• UHIT Udruženje hematologa i transfuziologa

    UHIT Udruženje hematologa i transfuziologa

    Više
  • BIHEM smjernice

    BIHEM smjernice

    Više
  • UHIT novosti i događaji

    UHIT novosti i događaji

    Više

Bosansko-hercegovačka kooperativna grupa za hematološke bolesti

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

 

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


• 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


Udruženja hematologa i transfuziologa u FBiH

zvanična web stranica Udruženja

CIljevi Udruženja: praćenje razvoja dostignuća iz oblasti hematologije, transfuziologije i transplantacije i upoznavanje članova Udruženja sa novinama u cilju unapređivanja njihovih znanja i osposobljavanja, razvijanje etičke svijesti, morala odgovornosti i svijesti članova Udruženja u skladu sa kodeksom etike zdravstvenih radnika FBiH i međusobna razmjena mišljenja i iskustava u naučnom, stručnom radu iz područja hematologije i transfuziologije i srodnih naučnih disciplina.


Saznaj više
School Learning


    • Neutropenična dijeta

      Neutropenična dijeta je režim ishrane kojeg se pridržavate kad ste neutropenični. Važno je slijediti dijetu s niskom količinom sadržanih bakterija dok se imunološki sistem oporavlja.

      Više
    • Kako živjeti sa limfomom

      Brošura za pacijente u .pdf formatu. Šta je limfom? Koji je uzrok? Kako se postavlja dijagnoza?

      Više


    77

    članova


    16

    centara

    Our school goals

    Kako postati član?

    Poštovane kolege,

    pristupnicu je potrebno dostaviti poštom ili faksom te jedan primjerak odnijeti u računovodstvo ustanove u kojoj ste zaposleni da bi se vršila mjesečna uplata članarine.

    Više

    Kontakt telefon

    033 297 160

    Kontakt email

    info@uhit.ba