CD19-Targeted T-Cell Therapy Results in Safe, Rapid Reinduction of CR in Patients With Relapsed/Refractory B-Cell ALL

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• Phase I trial: NCT01044069[1]

Summary of Key Conclusions

• In patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), CD19-targeted therapy with 19-28z chimeric antigen receptor (CAR) T cells produces rapid, high CR rates

• Similar efficacy in patients with minimal residual disease (MRD) and morphologic residual disease

• 70% of eligible patients transitioned to allogeneic stem cell transplantation (allo-SCT)

• Cytokine release syndrome (CRS) observed with 19-28z CAR T-cell treatment but can be effectively managed with steroids or tocilizumab

o Steroid treatment results in lymphotoxicity, leading to relapse

o No lymphotoxicity with tocilizumab

• Authors conclude reinduction rates and facilitation of allo-SCT justify further evaluation of 19-28z CAR T-cell therapy in phase II protocols

Background

• Up to 90% of adults with B-cell ALL achieve first CR with induction therapy

o Most relapse and become refractory to chemotherapy

o Allo-SCT standard of care for relapsed B-cell ALL

• Not all patients eligible

• New chemotherapy-free treatments needed for transplantation-ineligible relapsed patients

• 19-28z CAR T cells: novel CD19-targeted T-cell therapy

o T cells isolated from patients with relapsed/refractory B-cell ALL

• Genetically modified with CAR construct 19-28z CD19 binding domain fused to signaling domains of CD28 costimulatory receptor and zeta chain of CD3 receptor complex
• CD19: universal B-cell antigen expressed on normal and malignant B cells

o CD19 binding triggers cytotoxicity, cytokine release, and proliferation

• Role of CAR design in outcomes not yet fully understood

• Current study evaluated safety and efficacy of 19-28z CAR T-cell therapy in patients with relapsed/refractory B-cell ALL

Summary of Study Design

• Patients with B-cell ALL that is relapsed, refractory, MRD-positive, or in first CR

• Older than 18 years of age

• No exclusion for Philadelphia chromosome (Ph)–positive, extramedullary disease, central nervous system leukemia, and/or relapse following prior allo-SCT

• Treatment protocol for patients with relapsed B-cell ALL (n = 14)

o Leukapheresis

o Reinduction chemotherapy

o T-cell infusion (3 x 106 19-28z CAR T cells/kg)

o Monitoring for disease status and CAR T cells

• Polymerase chain reaction
• Flow cytometry
• Deep sequencing

• Treatment protocol for patients with B-cell ALL in first CR (n = 2)

o Leukapheresis followed by expectant monitoring

o Reinduction chemotherapy at relapse

o T-cell infusion, monitoring of CAR T cells and disease status as for relapsed patients

• Post–CAR T-cell treatment options

o Allo-SCT

o Different salvage therapy

o Monitoring, for patients not eligible for allo-SCT

Baseline Characteristics

• N = 16

• 86% of patients had residual disease after salvage reinduction chemotherapy prior to receiving CAR T-cell infusion

Main Findings

• 19-28z CAR T cells effective as salvage therapy

o Most patients induced into remission achieved complete molecular remission (CRm)

o Average time to CR: 24.5 days

• In patients with relapsed B-cell ALL and 60% to 70% bone marrow blasts after reinduction chemotherapy, rapid ablation of leukemia observed following CAR T-cell infusions[2]

o At 1-2 weeks post–CAR T-cell infusion

• Bone marrow aplastic
• Only CAR T cells present

o At 1-2 months post–CAR T-cell infusion

• Complete bone marrow restoration
• Functional and cellular recovery

• Adverse events observed

o Fevers

o Malaise

o Hypotension

o Hypoxia

o Neurologic changes

• Seizures
• Mental status changes
• Obtundation

• Toxicities correlated with pretreatment tumor burden

o Fevers

• Higher grade, longer duration in patients with pretreatment morphologic residual disease
• Low-grade fevers, if any, and shorter duration of fever with pretreatment MRD

o CRS also highest in patients with more residual disease (sIL2R?, TNF?, fractalkine, and GMCSF)[2]

• Management of CRS with steroids reduced fevers, but CAR T cells failed to expand in the blood and crashed soon after steroid treatment
• Management of CRS with tocilizumab reduced fevers without affecting CAR T-cell expansion

• Correlation with clinical outcomes

o All relapses (n = 3) occurred in patients treated with steroids

o No relapses in those treated with tocilizumab or managed conservatively

o 5-fold higher CAR T-cell expansion in bone marrow among patients with CRS and morphologic residual disease

• Allo-SCT post–19-28z CAR T-cell infusion

o 7 of 16 patients (44%) proceeded to allo-SCT to date, representing 70% of eligible patients

• 3 patients in CR medically ineligible for allo-SCT
• 1 patient pending evaluation with BMT service
• 2 patients declined transplant

o Post–allo-SCT follow-up: 2-24 months

o No post–allo-SCT relapses to date

Other Outcomes

• Pheresis products initiated with CD3 T cells ranging from 3.7% to 86%

• 15 of 16 patients achieved a CAR T-cell dose of 3 x 106 19-28z T cells/kg

• Average CAR T-cell transfer efficiency: 24% (range: 5% to 61%)

• Average CAR T-cell production time: 11 days

 References

1. Davila ML, Riviere I, Wang X, et al. Safe and effective re-induction of complete remissions in adults with relapsed B-ALL using 19-28z CAR CD19-targeted t cell therapy. Program and abstracts of the 55th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2013; New Orleans, Louisiana. Abstract 69.

2. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5:177ra38