussion

Conclusion

A combination of haplo-HSCT with post-transplant anti-GD2 antibody and nivolumab led to a long-term response in an adolescent with primary resistant NB in spite of a large residual tumor mass.

Acknowledgements

We are much appreciated to Dr. Andrew P. Litvinov for supporting MIBG images and to Dr. Elena Babenko for performing the MACS selection.

Conflict of interests

None declared.

References

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Shinagawa T, Kitamura T, Katanoda K, Matsuda T, Ito Y, Sobue T. The incidence and mortality rates of neuroblastoma cases before and after the cessation of the mass screening program in Japan: A Descriptive Study. Int J Cancer. 2017; 140(3): 618-625.
Hertwig F, Peifer M, Fischer M. Telomere maintenance is pivotal for high-risk neuroblastoma. Cell Cycle. 2016; 15(3): 311-312.
Suzuki M, Kushner BH, Kramer K, Basu EM, Roberts SS, Hammond WJ et al. Treatment and outcome of adult-onset neuroblastoma. Int J Cancer 2018; 143(5): 1249-1258.
Illhardt T, Toporski J, Feuchtinger T, Turkiewicz D, Teltschik HM, Ebinger M et al. Haploidentical stem cell transplantation for refractory/relapsed neuroblastoma. Biol Blood Marrow Transplant 2018; 24(5): 1005-1012.
Lang P, Flaadt T, Ebinger M, Schlegel P, Lode H, Ladenstein R et al. Haploidentical stem cell transplantation and subsequent immunotherapy with antiGD2 antibody for patients with relapsed metastatic neuroblastoma. Clin Cancer Res 2019; 7(2_s): Abstract A013.
Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol 2009; 27(7): 1007-1013.
London WB, Bagatell R, Weigel BJ, Fox E, Guo D, Van Ryn C et al. Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials. Cancer 2017; 123(24): 4914-4923.
Moreno L, Rubie H, Varo A, Le Deley MC, Amoroso L, Chevance A et al. Outcome of children with relapsed or refractory neuroblastoma: A meta‐analysis of ITCC/SIOPEN European phase II clinical trials. Pediatr Blood Cancer 2017; 64(1): 25-31.
Kazantsev IV, Gevorgyan AG, Yukhta TV, Tolkunova PS, Kozlov AV, Andreeva TV et al. High-dose chemotherapy with autologous hematopoietic stem cell transplantation in high-risk neuroblastoma patients: R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg experience. Russian Journal of Pediatric Hematology and Oncology. 2018; 5(4): 11-20. (In Russian).
Indolfi P, Corbacioglu S, Perrotta S, Rossi F, Marte A, Pota E et al. Targeted molecular therapy (modified RIST regimen) in relapsed high risk stage IV neuroblastoma: two cases report. Theory Clin Pract Pediatr. 2018; 2(1): 1-3.
Liu KX, Naranjo A, Zhang FF, Dubois SG, Braunstein SE, Voss SD et al. Role of radiotherapy dose-escalation for high-risk neuroblastoma with post-surgical primary site gross residual disease: A report from the COG ANBL0532 Study. Int J Radiat Oncol Biol Phys. 2019; 105(1s): S3.
Casey DL, Kushner BH, Cheung NKV, Modak S, LaQuaglia MP, Wolden SL. Dose-escalation is needed for gross disease in high-risk neuroblastoma. Pediatr Blood Cancer. 2018; 65(7): e27009.
Ladenstein R, Pötschger U, Valteau-Couanet D, Luksch R, Castel V, Ash S et al. Investigations of the role of dinutuximab beta-based immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1). Cancers. 2020; 12(2): 309.
Mueller I, Ehlert K, Endres S, Pill L, Siebert N, Kietz S et al. Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO. MAbs 2018; 10(1): 55-61.
Mody R, Yu AL, Naranjo A, Zhang FF, London WB, Shulkin BL et al. Irinotecan, temozolomide, and dinutuximab with GM-CSF in children with refractory or relapsed neuroblastoma: A report from the Children's Oncology Group. J Clin Oncol. 2020: JCO2000203. [Epub ahead of print].
Herrscher H, Robert C. Immune checkpoint inhibitors in the metastatic, neoadjuvant, and adjuvant settings. Curr Opin Oncol. 2020; 32(2): 106-113.
Gröbner SN, Worst BC, Weischenfeldt J, Buchhalter I. Kleinheinz K, Rudneva VA et al. The landscape of genomic alterations across childhood cancers. Nature 2018; 555(7696): 321-327.
Geoerger B, Kang HG, Yalon-Oren M, Marshall LV, Vezina C, Pappo A et al. Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): Interim analysis of an open-label, single-arm, Phase 1-2 trial. Lancet Oncol. 2020;21(1): 121-133.
Davis KL, Fox E, Merchant MS, Reid JM, Kudgus RA, Xiaowei L et al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): A multicentre, open-label, single-arm, Phase 1-2 trial. Lancet Oncol. 2020;21(4): 541-550.
Ehlert K, Hansjuergens I, Zinke A, Sylke O, Siebert N, Henze G et al. Nivolumab and dinutuximab beta in two patients with refractory neuroblastoma. J Immunother Cancer. 2020;8(1): e000540.
Siebert N, Zumpe M, Jüttner M, Troschke-Meurer S, Lode HN. PD-1 blockade augments anti-neuroblastoma immune response induced by anti-GD2 antibody ch14.18/CHO. Oncoimmunology. 2017; 6(10): e1343775.
Soiffer RJ. Checkpoint inhibition to prevent or treat relapse in allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2019;54(Suppl 2):798-802.
Ijaz A, Khan AY, Malik SU, Faridi W, Fraz MA, Usman M et al. Significant risk of graft-versus-host disease with exposure to checkpoint inhibitors before and after allogeneic transplantation. Biol Blood Marrow Transplant 2019; 25(1): 94-99.
Lepik KV, Kozlov AV, Borzenkova ES, Popova MO, Moiseev IS, Darskaya EI. Safety and efficacy of nivolumab applied at different dosage in the patients with relapsing Hodgkin lymphoma after allogeneic hematopoietic stem cell transplantation. Cell Ther Transplant. 2018; 7(2): 28-35.
Fedorova LV, Lepik KV, Mikhailova NB, Kondakova EV, Zalyalov YuR, Beynarovich AV et al. Interim analysis of effectiveness and safety of Nivolumab 40 mg in relapsed/refractory Hodgkin lymphoma. Cell Ther Transplant. 2018; 7(3): 53-54.
Okamoto Y, Kodama Y, Nishikawa T, Rindiarti A, Tanabe T, Nakagawa S et al. Persistent positive metaiodobenzyl- guanidine scans after autologous peripheral blood stem cell transplantation may indicate maturation of stage 4 neuroblastoma. Pediatr Hematol Oncol. 2017;34(3):157-164.
Tolkunova PS, Kazantsev IV, Gevorgyan AG, Youkhta TV, Kozlov AV, Morozova EV et al. Long-term disease stabilization in a patient with relapsed neuroblastoma after allogeneic hematopoietic stem cell transplantation. Clinical case and literature review. Russian Journal of Pediatric Hematology and Oncology. 2018; 5(1): 68-72. (In Russian).

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Казанцев1, Татьяна В. Юхта1, Асмик Г. Геворгян1, Полина С. Толкунова1, Андрей В. Шамин2, Вадим В. Байков3, Николай А. Воробьев4, Андрей В. Козлов1, Марина А. Карзакова2, Полина С. Куга1, Александр Н. Швецов1, Елена В. Морозова1, Светлана С. Сафонова1, Юрий А. Пунанов1, Людмила С. Зубаровская1, Борис В. Афанасьев1 " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(810) "

Илья В. Казанцев¹, Татьяна В. Юхта¹, Асмик Г. Геворгян¹, Полина С. Толкунова¹, Андрей В. Шамин², Вадим В. Байков³, Николай А. Воробьев⁴, Андрей В. Козлов¹, Марина А. Карзакова², Полина С. Куга¹, Александр Н. Швецов¹, Елена В. Морозова¹, Светлана С. Сафонова¹, Юрий А. Пунанов¹, Людмила С. Зубаровская¹, Борис В. Афанасьев¹

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¹ НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
² Самарская областная детская больница им. Н. Ивановой, Самара, Россия
³ Кафедра патологической анатомии, Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова, Санкт-Петербург, Россия
⁴ Медицинский институт им. Березина, Санкт-Петербург, Россия; Северо-Западный государственный медицинский университет им. И. Мечникова; Санкт-Петербургский государственный университет, Санкт-Петербург, Россия
⁵ Отдел и кафедра рентгенологии, Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26532" ["VALUE"]=> array(2) { ["TEXT"]=> string(4513) "Нейробластома (НБ) является наиболее частой экстракраниальной опухолью у детей. Она характеризуется чрезвычайной биологической гетерогенностью с вариабельным клиническим течением. Старший возраст является важным фактором риска. У этих пациентов могут отсутствовать другие частые факторы риска, но у них, тем не менее, развивается хеморезистентное заболевание с плохим прогнозом. Поскольку сейчас нет консенсуса по оптимальному лечению пациентов с первично-резистентной НБ, для них исследуют различные клинические опции, включая иммунотерапевтические подходы. Иммунотерапия динутуксимабом бета (ДБ) показала свою эффективность в качестве поддерживающей терапии. Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) от гаплоидентичного донора может быть эффективной консолидирующей терапией в некоторых случаях. Однако все виды иммунотерапии намного менее эффективны у пациентов с большой остаточной опухолью. Поскольку нет данных об эффективности ингибиторов иммунных контрольных точек при НБ, некоторые пациенты могут выиграть от этого варианта лечения, как части комплексной иммунотерапии. <h3>Описание клинического случая</h3> У 12-летней девочки была диагностирована большая паравертебральная опухоль в грудной и абдоминальной области с костными метастазами. Поскольку вначале не было ответа на несколько линий химиотерапии и была возможна только частичная резекция опухоли, была проведена ТГСК от гаплоидентичного донора в качестве терапии спасения. Так как было отмечено только минимальное снижение объема опухоли с хорошей динамикой при MIBG-сканировании, то была начата дополнительная посттрансплантационная терапия. Для локального контроля была назначена лучевая терапия на опухоль. Пациентка получала также комбинированную иммунотерапию препаратом ДБ и ниволумабом. В настоящее время, через 3,5 года после гапло-ТГСК, несмотря на значительную остаточную опухоль, она остается MIBG-отрицательная и имеет признаки дифференцировки. <h3>Выводы</h3> Сочетание гапло-ТГСК с назначением антител к гликолипиду GD2 и ниволумаба может вести к долговременному ответу у подростка с первично-резистентной НБ, несмотря на большую остаточную опухолевую массу. <h2>Ключевые слова</h2> Нейробластома, детский возраст, резистентная, трансплантация гемопоэтических клеток, иммунотерапия." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4389) "

Нейробластома (НБ) является наиболее частой экстракраниальной опухолью у детей. Она характеризуется чрезвычайной биологической гетерогенностью с вариабельным клиническим течением. Старший возраст является важным фактором риска. У этих пациентов могут отсутствовать другие частые факторы риска, но у них, тем не менее, развивается хеморезистентное заболевание с плохим прогнозом. Поскольку сейчас нет консенсуса по оптимальному лечению пациентов с первично-резистентной НБ, для них исследуют различные клинические опции, включая иммунотерапевтические подходы. Иммунотерапия динутуксимабом бета (ДБ) показала свою эффективность в качестве поддерживающей терапии. Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) от гаплоидентичного донора может быть эффективной консолидирующей терапией в некоторых случаях. Однако все виды иммунотерапии намного менее эффективны у пациентов с большой остаточной опухолью. Поскольку нет данных об эффективности ингибиторов иммунных контрольных точек при НБ, некоторые пациенты могут выиграть от этого варианта лечения, как части комплексной иммунотерапии.

Описание клинического случая

У 12-летней девочки была диагностирована большая паравертебральная опухоль в грудной и абдоминальной области с костными метастазами. Поскольку вначале не было ответа на несколько линий химиотерапии и была возможна только частичная резекция опухоли, была проведена ТГСК от гаплоидентичного донора в качестве терапии спасения. Так как было отмечено только минимальное снижение объема опухоли с хорошей динамикой при MIBG-сканировании, то была начата дополнительная посттрансплантационная терапия. Для локального контроля была назначена лучевая терапия на опухоль. Пациентка получала также комбинированную иммунотерапию препаратом ДБ и ниволумабом. В настоящее время, через 3,5 года после гапло-ТГСК, несмотря на значительную остаточную опухоль, она остается MIBG-отрицательная и имеет признаки дифференцировки.

Выводы

Сочетание гапло-ТГСК с назначением антител к гликолипиду GD2 и ниволумаба может вести к долговременному ответу у подростка с первично-резистентной НБ, несмотря на большую остаточную опухолевую массу.

Ключевые слова

Нейробластома, детский возраст, резистентная, трансплантация гемопоэтических клеток, иммунотерапия.

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Ilya V. Kazantsev¹, Tatiana V. Iukhta¹, Asmik G. Gevorgian¹, Polina S. Tolkunova¹, Andrew V. Shamin², Vadim V. Baykov³, Nikolay A. Vorobyov⁴, Andrew V. Kozlov¹, Marina A. Karsakova², Polina S. Kuga¹, Alexander N. Shvetsov¹, Elena V. Morozova¹, Svetlana S. Safonova¹, Yuri A. Punanov¹, Ludmila S. Zubarovskaya¹, Boris V. Afanasyev¹

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¹ RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia
² N. N. Ivanova Samara Regional Pediatric Hospital, Samara, Russia
³ Chair of Pathology, Pavlov University, St. Petersburg, Russia
⁴ Dr. Berezin Medical Institute, St. Petersburg, Russia; I. Mechnikov North-Western State Medical University; Saint Petersburg State University, St. Petersburg, Russia
⁵ Department and Chair of Roentgenology, Pavlov University, St. Petersburg, Russia

Correspondence
Dr. Ilya V. Kazantsev, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (963) 348 0524
E-mail: Ilya_Kazantsev@inbox.ru

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Neuroblastoma (NB) is the most frequent pediatric extracranial solid tumor characterized by extreme biological heterogeneity with variable clinical course. Older age is an important risk factor. These patients may lack other common risk features but still have a chemoresistant disease with dismal prognosis. As there is currently no consensus on optimal treatment for patients with primary resistant NB, a number of clinical options is being explored including immunotherapy-based approaches. Immunotherapy with dinutuximab beta (DB) have proven its effectiveness as maintenance therapy. Allogeneic stem cell transplantation from haploidentical donor (haplo-HSCT) may be an effective consolidation in some cases. However, all forms of immunotherapy are much less effective in patients with large residual tumor. While there is no data on immune checkpoints inhibitors effectiveness in NB, some patients may benefit from this option as a part of complex immunotherapy strategy.

Case presentation

A 12-year old girl with gross paravertebral thoracic and abdominal tumor was diagnosed with undifferentiated neuroblastoma and bone metastases. While there was no response to several lines of chemotherapy, and only partial tumor resection was possible, the hematopoietic stem cell transplantation from haploidentical donor (haplo-HSCT) was performed as salvage therapy. Since there was only minor decrease in tumor volume with good dynamics by MIBG scan, additional post-transplant therapy was initiated. External beam radiotherapy was given for local control. The patient also received combined immunotherapy with DB and nivolumab. Currently, 3.5 years post haplo-HSCT, despite still gross residual tumor mass, it is MIBG-negative and shows signs of differentiation.

Conclusion

The combination of haplo-HSCT with post-transplant anti-GD2 and nivolumab may lead to a long-term response in an adolescent with primary resistant NB in spite of a large residual tumor mass.

Keywords

Neuroblastoma, pediatric, resistant, hematopoietic transplantation, immunotherapy.

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Kazantsev1, Tatiana V. Iukhta1, Asmik G. Gevorgian1, Polina S. Tolkunova1, Andrew V. Shamin2, Vadim V. Baykov3, Nikolay A. Vorobyov4, Andrew V. Kozlov1, Marina A. Karsakova2, Polina S. Kuga1, Alexander N. Shvetsov1, Elena V. Morozova1, Svetlana S. Safonova1, Yuri A. Punanov1, Ludmila S. Zubarovskaya1, Boris V. Afanasyev1 " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(589) "

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Case presentation

Conclusion

The combination of haplo-HSCT with post-transplant anti-GD2 and nivolumab may lead to a long-term response in an adolescent with primary resistant NB in spite of a large residual tumor mass.

Keywords

Neuroblastoma, pediatric, resistant, hematopoietic transplantation, immunotherapy.

Case presentation

Conclusion

The combination of haplo-HSCT with post-transplant anti-GD2 and nivolumab may lead to a long-term response in an adolescent with primary resistant NB in spite of a large residual tumor mass.

Keywords

Neuroblastoma, pediatric, resistant, hematopoietic transplantation, immunotherapy.

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Она характеризуется чрезвычайной биологической гетерогенностью с вариабельным клиническим течением. Старший возраст является важным фактором риска. У этих пациентов могут отсутствовать другие частые факторы риска, но у них, тем не менее, развивается хеморезистентное заболевание с плохим прогнозом. Поскольку сейчас нет консенсуса по оптимальному лечению пациентов с первично-резистентной НБ, для них исследуют различные клинические опции, включая иммунотерапевтические подходы. Иммунотерапия динутуксимабом бета (ДБ) показала свою эффективность в качестве поддерживающей терапии. Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) от гаплоидентичного донора может быть эффективной консолидирующей терапией в некоторых случаях. Однако все виды иммунотерапии намного менее эффективны у пациентов с большой остаточной опухолью. Поскольку нет данных об эффективности ингибиторов иммунных контрольных точек при НБ, некоторые пациенты могут выиграть от этого варианта лечения, как части комплексной иммунотерапии. <h3>Описание клинического случая</h3> У 12-летней девочки была диагностирована большая паравертебральная опухоль в грудной и абдоминальной области с костными метастазами. Поскольку вначале не было ответа на несколько линий химиотерапии и была возможна только частичная резекция опухоли, была проведена ТГСК от гаплоидентичного донора в качестве терапии спасения. Так как было отмечено только минимальное снижение объема опухоли с хорошей динамикой при MIBG-сканировании, то была начата дополнительная посттрансплантационная терапия. Для локального контроля была назначена лучевая терапия на опухоль. Пациентка получала также комбинированную иммунотерапию препаратом ДБ и ниволумабом. В настоящее время, через 3,5 года после гапло-ТГСК, несмотря на значительную остаточную опухоль, она остается MIBG-отрицательная и имеет признаки дифференцировки. <h3>Выводы</h3> Сочетание гапло-ТГСК с назначением антител к гликолипиду GD2 и ниволумаба может вести к долговременному ответу у подростка с первично-резистентной НБ, несмотря на большую остаточную опухолевую массу. <h2>Ключевые слова</h2> Нейробластома, детский возраст, резистентная, трансплантация гемопоэтических клеток, иммунотерапия." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4389) "

Описание клинического случая

Выводы

Ключевые слова

Нейробластома, детский возраст, резистентная, трансплантация гемопоэтических клеток, иммунотерапия.

Описание клинического случая

Выводы

Ключевые слова

Нейробластома, детский возраст, резистентная, трансплантация гемопоэтических клеток, иммунотерапия.

" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "26531" ["VALUE"]=> array(2) { ["TEXT"]=> string(1561) "1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия 2 Самарская областная детская больница им. Н. Ивановой, Самара, Россия 3 Кафедра патологической анатомии, Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова, Санкт-Петербург, Россия 4 Медицинский институт им. Березина, Санкт-Петербург, Россия; Северо-Западный государственный медицинский университет им. И. Мечникова; Санкт-Петербургский государственный университет, Санкт-Петербург, Россия 5 Отдел и кафедра рентгенологии, Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1465) "

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