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BLINATUMOMAB AND DONOR LYMPHOCYTE INFUSION (DLI) FOR MOLECULAR RELAPSE AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PEDIATRIC PATIENTS
Author(s): ,
Francesco Muriano
Affiliations:
Hematology,AOU Federico II,Naples,Italie;Hematology,AOU Federico II,Naples,Italien;Hematology,AOU Federico II,Naples,Italia;Hematology,AOU Federico II,Naples,Italy;Hematology,AOU Federico II,Naples,Italia;Hematology,AOU Federico II,Naples,Italië;Hematology,AOU Federico II,Naples,Itália;Hematology,AOU Federico II,Naples,Италия;Hematology,AOU Federico II,Naples,Italien
,
Fabiana Cacace
Affiliations:
BMT UNIT,AORN Santobono Pausilipon,Naples,Italie;BMT UNIT,AORN Santobono Pausilipon,Naples,Italien;BMT UNIT,AORN Santobono Pausilipon,Naples,Italia;BMT UNIT,AORN Santobono Pausilipon,Naples,Italy;BMT UNIT,AORN Santobono Pausilipon,Naples,Italia;BMT UNIT,AORN Santobono Pausilipon,Naples,Italië;BMT UNIT,AORN Santobono Pausilipon,Naples,Itália;BMT UNIT,AORN Santobono Pausilipon,Naples,Италия;BMT UNIT
,
Valeria Caprioli
Affiliations:
BMT UNIT,AORN Santobono Pausilipon,Naples,Italie;BMT UNIT,AORN Santobono Pausilipon,Naples,Italien;BMT UNIT,AORN Santobono Pausilipon,Naples,Italia;BMT UNIT,AORN Santobono Pausilipon,Naples,Italy;BMT UNIT,AORN Santobono Pausilipon,Naples,Italia;BMT UNIT,AORN Santobono Pausilipon,Naples,Italië;BMT UNIT,AORN Santobono Pausilipon,Naples,Itália;BMT UNIT,AORN Santobono Pausilipon,Naples,Италия;BMT UNIT
,
Maria Rosaria D'amico
Affiliations:
BMT UNIT,AORN Santobono Pausilipon,Naples,Italie;BMT UNIT,AORN Santobono Pausilipon,Naples,Italien;BMT UNIT,AORN Santobono Pausilipon,Naples,Italia;BMT UNIT,AORN Santobono Pausilipon,Naples,Italy;BMT UNIT,AORN Santobono Pausilipon,Naples,Italia;BMT UNIT,AORN Santobono Pausilipon,Naples,Italië;BMT UNIT,AORN Santobono Pausilipon,Naples,Itália;BMT UNIT,AORN Santobono Pausilipon,Naples,Италия;BMT UNIT
,
Giuseppina De Simone
Affiliations:
BMT UNIT,AORN Santobono Pausilipon,Naples,Italie;BMT UNIT,AORN Santobono Pausilipon,Naples,Italien;BMT UNIT,AORN Santobono Pausilipon,Naples,Italia;BMT UNIT,AORN Santobono Pausilipon,Naples,Italy;BMT UNIT,AORN Santobono Pausilipon,Naples,Italia;BMT UNIT,AORN Santobono Pausilipon,Naples,Italië;BMT UNIT,AORN Santobono Pausilipon,Naples,Itália;BMT UNIT,AORN Santobono Pausilipon,Naples,Италия;BMT UNIT
,
Giovanna Giagnuolo
Affiliations:
Hematology,AORN Santobono Pausilipon,Naples,Italie;Hematology,AORN Santobono Pausilipon,Naples,Italien;Hematology,AORN Santobono Pausilipon,Naples,Italia;Hematology,AORN Santobono Pausilipon,Naples,Italy;Hematology,AORN Santobono Pausilipon,Naples,Italia;Hematology,AORN Santobono Pausilipon,Naples,Italië;Hematology,AORN Santobono Pausilipon,Naples,Itália;Hematology,AORN Santobono Pausilipon,Naples
,
Giuseppe Menna
Affiliations:
Hematology,AORN Santobono Pausilipon,Naples,Italie;Hematology,AORN Santobono Pausilipon,Naples,Italien;Hematology,AORN Santobono Pausilipon,Naples,Italia;Hematology,AORN Santobono Pausilipon,Naples,Italy;Hematology,AORN Santobono Pausilipon,Naples,Italia;Hematology,AORN Santobono Pausilipon,Naples,Italië;Hematology,AORN Santobono Pausilipon,Naples,Itália;Hematology,AORN Santobono Pausilipon,Naples
Francesco Paolo Tambaro
Affiliations:
BMT UNIT,AORN Santobono Pausilipon,Naples,Italie;BMT UNIT,AORN Santobono Pausilipon,Naples,Italien;BMT UNIT,AORN Santobono Pausilipon,Naples,Italia;BMT UNIT,AORN Santobono Pausilipon,Naples,Italy;BMT UNIT,AORN Santobono Pausilipon,Naples,Italia;BMT UNIT,AORN Santobono Pausilipon,Naples,Italië;BMT UNIT,AORN Santobono Pausilipon,Naples,Itália;BMT UNIT,AORN Santobono Pausilipon,Naples,Италия;BMT UNIT
(Abstract release date: 05/12/22) EHA Library. Muriano F. 06/10/22; 357213; P350
Francesco Muriano
Francesco Muriano
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P350

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Clinical

Background

Detection of measurable residual disease (MRD) after Hematopoietic Stem Cell Transplantation (HSCT) is an early predictor of frank relapse. The role of DLI as a pre-emptive treatment to prevent relapse is still debated. Blinatumomab, a CD3/CD19 bispecific T-cell engager molecule, is approved in adult patients with MRD and in children with relapsed or refractory acute lymphoblastic leukemia (ALL).

Aims

We evaluated the safety and feasibility of blinatumomab plus DLI to treat MRD-positive pediatricALLafter HSCT. Here, we report our experience of three patients with post-transplant MRD-positive ALL who received blinatumomab and DLI.

Methods

Three pediatric patients with high-risk B-ALLwere treated according to AEIOP ALL 2009 and AIEOP ALL 2017 protocols and referred for allo-HSCT. Patients became MRD-positive after allo-HSCT and received blinatumomab with DLI.Patients’ characteristics are summarized in the Table.

 

Results
Patient 1 developed CNS relapse during maintenance, then received salvage therapy according to the INTREALL HR 2010 and 1 course of blinatumomab, achieving MRD-positive CR1.Patient 2, a 16-year old female, had secondary ALL and achieved CR1 after 1 course of chemotherapy and subsequently received 2 courses of blinatumomab, due to chemotherapy-associated toxicity and achieved MRD-undetectable CR1. Patient 3, a 17-year old male was primary refractory to 2 lines of chemotherapy and blinatumomab, received 2 courses of inotuzumab and achieved an MRD-positive complete remission (CR).All patients proceeded to allo-SCT and were MRD-positive at 8, 31 and 14 weeks post-allo-SCT, respectively. All patients discontinued immunosuppressive therapy and received 2, 1 and 4 courses of DLI with blinatumomab, respectively. Blinatumomab was started one week after each DLI, was given at a dose of 15-28cg/kg for a total of 4 weeks each course. Only patient 3 experienced Grade 2 liver GVHD. None of the patients experienced serious adverse events requiring blinatumomab discontinuation. Patient 3 developed isolated CNS relapse after 4 courses of combined DLI plus blinatumomab; patient 2 achieved and remains in MRD-undetectable CR with current follow up and a patient 1 achieved MRD-negative CR after two courses of combined treatment and CNS relapse. 

Conclusion

The role of cellular therapy with DLI is still debated in ALL. Most post-transplant relapses are associated withloss of surface HLA bythe leukemia cells, hence DLI alone has limited efficacy in patients with post HSCT relapse. Blinatumomab directs T cells to bind CD19 present on malignant B cells and engages CD3 on T cells causing activation and inducing cytotoxicity against ALL blasts. We, therefore, tested the efficacy of blinatumomab plus DLI in 3 MRD-positive patients with ALL after allogeneic HSCT. The use of blinatumomab allowed recruitment of fit donor-derived T lymphocytes (not exposed to immune suppressive agents) against ALL B cells. This hypothesis is supported by the fact thatpatient 3, who received blinatumomab pre-HSCT and had disease progression, probably due to lack of T cells showed by flow cytometry, achieved MRD-undetectablestatus after receiving DLI plus blinatumomab post-transplant. Twopatients reached stable MRD-undetectablestatusand 2 subsequently developed CNS relapse; none received CNS prophylaxis post-HSCT. We hypothesize that blinatumomab plus DLI can clear the hematologic disease, but it is not effective in preventing CNS relapse. Although very interesting, this hypothesis should be confirmed in a larger number of patients.

Keyword(s): Allogeneic hematopoietic stem cell transplant, Antibody targeting, Donor lymphocyte infusion, Minimal residual disease (MRD)

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P350

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Clinical

Background

Detection of measurable residual disease (MRD) after Hematopoietic Stem Cell Transplantation (HSCT) is an early predictor of frank relapse. The role of DLI as a pre-emptive treatment to prevent relapse is still debated. Blinatumomab, a CD3/CD19 bispecific T-cell engager molecule, is approved in adult patients with MRD and in children with relapsed or refractory acute lymphoblastic leukemia (ALL).

Aims

We evaluated the safety and feasibility of blinatumomab plus DLI to treat MRD-positive pediatricALLafter HSCT. Here, we report our experience of three patients with post-transplant MRD-positive ALL who received blinatumomab and DLI.

Methods

Three pediatric patients with high-risk B-ALLwere treated according to AEIOP ALL 2009 and AIEOP ALL 2017 protocols and referred for allo-HSCT. Patients became MRD-positive after allo-HSCT and received blinatumomab with DLI.Patients’ characteristics are summarized in the Table.

 

Results
Patient 1 developed CNS relapse during maintenance, then received salvage therapy according to the INTREALL HR 2010 and 1 course of blinatumomab, achieving MRD-positive CR1.Patient 2, a 16-year old female, had secondary ALL and achieved CR1 after 1 course of chemotherapy and subsequently received 2 courses of blinatumomab, due to chemotherapy-associated toxicity and achieved MRD-undetectable CR1. Patient 3, a 17-year old male was primary refractory to 2 lines of chemotherapy and blinatumomab, received 2 courses of inotuzumab and achieved an MRD-positive complete remission (CR).All patients proceeded to allo-SCT and were MRD-positive at 8, 31 and 14 weeks post-allo-SCT, respectively. All patients discontinued immunosuppressive therapy and received 2, 1 and 4 courses of DLI with blinatumomab, respectively. Blinatumomab was started one week after each DLI, was given at a dose of 15-28cg/kg for a total of 4 weeks each course. Only patient 3 experienced Grade 2 liver GVHD. None of the patients experienced serious adverse events requiring blinatumomab discontinuation. Patient 3 developed isolated CNS relapse after 4 courses of combined DLI plus blinatumomab; patient 2 achieved and remains in MRD-undetectable CR with current follow up and a patient 1 achieved MRD-negative CR after two courses of combined treatment and CNS relapse. 

Conclusion

The role of cellular therapy with DLI is still debated in ALL. Most post-transplant relapses are associated withloss of surface HLA bythe leukemia cells, hence DLI alone has limited efficacy in patients with post HSCT relapse. Blinatumomab directs T cells to bind CD19 present on malignant B cells and engages CD3 on T cells causing activation and inducing cytotoxicity against ALL blasts. We, therefore, tested the efficacy of blinatumomab plus DLI in 3 MRD-positive patients with ALL after allogeneic HSCT. The use of blinatumomab allowed recruitment of fit donor-derived T lymphocytes (not exposed to immune suppressive agents) against ALL B cells. This hypothesis is supported by the fact thatpatient 3, who received blinatumomab pre-HSCT and had disease progression, probably due to lack of T cells showed by flow cytometry, achieved MRD-undetectablestatus after receiving DLI plus blinatumomab post-transplant. Twopatients reached stable MRD-undetectablestatusand 2 subsequently developed CNS relapse; none received CNS prophylaxis post-HSCT. We hypothesize that blinatumomab plus DLI can clear the hematologic disease, but it is not effective in preventing CNS relapse. Although very interesting, this hypothesis should be confirmed in a larger number of patients.

Keyword(s): Allogeneic hematopoietic stem cell transplant, Antibody targeting, Donor lymphocyte infusion, Minimal residual disease (MRD)

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