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. Do we need to intensify therapy in PTCL ?
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 (20-60)
Male/female ratio /18
Histological subtype
Anaplastic large cell
Unspecified
AILD
Other
Stage III-IV
Extranodal sites ≥
aaIPI score ≥
Therapy
HDS
MACOP-B/MAD
HDS: High-dose sequential;
MAD: mitoxantrone-Ara-C-Dex
Corradini et al. Leukemia 2006

7. 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 (%)

8. 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

9. Multivariate analysis
5-year OS
Not CR vs CR HR ( ) P <
5-year EFS
Not CR vs CR HR ( ) P <
aaIPI 2-3 vs 0-1 HR ( ) 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. 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

12. 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: % at 2 yrs

13. RIC treatment plan Allo-SCT Cyclosporine Thiotepa 10 mg/kg
Fludarabine 30 mg/mq
Cyclophosphamide 30 mg/kg
MTX
MTX
MTX
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. 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%

16. 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.

17. 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%

18. 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

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
63%
73%
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 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 mg
Intrathecal Ara-C mg
Intrathecal Dexamethasone mg
First cycle HYPER-C-HiDAM (Methotrexate 1.5 gr/m2 in c.i. day +1; Cyclophosphamide 300 mg/m2 every 12 hours days ; ARA-C 2 gr/m2 every 12 hours days ); 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.

28. 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 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. 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