Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2022; 21: 53-59
Иммунотерапия острого лимфобластного лейкоза у детей до года с применением блинатумомаба и инфузии донорских лимфоцитов после гаплоидентичной трансплантации гемопоэтических стволовых клеток
https://doi.org/10.24287/1726-1708-2022-21-4-53-59Аннотация
Острый лимфобластный лейкоз (ОЛЛ) у пациентов до года характеризуется высокой частотой перестроек гена KMT2A и неблагоприятным исходом. Несмотря на интенсификацию химиотерапии, отмечается высокий уровень рецидивов. Аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) – единственный метод, направленный на излечение от заболевания. В течение последних десятилетий инфузия донорских лимфоцитов (ИДЛ) использовалась в качестве «терапии спасения» для профилактики и лечения посттрансплантационных рецидивов В-клеточного ОЛЛ с доказанным противолейкозным эффектом. Комбинация блинатумомаба и ИДЛ является многообещающим методом иммуноадоптивной терапии резистентных форм ОЛЛ, основанным на индукции реакции «трансплантат против лейкемии» путем активации донорских Т-лимфоцитов. Мы проанализировали результаты комбинированной иммуноадоптивной терапии биспецифическим активатором Т-клеток блинатумомаб и ИДЛ у 3 младенцев с ОЛЛ, а также результат монотерапии биспецифическим активатором Т-клеток у 1 младенца. Данное исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГБОУ ВО ПСПбГМУ им. И.П. Павлова Минздрава России. Все пациенты инициально имели реаранжировку гена KMT2A и были отнесены к группе высокого риска. Показаниями к проведению иммуноадоптивной терапии стали сверхранний комбинированный рецидив заболевания после гаплоидентичной ТГСК у 1 пациента и минимальная остаточная болезнь (МОБ) у 3 больных. Всем пациентам удалось достичь клиникогематологической ремиссии заболевания, 3 (75%) пациентам – МОБ-негативной ремиссии. Медиана длительности костномозгового ответа составила 24 (8–63) мес. Один пациент развил костномозговой рецидив заболевания через 8 мес после терапии, у 2 детей отмечалось появление изолированных экстрамедуллярных рецидивов. Мы не увидели токсических осложнений и индукции реакции «трансплантат против хозяина» при проведении иммуноадоптивной терапии. На момент последнего контакта все пациенты живы, 3 остаются в стойкой клинико-гематологической ремиссии заболевания.
Список литературы
1. Hunger S.P., Mullighan C.G. Acute Lymphoblastic Leukemia in Children. N Engl J Med 2015; 373 (16): 1541–52. DOI:10.1056/nejmra1400972
2. Stutterheim J., van der Sluis I.M., de Lorenzo P., Alten J., Ancliffe P., Attarbaschi А., et al. Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol. J Clin Oncol 2021; 39 (6): 652–62. DOI:10.1200/jco.20.02333
3. Clesham K., Rao V., Bartram J., Ancliff P., Ghorashian S., O’Connor D., et al. Blinatumomab for infant acute lymphoblastic leukemia. Blood 2020; 135 (17): 1501–4. DOI:10.1182/blood.2019004008
4. Van Dongen J.J., Seriu T., Panzer-Grümayer E.R., Biondi A., Pongers-Willemse M.J., Corral et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998; 352 (9142): 1731–8. DOI:10.1016/s0140-6736(98)04058-6
5. Faderl S., Kantarjian H.M., Talpaz M., Estrov Z. Clinical significance of minimal residual disease in leukemia. Int J Oncol 2020; 17 (6): 1277–87. DOI:10.3892/ijo.17.6.1277
6. Pieters R., de Groot-Kruseman H., van der Velden V., Fiocco M., van den Berg H., de Bont Е., et al. Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol 2016; 34 (22): 2591–601. DOI:10.1200/jco.2015.64.6364
7. Conter V., Bartram C.R., Valsecchi M.G., Schrauder A., Panzer-Grümayer R., Möricke А., et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 2010; 115 (16): 3206–14. DOI:10.1182/blood-2009-10-248146
8. Schrappe M., Bleckmann K., Zimmermann M., Biondi A., Möricke A., Locatelli F., et al. Reduced-Intensity Delayed Intensification in Standard-Risk Pediatric Acute Lymphoblastic Leukemia Defined by Undetectable Minimal Residual Disease: Results of an International Randomized Trial (AIEOP-BFM ALL 2000). J Clin Oncol 2018; 36 (3): 244–53. DOI:10.1200/jco.2017.74.4946
9. Schrappe M., Valsecchi M.G., Bartram C.R., Schrauder A., Panzer-Grümayer R., Möricke А., et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood 2011; 118 (8): 2077–84. DOI:10.1182/blood-2011-03-338707
10. Li A., Goldwasser M.A., Zhou J., Armstrong S.A., Wang H., Dalton V., et al. Distinctive IGH gene segment usage and minimal residual disease detection in infant acute lymphoblastic leukaemias. Br J Haematol 2005; 131 (2): 185–92. DOI:10.1111/j.1365-2141.2005.05754.x
11. Van der Velden V.H.J., Corral L., Valsecchi M.G., Jansen M.W.J.C., De Lorenzo P., Cazzaniga G., et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia 2009; 23 (6): 1073–9. DOI:10.1038/leu.2009.17
12. Popov A., Buldini B., De Lorenzo P., Disarò S., Verzhbitskaya T., Movchan L., et al. Prognostic value of minimal residual disease measured by flow-cytometry in two cohorts of infants with acute lymphoblastic leukemia treated according to either MLL-Baby or Interfant protocols. Leukemia 2020; 34 (11): 3042–6. DOI:10.1038/s41375-020-0912-z
13. Interfant-21 Treatment Protocol for Infants Under 1 Year With KMT2A-rearranged ALL or Mixed Phenotype Acute Leukemia. ClinicalTrials. gov Identifier: NCT05327894
14. Van Der Sluis I.M., De Lorenzo P., Kotecha R.S., Attarbaschi A., Escherich G., Nysom K., et al. A Phase 2 Study to Test the Feasibility, Safety and Efficacy of the Addition of Blinatumomab to the Interfant06 Backbone in Infants with Newly Diagnosed KMT2A-Rearranged Acute Lymphoblastic Leukemia. A Collaborative Study of the Interfant Network. Blood 2021; 138 (Suppl 1): 361. DOI:10.1182/blood2021-144843
15. Chauvet P., Paviglianiti A., Labopin M., Labussiere H., Boissel N., Robin M., et al. Combining blinatumomab and donor lymphocyte infusion in B-ALL patients relapsing after allogeneic hematopoietic cell transplantation: A study of the SFGM-TC. Bone Marrow Transplant 2022 DOI:10.21203/rs.3.rs-1754921/v1
16. Durer S., Durer C., Shafqat M., Comba I.Y., Malik S., Faridi W., et al. Concomitant use of blinatumomab and donor lymphocyte infusion for mixed-phenotype acute leukemia: a case report with literature review. Immunotherapy 2019; 11 (5): 373–8. DOI:10.2217/imt-2018-0104
17. Takachi T., Watanabe T., Miyamura T., Moriya Saito A., Deguchi T., Hori T., et al. Hematopoietic stem cell transplantation for infants with highrisk KMT2A gene–rearranged acute lymphoblastic leukemia. Blood Adv 2021; 5 (19): 3891–9. DOI:10.1182/bloodadvances.2020004157
18. Gaballa M.R., Banerjee P., Milton D.R., Jiang X., Ganesh C., Khazal S., et al. Blinatumomab maintenance after allogeneic hematopoietic cell transplantation for B-lineage acute lymphoblastic leukemia. Blood 2022; 139 (12): 1908–19. DOI:10.1182/blood.2021013290
19. Muriano F., Cacace F., Caprioli V., D’amico M.R., De Simone G., Giagnuolo G., et al. P350: Blinatumomab and donor lymphocyte infusion (DLI) for molecular relapse after hematopoietic stem cell transplantation in pediatric patients. HemaSphere, 2022; 6: 250–1. DOI:10.1097/01.hs9.0000844288.52565.46
20. Wölfl M., Rasche M., Eyrich M., Schmid R., Reinhardt D., Schlegel P.G. Spontaneous reversion of a lineage switch following an initial blinatumomab-induced ALL-to-AML switch in MLL-rearranged infant ALL. Blood Adv 2018; 2 (12): 1382–5. DOI:10.1182/bloodadvances.2018018093
21. Rossi J.G., Bernasconi A.R., Alonso C.N., Rubio P.L., Gallego M.S., Carrara C.A., et al. Lineage switch in childhood acute leukemia: An unusual event with poor outcome. Am J Hematol 2012; 87 (9): 890–7. DOI:10.1002/ajh.23266
Pediatric Hematology/Oncology and Immunopathology. 2022; 21: 53-59
Immunotherapy of high-risk infant acute lymphoblastic leukemia using blinatumomab and infusion of donor lymphocytes
https://doi.org/10.24287/1726-1708-2022-21-4-53-59Abstract
Pleuropulmonary blastoma (PPB) is a very rare tumor of childhood that arises from the mesenchyme of the lung and is associated Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. Despite intensified therapy protocols, infant ALL remains a difficult-to-treat disease, with a high relapse rate. Allogeneic bone marrow transplantation is the only curative method aimed to curing the disease. Over the last decades, donor lymphocyte infusion (DLI) has been used as a salvage therapy after post-transplant relapses in B-ALL patients with a proven antileukemic effect. The combination of blinatumomab and DLI is a promising immunoadoptive therapy for resistant ALL based on the induction of “graft versus leukemia” effect by activating donor T-lymphocytes. We analyzed the results of combined immunoadoptive therapy with a bispecific T-cell activator blinatumomab and DLI in 3 infants with ALL, as well as the outcome of monotherapy with a bispecific T-cell activator in one infant. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. All infants initially had the KMT2A gene rearrangement and were classified as high-risk. The indication for immunoadoptive therapy was an early combined relapse of the disease after haploidentical hematopoietic stem cell transplantation in one patient and minimal residual disease (MRD) in three patients. All patients achieved long term hematological remission of the disease, 3 (75%) patients – MRD negative remission. The median duration of bone marrow response was 24 (8–63) months. One patient developed a bone marrow relapse in 8 months after therapy, two patients developed isolated extramedullary relapse. We did not see toxic complications and induction of graft-versus-host disease during immunoadoptive therapy. At the time of the follow up, all patients are alive, three remains in lasting hematological remission.
References
1. Hunger S.P., Mullighan C.G. Acute Lymphoblastic Leukemia in Children. N Engl J Med 2015; 373 (16): 1541–52. DOI:10.1056/nejmra1400972
2. Stutterheim J., van der Sluis I.M., de Lorenzo P., Alten J., Ancliffe P., Attarbaschi A., et al. Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol. J Clin Oncol 2021; 39 (6): 652–62. DOI:10.1200/jco.20.02333
3. Clesham K., Rao V., Bartram J., Ancliff P., Ghorashian S., O’Connor D., et al. Blinatumomab for infant acute lymphoblastic leukemia. Blood 2020; 135 (17): 1501–4. DOI:10.1182/blood.2019004008
4. Van Dongen J.J., Seriu T., Panzer-Grümayer E.R., Biondi A., Pongers-Willemse M.J., Corral et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998; 352 (9142): 1731–8. DOI:10.1016/s0140-6736(98)04058-6
5. Faderl S., Kantarjian H.M., Talpaz M., Estrov Z. Clinical significance of minimal residual disease in leukemia. Int J Oncol 2020; 17 (6): 1277–87. DOI:10.3892/ijo.17.6.1277
6. Pieters R., de Groot-Kruseman H., van der Velden V., Fiocco M., van den Berg H., de Bont E., et al. Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol 2016; 34 (22): 2591–601. DOI:10.1200/jco.2015.64.6364
7. Conter V., Bartram C.R., Valsecchi M.G., Schrauder A., Panzer-Grümayer R., Möricke A., et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 2010; 115 (16): 3206–14. DOI:10.1182/blood-2009-10-248146
8. Schrappe M., Bleckmann K., Zimmermann M., Biondi A., Möricke A., Locatelli F., et al. Reduced-Intensity Delayed Intensification in Standard-Risk Pediatric Acute Lymphoblastic Leukemia Defined by Undetectable Minimal Residual Disease: Results of an International Randomized Trial (AIEOP-BFM ALL 2000). J Clin Oncol 2018; 36 (3): 244–53. DOI:10.1200/jco.2017.74.4946
9. Schrappe M., Valsecchi M.G., Bartram C.R., Schrauder A., Panzer-Grümayer R., Möricke A., et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood 2011; 118 (8): 2077–84. DOI:10.1182/blood-2011-03-338707
10. Li A., Goldwasser M.A., Zhou J., Armstrong S.A., Wang H., Dalton V., et al. Distinctive IGH gene segment usage and minimal residual disease detection in infant acute lymphoblastic leukaemias. Br J Haematol 2005; 131 (2): 185–92. DOI:10.1111/j.1365-2141.2005.05754.x
11. Van der Velden V.H.J., Corral L., Valsecchi M.G., Jansen M.W.J.C., De Lorenzo P., Cazzaniga G., et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia 2009; 23 (6): 1073–9. DOI:10.1038/leu.2009.17
12. Popov A., Buldini B., De Lorenzo P., Disarò S., Verzhbitskaya T., Movchan L., et al. Prognostic value of minimal residual disease measured by flow-cytometry in two cohorts of infants with acute lymphoblastic leukemia treated according to either MLL-Baby or Interfant protocols. Leukemia 2020; 34 (11): 3042–6. DOI:10.1038/s41375-020-0912-z
13. Interfant-21 Treatment Protocol for Infants Under 1 Year With KMT2A-rearranged ALL or Mixed Phenotype Acute Leukemia. ClinicalTrials. gov Identifier: NCT05327894
14. Van Der Sluis I.M., De Lorenzo P., Kotecha R.S., Attarbaschi A., Escherich G., Nysom K., et al. A Phase 2 Study to Test the Feasibility, Safety and Efficacy of the Addition of Blinatumomab to the Interfant06 Backbone in Infants with Newly Diagnosed KMT2A-Rearranged Acute Lymphoblastic Leukemia. A Collaborative Study of the Interfant Network. Blood 2021; 138 (Suppl 1): 361. DOI:10.1182/blood2021-144843
15. Chauvet P., Paviglianiti A., Labopin M., Labussiere H., Boissel N., Robin M., et al. Combining blinatumomab and donor lymphocyte infusion in B-ALL patients relapsing after allogeneic hematopoietic cell transplantation: A study of the SFGM-TC. Bone Marrow Transplant 2022 DOI:10.21203/rs.3.rs-1754921/v1
16. Durer S., Durer C., Shafqat M., Comba I.Y., Malik S., Faridi W., et al. Concomitant use of blinatumomab and donor lymphocyte infusion for mixed-phenotype acute leukemia: a case report with literature review. Immunotherapy 2019; 11 (5): 373–8. DOI:10.2217/imt-2018-0104
17. Takachi T., Watanabe T., Miyamura T., Moriya Saito A., Deguchi T., Hori T., et al. Hematopoietic stem cell transplantation for infants with highrisk KMT2A gene–rearranged acute lymphoblastic leukemia. Blood Adv 2021; 5 (19): 3891–9. DOI:10.1182/bloodadvances.2020004157
18. Gaballa M.R., Banerjee P., Milton D.R., Jiang X., Ganesh C., Khazal S., et al. Blinatumomab maintenance after allogeneic hematopoietic cell transplantation for B-lineage acute lymphoblastic leukemia. Blood 2022; 139 (12): 1908–19. DOI:10.1182/blood.2021013290
19. Muriano F., Cacace F., Caprioli V., D’amico M.R., De Simone G., Giagnuolo G., et al. P350: Blinatumomab and donor lymphocyte infusion (DLI) for molecular relapse after hematopoietic stem cell transplantation in pediatric patients. HemaSphere, 2022; 6: 250–1. DOI:10.1097/01.hs9.0000844288.52565.46
20. Wölfl M., Rasche M., Eyrich M., Schmid R., Reinhardt D., Schlegel P.G. Spontaneous reversion of a lineage switch following an initial blinatumomab-induced ALL-to-AML switch in MLL-rearranged infant ALL. Blood Adv 2018; 2 (12): 1382–5. DOI:10.1182/bloodadvances.2018018093
21. Rossi J.G., Bernasconi A.R., Alonso C.N., Rubio P.L., Gallego M.S., Carrara C.A., et al. Lineage switch in childhood acute leukemia: An unusual event with poor outcome. Am J Hematol 2012; 87 (9): 890–7. DOI:10.1002/ajh.23266
