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Acute Lymphoblastic Lymphoma: Treatment Update
- 1. Acute lymphoblastic lymphoma: Updatesfrom ASCO and EHA Nina Shah, MD Department of Stem Cell Transplantation and Cellular Therapy M.D. Anderson Cancer Center Houston, TX
- 2. Treatment paradigm Induction ConsolidationMaintenance Relapse HSCT MRD monitoring
- 3. Long-term data withHVCAD1 • Ph+ adults • HVCAD + dasatinib induction (included MTX/Ara-C): total 8 cycles • Dasatinib/vincristine/prednisone x 2 years • Indefinite dasatinib • Median f/u 67 months: – 46% alive – 43% in CR 1. Ravandi et al, Cancer 2015
- 4. Upfront treatment ofALL • Kim et al, EHA abs #p167 • Phase II trial: Rituximab + vincristine/prednisolone/daunorubicin/L- asparaginase consolidation chemo-R maintenance • N=36 • 1-year and 21 –month RFS were 71.5% and 49.1%,
- 5. Treatment of MRDin ALL • Blinatumomab: “BiTE” technology directed at CD19 and CD3 to bring target cells close to effector cells • Original phase 2 data showed 43% CR in R/R pts1 • Phase 2 results from ASH 2014 (Goekbuget et al) for pts with MRD positivity • MRD response rate of 80% 1. Topp et al, Lancet Oncol, 2015
- 6. Upfront treatment ofALL- older pts • Pfeifer et al, EHA abs #S113 • Nilotinib + chemotherapy for pts >55 years • Ph+ ALL • Induction: nilotinib + vincristine and Dex, weekly x 4 weeks • Consolidation: nilotinib, methotrexate (MTX) and asparaginase for cycles 1, 3 and 5 and cytarabine for cycles 2, 4 and 6. • Maintenance: nilotinib, 6-MP, MTX and Dex/VCR • CHR=87% • MMR 46% • Well-tolerated An option for our older Ph+ ALL patients
- 7. Upfront treatment ofALL- older pts • Papayannidis, EHA abs #P163 • Sequential nilotinib (400 BID) with imatinib (300 BID) alternating for 6 weeks for 24 weeks/ indefinitely • OS at 1 year is 82%, and 64% at 2 years • Median time to relapse of 9.2 months
- 8. Upfront treatment ofALL-older pts • Jabbour, EHA Abs #S114 • Inotuzumab-ozogamicin + mini Hyper-CVD • Pts >60 years • N= 33 • CR/CRp = 97% • 2-year PFS: 85% • 2- year OS: 70%
- 9. T-ALL • Lepretre etal, ASH 2014 • Pediatric-like regimen • corticosteroid prephase 5-drug induction with sequential cyclophosphamide high dose consolidationlate intensification • CNS prophylaxis with IT injections and cranial irradiation, • 2-year maintenance. • 5 years DFS, EFS and OS: 71%, 61% and 66%,
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- 11. Relapsed ALL • Bertrandet al, ASCO abs #7004 • Randomized phase II study of ERY001 (erythrocyte encapsulated l-asparaginase) and native l- asparaginase (L-ASP) with COOPRALL regimen • ERY001 improves PKs, tolerability and maintains circulating asparaginase • ERY001 significantly reduced the incidence of ASPA hypersensitivity (0% vs 43%; p < 0.001) • Lengthened time of ASPA activity (21 vs 9 days) • The CR rate: ERY001 (65%) vs L-ASP (39%) p = 0.026 • 12 mo EFS rate was 65% vs 49%
- 12. Relapsed ALL- CD19CAR T cells • Park et al, ASCO abs #7010 • 19-28z CAR T cells (anti-CD19 scFv linked to CD28 and CD3ζ signaling domain) • Long-term outcome of phase I trial • N= 33, 32 evaluable • overall CR rate of 91% (29/32) • MRD negative CR rate was 82% • 6-month overall survival (OS) rate of all patients was 58%, 70% for those achieving CR • Cytokine release syndrome (CRS) in 7, managed with anti IL-6 or steroids
- 13. Relapsed ALL- CD19CAR T cells with CD8 and CD4-selection • Turtle, et al ASH 2014 • Selection of CD4 and CD8 cells in separate cultures • CD3/CD28 stimulation • Transduction with anti-CD19 scFv linked to 4- 1BB and CD3 zeta signaling domains • Product = 1:1 ratio of CD4 :CD8 CAR T cells • CR in 5/7 ALL pts (early data)
- 14. CAR-T cells upfrontduring HSCT • Kebriaei et al, EHA abs #S802 • 2nd generation CD19-specific CAR (CD19RCD28) that activates via CD3z/CD28 • From donor derived T cells for patients with advanced CD19+lymphoid malignancies (ALL =13, 16 total) • Infused at median 64 days after allo-transplant • No toxicities • 50% patients (n=8) alive and in CR at median 7.2 • months (range 2.1-21.3 months) following HSCT
- 15. Relapsed ALL- Blinatumomab •Topp et al, ASCO abs #7051 • Bispecific T-cell engager antibody construct to link cytotoxic T cells (CD3) and CD19-positive B cells • Re-exposure to blinatumomab after CD19-positive relapse: Experience from three trials (n=11)
- 16. Treatment of ALL-olderpts with relapsed disease • Kantarjian1 et al, EHA Abs #S115 • Blinatumomab 4 weeks on, 1 week off, up to 5 cycles • N=36 • CR/CRh = 56% with 60% of these MRD negative • RFS 7.4 mo • Cyotpenias, 1 pt with cytokine release syndrome
- 17. Relapsed ALL- trialsin progress • DeAngelo et al, EHA abs #LB2073 • Inotuzumab ozogamicin (InO) vs SOC (FLAG or mitoxantrone-Ara C or HiDAC) in adults with relapsed/refractory ALL
- 18. Conclusions • Paradigm forALL still rests on long sequence of induction, consolidation and maintenance chemotherapy • Addition of TKIs for Ph+ • Efforts to eradiate MRD (Blinatumomab) • More options for our older pts • Relapsed ALL is still a challenge: – Inotuzumab – HSCT – CAR-T cell therapy
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Editor's Notes
- #12 Ara c mitoxantrone dex asp