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The role of allogeneic transplantation in peripheral T-cell lymphomas

The role of allogeneic transplantation in peripheral T-cell lymphomas. Paolo Corradini, M.D. Dept. of Hematology and Bone Marrow Transplantation – University of Milano, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy. A very difficult task !. La Palud sur Verdon, France.

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The role of allogeneic transplantation in peripheral T-cell lymphomas

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  1. The role of allogeneic transplantation in peripheral T-cell lymphomas Paolo Corradini, M.D. Dept. of Hematology and Bone Marrow Transplantation – University of Milano, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy

  2. A very difficult task ! La Palud sur Verdon, France

  3. Background • PTCLs are a quite heterogeneous group of malignancies characterized by a poor outcome • Antracycline-containing regimens obtain 41% overall and 33% event-free survival rates at 5 years (Gisselbrecht et al. Blood 1998)

  4. Question # 1: Do we need to intensify therapy in PTCL ? Question #2: auto or allo-SCT ?

  5. Limitations of studies on auto-SCT in relapsed PTCL • Inclusion of patients with relapsed ALK-positive ALCL have overestimated the benefit of auto- SCT • Some studies did not report the IPI score • Several studies are retrospective

  6. Prospective phase II study on 62 pts receiving auto-SCT frontline Parameter n (%) • Age, median (range), years 43 (20-60) • Male/female ratio 44/18 • Histological subtype Anaplastic large cell 19 30 Unspecified 28 45 AILD 10 16 Other 5 8 • Stage III-IV 51 82 • Extranodal sites ≥ 2 32 52 • aaIPI score ≥ 2 44 71 • Therapy HDS 32 52 MACOP-B/MAD 30 48 HDS: High-dose sequential; MAD: mitoxantrone-Ara-C-Dex Corradini et al. Leukemia 2006

  7. 55% 30% 34% B Disease-free Survival (%) Disease-Free Survival Overall Survival Overall Survival (%) C Event-Free Survival median follow-up 5 years: disappointing results ! Event-free Survival (%)

  8. P=0.02 IPI 0-1 Event-free Survival (%) 48% 24% IPI 2-3 Figure 2 A B P=0.005 ALCL alk+ P=0.006 62% ALCL alk+ 54% Overall Survival (%) non-ALCL alk+ Event-free Survival (%) non-ALCL alk+ 21% 18% C Prognostic factors for auto-SCT in PTCL: aaIPI Alk-positivity Pre-transplant CR

  9. Multivariate analysis 5-year OS Not CR vs CR HR 7.78 (2.86-18.57) P < 0.0001 5-year EFS Not CR vs CR HR 8.54 (3.84-18.89) P < 0.0001 aaIPI 2-3 vs 0-1 HR 2.64 (1.07-6.56) P = 0.04 Abbreviations: CR: Complete Remission; aaIPI: age.adjusted International Prognostic Index;

  10. What about the Graft-versus-Lymphoma effect in PTCL ? In the last 20 years very few allotransplants were performed with some long-term responses, but with a particularly high non-relapse mortality

  11. Aggressive NHL (n= 111)myeloablative allogeneic SCT from related and unrelated donor 42% 2 year Overall Survival PTCL better OS vs non PTCL Sung-Won K, Blood 2006

  12. Graft-versus-Lymphoma effect in relapsed peripheral T-cell non-Hodgkin lymphomas after reduced-intensity conditioning followed by allogeneic SCT Corradini P et al., J Clin Oncol 2004 17 patients (15 chemosensitive) Estimated OS 80%, PFS: 60% at 3 yrs Nonrelapse mortality: 6% at 2 yrs

  13. RIC treatment plan Thiotepa 10 mg/kg Fludarabine 30 mg/mq Cyclophosphamide 30 mg/kg MTX MTX MTX -6 -4 -3 -2 -1 0 +1 +3 +6 +30 +60 +70 +90 +120 +150 +180 Allo-SCT Cyclosporine Corradini et al. Blood 2002

  14. PFS in relapsed PTCL Median Follow-up 36 months Corradini P et al., J Clin Oncol 2004

  15. Prospective observational study in relapsed PTCLPatients Characteristics n= 32

  16. Patients Characteristics n= 32 N= 8 ALCL (5 ALK neg, 3 ALK pos), N= 3 intestinal, N=4 AILD, N=1 others.

  17. Transplant characteristics

  18. Overall Survival 72% 62% 56% P = NS N= 22 alive (16 CR, 3 PR, 3 PD) N= 10 death (7 disease, 3 toxicity) median follow-up 30 months

  19. Overall Survival and Time to SCT P = NS median follow-up 30 months

  20. Progression-free Survival 57% 53% 47% P = NS Median time to relapse 5 months median follow-up 30 months

  21. Progression-free survival and disease status 73% 63% 56% 30% 30% P<0.009 median follow-up 30 months

  22. DLBCL versus PTCL only HLA-matched siblings 68% 66% 59% 59% P = NS P = NS PTCL n = 27 (6 death disease, 3 death toxicity) DLBCL n = 31 (5 death disease, 5 death toxicity)

  23. Conclusions • RIC allo-SCT has decreased NRM • Allo-SCT has showed promising results for disease control in relapsed patients • Allo-SCT frontline ? • New agents are urgently required !

  24. Multicenter prospective phase II study for PTCL at diagnosis ENDPOINTS Primary: To evaluate the efficacy (ie complete clinical response at one year) of an intensified chemo-immunotherapy program including stem cell transplantation in patients with PTCL Secondary: Overall survival Disease ‑ free-survival Treatment – related mortality

  25. GITIL phase II study in alk negative PTCL • Clin A age 18 -60 yrs CHOP-C x 2 then high-dose CT (mtx, ara-c, cy) followed by auto or alloRIC according to a genetic stratification Primary end point: CR rate at one year • Clin B age 60 – 75 yrs CHOP-C x 6 (alemtuzumab 10 mg)

  26. Inclusion criteria: • Age ≥18 60 yrs (clin A); >60 <75 yrs (clin B) • Histologically proven diagnosis of PTCL, including the following categories: PTCL-U, AILD-T, ALKneg ALCL (ALK-negative anaplastic large cell lymphoma),intestinal T – NHL • Advanced stage disease (stage II-IV) or stage I and aaIPI score ≥ 2 • CD52 expression on neoplastic cells

  27. INDUCTION PHASE CLIN-A: CHOP-Campath (CHOP-C) for 2 cycles (repeated every 21 days): Lumbar puncture on days +1, +21 during the first 2 CHOP-C cycles then monthly for 6 months after transplant Intrathecal Methotrexate 12.5 mg Intrathecal Ara-C 40 mg Intrathecal Dexamethasone 4 mg First cycle HYPER-C-HiDAM (Methotrexate 1.5 gr/m2 in c.i. day +1; Cyclophosphamide 300 mg/m2 every 12 hours days +2-3-4; ARA-C 2 gr/m2 every 12 hours days +2-3-4); G-CSF 5 cg/kg/day starting from day +5. Second cycle HYPER-C-HiDAM withG-CSF 5 cg/kg/day starting from day +5 until peripheral blood stem cell harvest.

  28. Patients in PR or CR without a HLA-identical sibling or unrelated donor: autologous transplantation: BEAM regimen followed by reinfusion of PBSC on day 0 (>4 x 10e6 CD34+/kg). Patients in PR o CR with a HLA-identical donor: allogeneic transplantation: Conditioning regimen: Thiotepa 15 mg/kg (day –6) for patient < 45 years and 10 mg/ kg for patient ≥ 45 years; cyclophosphamide 30 mg/kg (days –4 and –3); fludarabine 30 mg/m2 (days –4 and –3) followed by alloSCT from a HLA-identical (or one antigen mismatched) sibling or from an allele matched unrelated donor on day 0 (5–8 x 10e6 CD34+ cell/kg). ATG will be part of the conditioning for mismatched siblings and unrelated donors. GVHD prophylaxis: CSA, adjusted to 200-300 ng/ml blood levels, and short course methotrexate (10 mg/m2 day +1, 8 mg/m2 day +3 and +6). In patient in CR after transplantation CSA is administered at full dose through day +100 and, if GVHD did not occur, the dose is tapered by 10% every 10 days thereafter.

  29. Aknowledgments Dept. of Hematology Istituto Nazionale dei Tumori University of Milano A. Dodero, R. Milani, F Zallio V. Montefusco, C. Carniti Dept. of Medical Oncology Istituto Nazionale Tumori University of Milano A.M. Gianni, P. Matteucci Dept. of Hematology University of Torino C. Tarella, M. Boccadoro • Dept. of Hematology • Ospedali Riuniti, Bergamo • Rambaldi T. Barbui • Dept Hematology • Bolzano Hospital • S Cortelazzo GITIL and GITMO study groups Rijukanfossen Norway

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