FRACTIONATED DOSING OF ARI-0001 CELLS (A3B1:CD8:4-1BB:CD3Z CAR19) AND EARLY TOCILIZUMAB ADMINISTRATION MAY REDUCE THE INCIDENCE OF SEVERE CYTOKINE RELEASE SYNDROME IN PATIENTS WITH CD19+ MALIGNANCIES
Author(s): ,
Valentín Ortiz-Maldonado
Affiliations:
Hematology,Hospital Clínic Barcelona,Barcelona,Spain
,
Ana Alonso-Saladrigues
Affiliations:
Hematology,Hospital Sant Joan de Déu,Barcelona,Spain
,
Miguel Caballero-Baños
Affiliations:
Immunology Platform Clínic-Sant Joan de Déu,Hospital Clínic Barcelona,Barcelona,Spain
,
Maria Castella
Affiliations:
Immunology,Hospital Clínic Barcelona,Barcelona,Spain
,
Ana Boronat
Affiliations:
Immunology,Hospital Clínic Barcelona,Barcelona,Spain
,
Enric Garcia-Rey
Affiliations:
Apheresis Unit,Hospital Sant Joan de Déu,Barcelona,Spain
,
Tycho Baumann
Affiliations:
Hematology,Hospital Clínic Barcelona,Barcelona,Spain
,
Marina Díaz-Beyá
Affiliations:
Hematology,Hospital Clínic Barcelona,Barcelona,Spain
,
Montserrat Torrebadell
Affiliations:
Hematology,Hospital Sant Joan de Déu,Barcelona,Spain
,
Albert Català
Affiliations:
Hematology,Hospital Sant Joan de Déu,Barcelona,Spain
,
Federico Ramos
Affiliations:
Neurology,Hospital Sant Joan de Déu,Barcelona,Spain
,
Sandra Pont
Affiliations:
Hematology,Hospital Sant Joan de Déu,Barcelona,Spain
,
Joan Cid
Affiliations:
Apheresis Unit,Hospital Clínic Barcelona,Barcelona,Spain
,
Miquel Lozano
Affiliations:
Apheresis Unit,Hospital Clínic Barcelona,Barcelona,Spain
,
Cristina Llanos
Affiliations:
Clinical Trials,Hospital Sant Joan de Déu,Barcelona,Spain
,
Berta Marzal
Affiliations:
Immunology,Hospital Clínic Barcelona,Barcelona,Spain
,
David Fernando Moreno
Affiliations:
Hematology,Hospital Clínic Barcelona,Barcelona,Spain
,
Pedro Castro
Affiliations:
Internal Medicine,Hospital Clínic Barcelona,Barcelona,Spain
,
Sara Fernández
Affiliations:
Internal Medicine,Hospital Clínic Barcelona,Barcelona,Spain
,
Yolanda Jordan
Affiliations:
Internal Medicine,Hospital Sant Joan de Déu,Barcelona,Spain
,
Jordi Esteve
Affiliations:
Hematology,Hospital Clínic Barcelona,Barcelona,Spain
,
Josep Maria Canals
Affiliations:
University of Barcelona,Barcelona,Spain
,
Esteve Trias
Affiliations:
Banc de Sang i Teixits,Barcelona,Spain
,
Jordi Yagüe
Affiliations:
Immunology,Hospital Clínic Barcelona,Barcelona,Spain
,
Montserrat Rovira
Affiliations:
Hematology,Hospital Clínic Barcelona,Barcelona,Spain
,
Alvaro Urbano-Ispizua
Affiliations:
Hematology,Hospital Clínic Barcelona,Barcelona,Spain
,
Manel Juan
Affiliations:
Immunology Platform Clínic-Sant Joan de Déu,Hospital Clínic Barcelona,Barcelona,Spain
,
Susana Rives
Affiliations:
Hematology,Hospital Sant Joan de Déu,Barcelona,Spain
Julio Delgado
Affiliations:
Hematology,Hospital Clínic Barcelona,Barcelona,Spain
EHA Library. Ortiz-Maldonado V. 06/16/19; 267390; S1636
Mr. Valentín Ortiz-Maldonado
Mr. Valentín Ortiz-Maldonado
Contributions
Abstract

Abstract: S1636

Type: Oral Presentation

Presentation during EHA24: On Sunday, June 16, 2019 from 09:00 - 09:15

Location: Amtrium

Background

Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) are major adverse events in patients receiving CART cell therapy. Forecasting the in vivo toxicity of “living drugs” like CART cells is complex and multifactorial. Some of these factors might be disease burden and CART cell dose, so adjusting dose to disease burden might be a plausible strategy to minimize toxicity. Nevertheless, reliably assessing disease burden is a tricky task due to technical issues and even hour-changing disease dynamics.

Aims

To characterize the impact of ARI-0001 cell dose fractioning on CRS and ICANS in two cohorts (fractioned vs single-full dose) of adult and pediatric patients with relapsed/refractory (R/R) CD19+ malignancies.

Methods

Eligibility criteria included patients with R/R CD19+ acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL) who had failed standard available therapy. All patients were conditioned with fludarabine (90 mg/m2) and cyclophosphamide (900 mg/m2) before receiving ARI-0001 cells (0.5-5 x106 cells/kg). Originally, patients received the entire ARI-0001 cell dose in a single infusion (day 0) (single dose [SD] cohort), but after 3 fatal toxic events (two of them CRS) a major amendment to the protocol was implemented. After the amendment, patients received 10%, 30% and 60% of the total ARI-0001 cell dose on days 0, +1 and +2 (fractionated dose [FC] cohort), with administration of fractions 2 and 3 contingent on the absence of CRS signs or symptoms. Also, before the amendment tocilizumab was administered to patients with grade ≥ 3 CRS and after amendment to patients with grade ≥ 2 CRS.

Results

As of February 2019, a total of 30 patients (23 adults/7 pediatrics) have received ARI-0001 cells (19 SD and 11 FD). Diagnoses were ALL (25), NHL (4) and CLL (1). Median age was 24 years (3-54), and 56% were men. 21/25 of ALL patients relapsed after alloHCT, and 3/4 of NHL patients relapsed after autoHCT. At screening, active disease (≥ 5% lymphoblasts in the bone marrow, or tumor masses by PET-CT) was documented in 62% of SD patients and 33% in FD patients. The remaining patients were in complete remission at screening.

CRS was observed in 16/19 (84%) of SD patients and 5/11 (45%) of FD patients. Indeed, fraction 3 was omitted in 2/11 (18%) FD patients due to early onset of CRS. Moreover, grade ≥ 3 CRS occurred in 5/19 (26%) of SD patients, including 2 fatal events, whilst 0/11 (0%) cases of grade ≥ 3 CRS were observed in FD patients. Finally, tocilizumab was administered to 26% (5/19) of SD patients and to 18% (2/11) of FD patients.

Grade 1-2 ICANS was documented in 3/19 (16%) of SD patients and in 3/11 (27%) of FD patients. The only 2 cases of grade 2 ICANS occurred in patients with known active CSF infiltration at the time of ARI-0001 cell infusion. No cases of grade ≥ 3 ICANS were seen neither in SD nor FD patients, and no specific treatment was required.

Conclusion

The fractionated administration of ARI-0001 cells may improve their safety profile by reducing the incidence of grade ≥ 3 CRS. The incidence of ICANS appeared equally low with both approaches. Based on these preliminary results, FD has been selected for a phase 2 multicenter trial on the use of ARI-0001 cells in patients with R/R ALL.

Session topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): ALL, Gene therapy, Immunotherapy, NHL

Abstract: S1636

Type: Oral Presentation

Presentation during EHA24: On Sunday, June 16, 2019 from 09:00 - 09:15

Location: Amtrium

Background

Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) are major adverse events in patients receiving CART cell therapy. Forecasting the in vivo toxicity of “living drugs” like CART cells is complex and multifactorial. Some of these factors might be disease burden and CART cell dose, so adjusting dose to disease burden might be a plausible strategy to minimize toxicity. Nevertheless, reliably assessing disease burden is a tricky task due to technical issues and even hour-changing disease dynamics.

Aims

To characterize the impact of ARI-0001 cell dose fractioning on CRS and ICANS in two cohorts (fractioned vs single-full dose) of adult and pediatric patients with relapsed/refractory (R/R) CD19+ malignancies.

Methods

Eligibility criteria included patients with R/R CD19+ acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL) who had failed standard available therapy. All patients were conditioned with fludarabine (90 mg/m2) and cyclophosphamide (900 mg/m2) before receiving ARI-0001 cells (0.5-5 x106 cells/kg). Originally, patients received the entire ARI-0001 cell dose in a single infusion (day 0) (single dose [SD] cohort), but after 3 fatal toxic events (two of them CRS) a major amendment to the protocol was implemented. After the amendment, patients received 10%, 30% and 60% of the total ARI-0001 cell dose on days 0, +1 and +2 (fractionated dose [FC] cohort), with administration of fractions 2 and 3 contingent on the absence of CRS signs or symptoms. Also, before the amendment tocilizumab was administered to patients with grade ≥ 3 CRS and after amendment to patients with grade ≥ 2 CRS.

Results

As of February 2019, a total of 30 patients (23 adults/7 pediatrics) have received ARI-0001 cells (19 SD and 11 FD). Diagnoses were ALL (25), NHL (4) and CLL (1). Median age was 24 years (3-54), and 56% were men. 21/25 of ALL patients relapsed after alloHCT, and 3/4 of NHL patients relapsed after autoHCT. At screening, active disease (≥ 5% lymphoblasts in the bone marrow, or tumor masses by PET-CT) was documented in 62% of SD patients and 33% in FD patients. The remaining patients were in complete remission at screening.

CRS was observed in 16/19 (84%) of SD patients and 5/11 (45%) of FD patients. Indeed, fraction 3 was omitted in 2/11 (18%) FD patients due to early onset of CRS. Moreover, grade ≥ 3 CRS occurred in 5/19 (26%) of SD patients, including 2 fatal events, whilst 0/11 (0%) cases of grade ≥ 3 CRS were observed in FD patients. Finally, tocilizumab was administered to 26% (5/19) of SD patients and to 18% (2/11) of FD patients.

Grade 1-2 ICANS was documented in 3/19 (16%) of SD patients and in 3/11 (27%) of FD patients. The only 2 cases of grade 2 ICANS occurred in patients with known active CSF infiltration at the time of ARI-0001 cell infusion. No cases of grade ≥ 3 ICANS were seen neither in SD nor FD patients, and no specific treatment was required.

Conclusion

The fractionated administration of ARI-0001 cells may improve their safety profile by reducing the incidence of grade ≥ 3 CRS. The incidence of ICANS appeared equally low with both approaches. Based on these preliminary results, FD has been selected for a phase 2 multicenter trial on the use of ARI-0001 cells in patients with R/R ALL.

Session topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): ALL, Gene therapy, Immunotherapy, NHL

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