options in Myeloablative HSCT

Transcription

1 Should Busilvex we use AlloSCT in AML options in Myeloablative HSCT Reduced Intensity or Myeloablative preparative protocols? Moderator: Andrea Bacigalupo Reduced Intensity: Arnon Nagler Myeloablative: Alessandro Rambaldi The 1 st World Congress on Controversies in Hematology (COHEM) Rome, Italy, 2-5 September, 2010

2 Discussion points Is the dose intensity relevant for leukemia control in AML? Are GVHD and infections mitigated by a reduced intensity conditioning regimen? Reducing the dose to limit toxicity: the only effective approach?

3 Is the dose intensity relevant for leukemia control in AML?

4 Overall Survival Benefit of Allogeneic SCT for AML in First CR John Koreth et al., JAMA 2010

5 A myeloablative allograft delivers the most effective form of anti-leukaemic therapy in patients with AML Is this true only for clinical trials?

6 Patients Characteristics Cy/TBI vs IV BuCy: Results IV BuCy (n=332) Age (y) 40 ( ) Disease status: CR1 270 (81%) at BMT CR2 62 (19%) WBC diag.: 15.0 ( )x10 9 /L Median time from diag to Tx (CR1): 48 days Median time of follow up: 15 (0.5-96) months Graft:* PB 249 (75%) BM 83 (25%) Cy /TBI (n=1147) Age (y) 39 (18-65) Disease status: CR1 917 (80%) at BMT CR2 230 (20%) WBC diag: 15.0 ( )x10 9 /L Median time from diag to Tx (CR1): 42 days Median time of follow up: 41 (1-112) months Graft:* PB 541 (47%) BM 606 (53%) * p=< With courtesy of ALWP EBMT; A. Nagler ASH 2009

7 Cy/TBI vs IV BuCy: Transplantation Outcome IV BuCy2 TBI/Cy Engraftment 97% 97% 2Y TRM 16% NS 18% 2Y Relapse 25% NS 21% Similar outcome whatever the parameters 2Y LFS 59% NS 61% in AML in remission: IV BuCy2 = TBI in CR1 60% NS 64% With courtesy of ALWP EBMT; A. Nagler ASH 2009

8 Cy/TBI vs IV BuCy: Leukemia-Free Survival 61 ± 2% 59 ± 3% Cy/TBI n=1147 IV BuCy n=332 P (Cox): 0.73 years With courtesy of ALWP EBMT; A. Nagler ASH 2009

9 A myeloablative allograft delivers the most effective form of anti-leukaemic therapy in patients with AML Remarkably, even patients with primary refractory disease can achieve durable remissions after a myeloablative allograft

10 Hematopoietic Stem-Cell Transplantation for Acute Leukemia in Relapse or Primary Induction Failure adverse pretransplantation variables first CR duration less than 6 months circulating blasts donor other than HLA-identical sibling Karnofsky score less than 90 poor-risk cytogenetics Duval M.: J Clin Oncol 28:

11 Outcome of Reduced Intensity Allografts in Patients Aged Over 45 Years with Acute Myeloid Leukaemia: Initial Results of the MRC AML15 Trial Russell N.et al Blood, : Abstract 523 (ASH Annual Meeting Abstracts) AlloRIC in 1 st CR may be effective in some patients aged >45 (those with both a sibling donor and intermediate cytogenetics being the most likely candidates)

12 Are GVHD and infections mitigated by a reduced intensity conditioning regimen?

13 GVHD and nonrelapse mortality stratified by donor type after NMA allohsct: the Seattle experience Gyurkocza et al. Clin Oncol 28:

14 Effect of Conditioning Regimen Intensity on CMV Infection in Allogeneic Hematopoietic Cell Transplantation Data from 537 nonmyeloablative (NM-HCT) and 2489 myeloablative hematopoietic cell transplant (M-HCT) recipients CMV disease rates were similar between the groups during the first 100 days after HCT, but NM-HCT recipients had an increased risk of late CMV disease Nakamae, et al.: Biology of Blood and Marrow Transplantation 694, 2009 Copyright 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

15 Effect of Conditioning Regimen Intensity on CMV Infection in Allogeneic Hematopoietic Cell Transplantation Survival after CMV disease in CMV high-risk patients Nakamae, et al.: Biology of Blood and Marrow Transplantation 694, 2009 Copyright 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

16 Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning Takahiro Fukuda, Blood 2003

17 Reducing the dose to limit toxicity: the only effective approach?

18 CyBu instead of BuCy in Allo HSCT SURVIVAL TRM Cy-Bu: significant reduction of VOD and TRM incidence with survival benefit Cantoni, N. et al.: BMT 2010

19 Comparison of IV Bu Once Daily with Every 6-hour Schedule IV Bu total dose: 12.8 mg/kg in both regimens IV BuFlu once daily IV BuCy2 Q-6 hours n Age 44y [13-65] 51y [18-68] Diseases 80% AML - 20% MDS 100% CML C max (µg/ml) AUC (µm x min) * Vd (L/m 2 ) Clearance (ml/min/m 2 ) T 1/2 (hour) «IV Busulfan from 0.8 mg/kg Q-6h to 3.2 mg/kg QD = highly predictable and linear pharmacokinetics.» * AUC for 1 administration Madden T., BBMT 2007 (13): 56-64

20 Busulfan and Fludarabine (i.v. Bu-Flu) Compares Favorably with i.v. Busulfan and Cyclophosphamide (i.v. BuCy2) as Pretransplant Conditioning Therapy in AML/MDS Andersson, BS et al.: Biology of Blood and Marrow Transplantation 14: (2008) Overall survival Event Free Survival

21 RANDOMIZED STUDY COMPARING INTRAVENOUS BUSULFAN (I.V. BU; BUSILVEX ) PLUS FLUDARABINE (BUFLU) VERSUS INTRAVENOUS BUSULFAN PLUS CYCLOPHOSPHAMIDE (BUCY2) AS CONDITIONING REGIMENS PRIOR TO ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLOHSCT) IN PATIENTS (AGED 40 AND 65 YEARS) WITH ACUTE MYELOID LEUKEMIA (AML) IN COMPLETE REMISSION (CR) Protocol GITMO AML R.2 EudraCT number: ClinicalTrial.gov: NCT Date Final: 10 October 2007 Date amended: 16 November 2009

22 Prospective comparison IV FB4 vs IV BuCy2 Related Donor Unrelated Donor BUFLU BUCY2 BUFLU BUCY

23 Prospective comparison IV FB4 vs IV BuCy2 CMNS 24 Italian BERGAMO, Ospedali Riuniti MILANO - Ospedale Maggiore MILANO-Istituto Nazionale dei Tumori BRESCIA - AO Spedali Civili di Brescia - USD-TMO MONZA - Osp. S. Gerardo de' Tintori VICENZA- Ospedale S.Bortolo UDINE-Policlinico Universitario BOLZANO - Ospedale Regionale Generale GENOVA - Ospedale San MartinoTORINO, San Giovanni Battista ALESSANDRIA, Azienda Ospedaliera SS Antonio e Biagio CUNEO Az Osp. S.Croce e Carle FIRENZE - A.O.U. Careggi ANCONA-Ospedali Riuniti SIENA-Az. Osp. Univers. Senese ROMA - Policlinico A. GemelliROMA - Universita' La Sapienza ROMA-Policl inico Universitario Tor Vergata PESCARA - Ospedale Civile BARI-Policlinico S.GIOVANNI ROTONDO Casa Sollievo della Sofferenza NAPOLI - AOU Policlinico Federico II PALERMO-Osped.V.Cervello 1 Israel TEL HASHOMER, (Prof Arnon Nagler) 2 French (potentially interested) NANTES (Prof Mohamad Mothy) MARSEILLE (Prof Didier Blaise)