Dr. Andrea Gallamini - Hematology Department Azienda Ospedaliera S. Croce e Carle Cuneo Italy

Transcription

1 High-dose sequential chemotherapy (HDS) followed by autologous stem cell transplantation (ASCT) in relapsed/refractory Hodgkin s lymphoma. Long term results. Dr. Andrea Gallamini - Hematology Department Azienda Ospedaliera S. Croce e Carle Cuneo Italy IV Russian conference on malignant lymphoma Moscow, October 25, 2007

2 J M Connors, Hematology, 2003

3 Novel approaches to primary treatment of HL and additional options for the treatment of relapsed disease have resulted in new questions: Should patients who receive chemotherapy alone for early stage disease and have a localized relapse at the site of initial disease receive RT or ASCT at the time of first relapse? Should patients who have a positive FDG-PET scan after the first cycles of chemotherapy receive an early alternative or salvage therapy? What options are available for patients relapsing after aggressive firstline regimens? Given the marked decrease in mortality following allogeneic transplant with RIC, are there circumstances where this approach would be favored over ASCT? How should newer agents with activity in HL be incorporated into treatment of relapse disease?

4 Relapsed/refractory HD HDS + ASCT WHY?

5 background - 1 a better outcome following HDT and autograft compared with conventionaldose treatments has been reported in refractory or relapsed Hodgkin's lymphoma (HL) patients Linch DC et al, Lancet 1993, 341: 1051 Reece DE et al, Blood 1994, 83: 1193 Horning SJ et al, Blood 1997, 89: 801 Sureda A et al, J Clin Oncol 2001, 19: 1395 Schmitz N et al, Lancet 2002, 359, 2065

6 144 p. in ralapse after standard 1-st line CT Most in advanced-stage (64%) 114 first relapse 30 multiple relapse Schmitz N.: Lancet 2002; 359,

7 New Prognostic Score Based on Treatment Outcome of Patients With Relapsed Hodgkin s Lymphoma Registered in the Database of the G H L S G Patients 422/4754 (9%) relapsed: 5-year FF2F and OS: After RT 107 (25%) (early stages) PD 17% 26% After CT+RT 133 (31%) (intermediate stages) Early relap. 33% 46% After CT+RT 182 (43%) (bulky or r.d.) (Advanced stages) Late relap. 43% 71% Josting et al: JCO 2002

8 Reference Group N Previous therapy Regimen TRM Relapsed (5-y FFS) Refractory (5-y FFS) Perz Bone Marrow Transplant Hammersm ith 67 ABVD, BEMOP- CA, COPP HDVP-16 + LACE 3% 78% 35% Martinez Leuk. Lymphoma 2007 Barcelona 61 MOPP, ABVD, MOPP/ABVD BEAC/BEAM 16.4% 52% 28% Josting Ann. Oncol 2005 GHSG 102 COPP/ABVD, ABVD, BEACOPP HDS + BEAM 4% 63% (3y) 41% (3y) Lavoie Blood 2005 Vancouver 100 MOPP/ABVD MVPP + CBV 17% (15 y.) 62% (15 y) 39% (15Y) Moskowitz Br. J. Hematol 2004 MSKCC 75 MOPP, ABVD, MOPP/ABVD ICEx2, TLI + HDCTX,VP16 10% % Czyz Ann. Oncol.2004 Polish Lymphoma 273 MOPP, ABVD, MOPP/ABVD BEAM, CBV 5% 62% 16% Sureda Ann. Oncol 2005 GEL/TAMO 375 MOPP, ABVD CBV, BEAM, BEAC 10% 49% --- Constans Ann. Oncol 2003 GEL/TAMO 62 MOPP, ABVD, MOPP/ABVD CBV, BEAM, BEAC 14.5% % Tarella Cancer 2003 IIL 102 ABVD MOPP/ABVD HDS +MITO / MEL or BEAM 8% 55% 33% Sweetenham JCO 1999 EBMT/Lymphoma WP 175 MOPP, MOPP/ABVD BEAM,CBV, TBI +CTX 10% 40% 20%

9 OS after Conventional Salvage Therapy or High Dose Chemotherapy and ASCT (GHSG Model) Risk factors: early relapse<12 mo, stage III-IV, hemoglobin<10.5g/dl F,<12 g/dl M. Josting et al: JCO 2002

10 Predictive factors on OS in relapsed/refractory HD: chemosensitivity OS: number of prior CT regimens (Nadermanee 1995) OS: interval between diagnosis and ASCT (Sweetenham 1999) OS: short time to relapse, stage IV and anemia at relapse. (Josting 2001) OS: B-symptoms, 1-st line therapy MOPP, 2 or more lines f therapy before ASCT, bulky at ASCT (Constans 2003). OS: refractory disease and B-symptoms at diagnosis (Tarella 2003). OS: < than PR before ASCT, 3 previous CT lines (Czyz 2004). OS: chemosensitivity to 2-nd line CT (Moskowitz 2004) OS: primary refractory disease, advanced disease at relapse (Lavoie 2005) OS: Bulky ad diagnosis, stage IV at transplant (Martinez 2007). OS: Mixed-cellularity or lymphocyte depletion, Hb< than 10 gr/dl at ASCT (Perz 2007).

11 Predictive factors on OS in relapsed/refractory HD: tumor biology/burden OS: number of prior CT regimens (Nadermanee 1995) OS: interval between diagnosis and ASCT (Sweetenham 1999) OS: short time to relapse, stage IV and anemia at relapse. (Josting 2001) OS: B-symptoms, 1-st line therapy MOPP, 2 or more lines f therapy before ASCT, bulky at ASCT (Constans 2003). OS: refractory disease and B-symptoms at diagnosis (Tarella 2003). OS: < than PR before ASCT, 3 previous CT lines (Czyz 2004). OS: chemosensitivity to 2-nd line CT (Moskowitz 2004) OS: primary refractory disease, advanced disease at relapse (Lavoie 2005) OS: Bulky ad diagnosis, stage IV at transplant (Martinez 2007). OS: Mixed-cellularity or lymphocyte depletion, Hb< than 10 gr/dl at ASCT (Perz 2007).

12 Primary Refractory Disease

13 Actuarial OS and FFTF of 131Primary progressive HD Patients and aggressive NHL Patients A Josting et al JCO, 2000

14 Actuarial OS of Primary Progressive HD Patients treated With or Without HDCT A Josting et al JCO, 2000

15 Tandem Autologous Stem Cell Transplantation for 46 Patients with primary refractory or Poor Risk Recurrent HD 1st: Melph: 150 mg/sqm; 2nd: FTBI or BCNU (450 mg/sqm) +VP16 60 mg/kg +Cy.100 mg/kg) H C Fung et al, Biol Blood Marrow Transplant, 2007

16 Relapsed/refractory HD HDS + ASCT WHY?

17 background - 2 intensive chemotherapy debulking prior to autograft seems to increase the probability of long-term survival, as reported by the MSKCC group,by the French Lymphoma study group and by the Milan INT group. Moskowitz CH et al, Blood 2001, 97: 616 Fermé C et al, J Clin Oncol 2002, 20: 467 Gianni AM et al, Ann Oncol 1993, 4: 889

18 Scheme of the high-dose sequential (HDS) chemotherapy with PBPC autografting CY 7 g/sqm G-CSF PBPC harves t MTX 8 g/sqm VP16 2 g/sqm G-CSF MITO /L-PAM + PBPC autograft CY=cyclophosphamide; MTX=methotrexate; VP16=etoposide; MITO = mitoxantrone; L-PAM=melphalan; PBPC=peripheral blood progenitor cells

19 S.G.: CT scan before hd-arac

20 S.G.: CT scan after hd-arac

21 AraC-containing HDS scheme (c-hds) for relapsed Hodgkin Lymphoma DHAP x 2 CY 7 g/sqm 1st PBPC harvest R 1 R 2 HD- ARAC 2nd PBPC harvest (MTX) VP16 ASCT (BEAM) G - C S F G - C S F G - C S F CTX: 7 g/m 2 - AraC: 24 g/m 2 MTX 8g/m 2 -VP-16 2 g/m 2 BEAM= BCNU 300 mg/m 2, VP mg/m 2 x4d, AraC 400mg/m 2 x4d, Melphalan: 140 mg/m 2 R1= 2 x 10 6 CD34+ cells +/kg. R2= >4 x 10 6 CD34+/kg

22 102 PATIENTS in 14 IIL CENTERS 24 primary refractory, 59 first recurrence, 19 multiple recurrences Tarella C. Cancer 2003; 97,

23 High-Dose Sequential Chemotherapy and Peripheral Blood Progenitor Cell Autografting in Patients with Refractory and/or Recurrent Hodgkin Lymphoma (IIL Study) Grade 3-4 extrahematologic morbidity: 10 episodes of pneumonia, 5 liver toxicities, 14 sepsis, 2 hemorrhagic cystitis, 1 cardiac, 1 neurologic 5-yr OS Ref=36%;1s Rel= 77 %; >2 Rel 59% 5-yr EFS Ref=33%;1s Rel= 63%; >2 Rel =47% OS according to disease status at the time pts receive HDS. EFS according to disease status at the time pts receive HDS. Tarella C. et al, Cancer, 2003

24 HDS in Relapsed and Refractory HD Lymphoma (GHSG Study) A Josting et al, Ann Oncol, 2005

25 Response at the Final Evaluation A Josting et al, Ann Oncol, 2005

26 HDS in Relapsed and Refractory HD Lymphoma (GHSG Study) A Josting et al, Ann Oncol, 2005

27 HDS in Relapsed and Refractory HD Lymphoma (GHSG Study) smds: 1/102 A Josting et al, Ann Oncol, 2005

28 UPDATED RESULTS: BZ 240 PATIENTS 8 Italian Hematology referral centers TO2 MI TO1 CN BG VR Accrual time: > p. s-hds, 63 c-hds ASC regimen: BEAM/Mito-Mel Median follow-up: 55.8 months PA

29 Table 1. Main patient characteristics at HDS Parameter No. (%) (total = 240) Male Female 127 (53) 113 (47) Age, yrs. mean (range) 32.3 (11-61) Ann Arbor Stage I-II III-IV nd 102 (43) 131 (55) 7 ( 3) B symptoms 124 (52) BM involv. 23 (10) Bulky disease 100 (42) Performance Status 2 34 (14) Previous Radiotherapy 102 (42)

30 Table 2. Main patient characteristics at diagnosis according to disease status subgroups Parameter Refractory (n=77) Patient subgroups relapse (1 therapy) (n=147) relapse (2 or more therapy) (n=16) Total (n=240) No. of patients No. (%) Age, yrs. mean (range) 30 (11-59) 33 (14-61) 35 (24-52) 28 (12-59) Ann Arbor Stage I-II III-IV nd (30) 68 (28) 99 (41) B symptoms (52) First line therapy: - ABVD - MOPP -MA/MA -Stanford - 2 or more therapy - other protocols nd (49) 49 (20) 9 ( 4) 8 ( 3) 6 ( 3) 19 ( 8) 16 ( 7)

31 Feasibility of the program 229 of 240 (95%) patients completed the program Autograft was performed with - PBPC in 187 patients (81.7%) - PBPC+BM cells in 16 patients (7.0%) - BM cells in 21 patients (9.2%) - nd in 5 patients (2.2%) Overall, the median value of harvested CD34+ve cells/kg was 6.4x10 6 /kg (range 1-43) 15 patients received post-graft consolidation RT

32 TRM and secondary malignancies there were 13 toxic deaths (TRM = 5.4%) 5 patients developed AML/MDS 5 patients developped solid tumors: 1 NHL, 1 breast cancer, 1 colon cancer, 1 lung cancer, 1 pancreatic cancer

33 Causes of Death (N = 101) Cause of death Frequency Percentage Disease Toxicity MDS/AML Solid tumor # Other Unknown CMV pneumonia, Hepatitis B, Septic shock, liver failure, cardiac arrest, post Tx GVHD, pulmorary embolism. # NH lymphoma, Intestinal neoplasm, adenok pancreas, adenok colon, breast cancer.

34 Table 3. Response to HDS according to disease status subgroups Parameter Refractory (n=77) relapse (1 therapy line ) (n=147) Patient subgroups relapse ( 2 therapy lines) (n=16) Total (n=240) No. of patients (%) HDS completion 70 (91) 143 (97) 16 (100) 229 (95) C R 31 (44) 81 (57) 6 (38) 118 (52) P R 16 (23) 18 (13) 2 (13) 11 ( 5) NR/progression 18 (26) 32 (22) 7 (44) 57 (25) Not evaluable 1 (1) 0 (0) 1 (6) 2 ( 1) Toxic death 4 (6) 12 (8) 0 (0) 16 ( 7) CR=complete remission, PR=partial remission, NR=no response.

35 Long term results of HDS (n= 240) Patients 10-y OS (%) p 10-y FFS (%) p all Status at HDS N of therapy lines Resistant <.001 Relapsed > >.05 <.001 Median follow-up: 55.8 (8-261) months

36 Kaplan-Meier s estimates of the overall survival distribution - log rank test. Parameter modality Log rank p Gender 0.0 (p>0.05) Age <45 vs >= (p>0.05) Ann Arbor Stage I-II vs III-IV 0.5 (p>0.05) B symptoms 2.4 (p>0.05) Bulky disease 2.7 (p>0.05) Performance Status (p>0.05) IPS <3 vs >=3 4.4 (p<0.05) MDS 2.7 (p>0.05) Secondary solid tumor 0.1 (p>0.05) Nodular sclerosis vs other 2.4 (p>0.05) C-HDS vs other 0.5 (p>0.05) CR achievement 90.8 (p<0.01) TBI 0.1 (p>0.05) LDH 11.7 (p<0.01) Disease status at HDS 39.1 (p<0.01) 1 therapy line vs. 2 o more 0.8 (p>0.05)

37 Overal survival: multivariate analysis In multivariate analysis the factors turning out significant were treatment response (HR=0.2; 95% ic: ) and high vs. normal LDH (HR 1.7; 95% ic: ).

38 15-y probability of overall survival (n= 240) 1,0 Overall survival cumulative proportion of survival 0,8 0,6 0,4 0,2 10-Y OS = , years from start of the treatment

39 15-y probability of Failure free survival (n= 240) Failure free survival 1,0 cumulative proportion of survival 0,8 0,6 0,4 0,2 10-Y FFS= , years from start of the treatment

40 Probability of overall survival according to status of disease at HDS 1,0 Status of disease at entry - overall survival cumulative proportion of survival 0,8 0,6 0,4 0,2 Log-Rank =7.5 p<0.01 relapsing disease resistant disease 0, years from start of the treatment

41 Probability of failure free survival according to status of disease at HDS 1,0 Status of disease at entry - failure free survival cumulative proportion of survival 0,8 0,6 0,4 0,2 relapsing disease resistant disease Log-Rank =2.9 p>0.05 0, years from start of the treatment

42 Status at transplantation: Overall survival 1,0 Status of disease at transplantation - overall survival cumulative proportion of survival 0,8 0,6 0,4 0,2 PR resistant disease CR Log-Rank =39.1 p<0.01 0, years from start of the treatment

43 Status at transplantation: Failure free survival 1,0 Status of disease at transplantation - failure free survival cumulative proportion of survival 0,8 0,6 0,4 0,2 resistant disease CR PR Log-Rank =28.0 p<0.01 0, years from start of the treatment

44 We need randomized trials A Randomized Trial of Chemotherapy with BEAM plus PBSCT vs Single-Agent HDCT Followed by BEAM plus PBSCT in Patients with Relapsed HD (HD-R2) JP Glossmann et al Ann Hematol, 2002)

45 CONCLUSIONS The intensified HDS regimen followed by ASCT is feasible at a multicenter level the regimen proved to be effective, with a high rate of CR and acceptable toxicity the 51.9% (CI: 68-90%) 10-y OS and 42.1% (CI: 54-79%) 10-y FFS values are consistent with previous reports with longterm results and confirm that autograft is the first choice treatment for relapsed HL patients The program has scarce activity in primary refractory HD and new strategies should be planned in this subset of patients Only randomized studies could definitely demonstrate a benefit of the HDS program versus a standard ASCT approach.