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

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)

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

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

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

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

Event-free Survival (%) 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% 48% IPI 0-1 P=0.02 IPI 2-3 24% Event-free Survival (%) C Prognostic factors for auto-SCT in PTCL: aaIPI Alk-positivity Pre-transplant CR

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;

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

42% 2 year Overall Survival PTCL better OS vs non PTCL 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

Corradini P et al., J Clin Oncol 2004 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

RIC treatment plan Allo-SCT Cyclosporine 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

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

Previous autologous SCT Prospective observational study in relapsed PTCL Patients Characteristics n= 32 No. lines (range) 2 (1-3) Previous autologous SCT 53% CR pre-allogeneic SCT 28% PR pre-allogeneic SCT 44%

Patients Characteristics n= 32 Histologic subtype Unspecified n= 14 Specified* n= 18 Age (median) 42 (15-64) Sex n=22 M n=10 F Median time from diagnosis to allo-SCT 16 months N= 8 ALCL (5 ALK neg, 3 ALK pos), N= 3 intestinal, N=4 AILD, N=1 others.

Transplant characteristics HLA-matched related 75% One antigen mismatched related 9% Haploidentical donor Matched unrelated donor 7% Stem cell source 78% PBSC 22% BM Reduced-Intensity Conditioning 100%

N= 10 death (7 disease, 3 toxicity) 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

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

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

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

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)

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 !

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

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)

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

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 with G-CSF 5 cg/kg/day starting from day +5 until peripheral blood stem cell harvest.

autologous transplantation: 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.

GITIL and GITMO study groups 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