Reduced-intensity Conditioning Transplantation Current Role and - PowerPoint PPT Presentation

Reduced-intensity Conditioning Transplantation — Current Role and Future Prospect He Huang M.D., Ph.D. Bone Marrow Transplantation Center The First Affiliated Hospital Zhejiang University School of Medicine, China

Contents  Introduction  RIC-HSCT for AML  RIC-HSCT for ALL  RIC-HSCT for CML  RIC-HSCT for MM  Future prospect

Effect of HSCT  High-dose chemotherapy and graft-versus- leukemia (GVL) effect.  Decrease recurrence rate  Long-term disease-free-survival  transplantation related mortality  GVHD  <50-55 years

Reduced-intensity Conditioning (RIC)  Regimens usually involve a combination of a purine analog (primarily fludarabine) with an alkylating agent (usually melphalan or busulfan).  Regimens are generally considered to include less than 16 mg/kg busulfan or less than 10 Gy total body irradiation (TBI). Blood 2004;104:865-872

RIC-HSCT: Regimens  TBI  TBI + Flu  TBI + ATG  Bu + Flu + ATG  Bu + Flu + alemtuzumab  Flu + melphalan  Flu + melphalan + alemtuzumab  Flu + CTX  Cisplatin + Flu + CTX

RIC for Allo-HSCT  The immune system plays a major role in controlling and curing certain malignancies.  Reduced-intensity Conditioning directed to selectively target the immune system.  leading to donor cell engraftment.  without causing significant damage to other organs as seen with the myeloablative regimens .  Older and weak patients can receive allo-HSCT.

RIC-HSCT is safe and effective Engraftment  Seattle Group: 322 patients  Conditioning Regimen: TBI or TBI + Flu  Only 21 patients experienced graft rejection Full T-cell chimerism (%) Months from transplantation J Clin Oncol 2005;23:1993-2003

RIC-HSCT is safe and effective Immunologic Recovery  Seattle Group  Conditioning Regimen: RIC: TBI + Flu Myeloablative: High-dose chemo- +/- TBI  Absolute CMV TH cell number after transplantation Time after HSCT RIC Myeloablative P value D 30 73300 700 <0.0001 D 80 165000 12400 <0.0001 D 365 175000 78300 0.21  RIC-HSCT may be improved immune reconstitution early post-HST. Experimental Hematology 2003;941-952

The current role of RIC-HSCT Allogeneic Transplants Registered with the CIBMTR, 1998-2004 10,000 Reduced Intensity Conditioning 9,000 Traditional 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 0 1998 1999 2000 2001 2002 2003 2004

The current role of RIC-HSCT EBMT Activity Survey on HSCT in Europe RIC Transplant, 1990-2005

EBMT BMT Act Activi vity ty Su Surv rvey on on HSC SCT in 2007 07 Donor r an and Sour urce ce Source Donor BM PB CB Total Allogeneic Total 1819 6037 433 8289 HLA-id sib 925 2858 34 3817 HLA-nid sib 115 311 4 430 Twin 13 28 -- 41 Unrelated 766 2840 395 4001 Autologous Total 194 12033 1 12228 *No. of patients receiving first transplants only in 2007. 25/03/2008

EBMT BMT Act Activi vity ty Su Surv rvey on on HSC SCT in 2007 07 General neral In Inform rmat ation ion Allo-SCT Auto-SCT Total Cord Blood Transplants 468 1 469 Reduced Intensity Conditioning Transplants 3260 -- 3260 Pts. receiving Donor Lymphocyte Infusion 1581 -- 1581 Pts. receiving Mesenchymal Stem Cell 121 32 153 Cardiovascular -- 95 95 Pts. receiving Neurological 6 88 94 Hematopoietic Stem Cell for nonhematopoietic use Tissue repair 2 18 20 25/03/2008

Contents  Introduction  RIC-HSCT for AML  RIC-HSCT for ALL  RIC-HSCT for CML  RIC-HSCT for MM  Future prospect

AML in older patients  More often antecedent hematologic disorder  Less proliferative  Lower white blood cell count  lower percentage of marrow blasts  expression of pglycoprotein in AML blasts  unfavorable cytogenetic profile  Low CR rate, short survival

AML in older patients  A ECOG research: 348 patients, older than 55 years.  Median overall survival is 6.7 months. Best Pract Res Clin Haematol 2008;21(4):667-675

RIC-HSCT for AML  A research from Israel group  112 consecutive patients  met eligibility criteria: myeloablative conditioning(45)  noneligible patients: RIC (67)  Conditioning Regimen:  Myeloablative: BuCy  RIC : busulfan 6.4 mg/kg (FB2) or 12.8 mg/kg (FB4) Leukemia 2006;20:322-328

RIC-HSCT for AML Group BuCy FB4 FB2 P value Patients 45 26 41 Median age 42(22-58) 51(18-64) 57(18-70) 0.001 OS (2 y) 50(34-66) 49(24-74) 47(30-65) NS DFS(2 y) 45(29-60) 49(25-72) 43(24-62) NS Relapse(2 33(21-51) 43(25-74) 49(34-72) NS y) NRM (2 y) 22(13-39) 8(2-31) 8(2-23) 0.05  RIC vs myeloablative: older patients, less NRM, similar survival. Leukemia 2006;20:322-328

RIC-HSCT for AML: CR Status  A Germany research.  122 patients, Median age: 57.5 years.  51 in CR1, 39 in CR2, 32 in advanced.  Conditioning Regimen: 2 Gy TBI ± fludarabine 30 mg/m2/d, from days 4 to 2.  Persistent, progressive, or relapsed malignancies in the absence of GvHD: rapid discontinuation of systemic immunosuppression.  relapse/disease progression or persistent mixed chimerism: DLI. Best Pract Res Clin Haematol 2008;21(4):667-675

RIC-HSCT for AML: CR Status Survival at 3 years was 46% for the 51 patients transplanted in first remission (CR1), 42% for the 39 patients transplanted in second remission (CR2), and approximately 18% for those transplanted with more active disease. Best Pract Res Clin Haematol 2008;21(4):667-675

RIC-HSCT for AML: cGVHD  RIC HSCT: low dose chemotherapy and GVL effect.  GVHD accompany with GVL effect.  GVHD = long survival?  A research from Barcelona group  93 patients, median age: 53 years  Conditioning Regimen: fludarabine (150 mg/m2) and oral busulfan (8 to 10 mg/kg).

RIC-HSCT for AML: cGVHD OS relapse With cGVHD Without cGVHD P<0.001 P<0.01 Without cGVHD With cGVHD  The development of chronic GVHD after transplant improves survival by reducing relapse. J Clin Oncol 2008;26:577-584

RIC vs chemo: Cohort Studies  Better understand the impact of transplantation  Identifying patients at the time of diagnosis  A recent study: 95 patients with AML in first remission  Median age: 52 years  Had an HLA- matched sibling : “donor” group  Did not have HLA- matched sibling : : “no donor” group  Conditioning Regimen: fludarabine, busulfan and ATG

RIC vs chemo: Cohort Studies DFS OS P=0.003 P=0.003  If a matched related donor is identified, RIC-allo-SCT should be proposed because it represents a valid and potentially curative option for AML patients not eligible for standard myeloablative allo-SCT.

RIC-HSCT for AML: Cord Blood  Not every patient has a HLA-match donor  A Minnesota group compared the Unrelated umbilical cord blood (UCB) an HLA matched related donor (MRD)  90 patients older than 55 years  Conditioning Regimen:  TBI(200 cGy)  Flu + CTX  Flu + busulfan  88% received two UCB units to optimize cell dose  93% received 1-2 HLA mismatched UCB grafts Biol Blood Marrow Transplant 2008;14(3):282-289

RIC-HSCT for AML: Cord Blood Engraftment Grade 2-4 aGVHD P=0.05 P=0.2 DFS cGVHD P=0.02 P=0.98 Biol Blood Marrow Transplant 2008;14(3):282-289

RIC-HSCT for AML: Cord Blood  Graft type had no impact on TRM or survival.  Supports the use of HLA mismatched UCB as an alternative graft source for older patients who need a transplant but do not have a MRD.

RIC-HSCT for AML: Summary  Older patients have poor Prognosis.  RIC-HSCT provide a similar survival rate compare with myeloablative HSCT, better than chemotherapy.  Better survival Require a Complete Remission.  Umbilical cord blood could be an alternative graft source.

Contents  Introduction  RIC-HSCT for AML  RIC-HSCT for ALL  RIC-HSCT for CML  RIC-HSCT for MM  Future prospect

ALL in older patients  Older patients have poor Prognosis(ECOG group). Rowe et al, 2005

RIC-HSCT for ALL  The toxicity of the conditioning regimen has been virtually removed  Relies almost entirely on harnessing the graft- versus-leukemia effect  Becoming established in AML  The experience in ALL is far more limited.

RIC-HSCT for ALL: Early trial  A retrospective studies from Japan  From 2000 to 2003, 33 patients  Age range from 17 to 68, median 55  13 patients in CR1, 6 patients in CR2  Conditioning Regimen: Flu based  2y DFS and OS was 18.6% and 29.7%  Cumulative incidence of progression at 3 years was 50.9%.  Cumulative incidence of nonprogression mortality at 3 years was 30.4%. Hamaki T et al, Bone Marrow Transplant. 2005

RIC-HSCT for ALL: Early trial CR1 CR2 others Hamaki T et al, Bone Marrow Transplant. 2005

RIC-HSCT for ALL: CR1  97 adult patients with ALL from the EBMT Registry  Median age: 38 years  28 patients in CR1, 37 patients were Ph+  Conditioning Regimen: low dose TBI + ATG Patients 2y OS 2y DFS TRM All(n=97) 31% 21% 28% CR1(n=28) 52% 42% 18% Mohty M et al, Haematologica. 2008

RIC-HSCT for ALL: CR1  A retrospective studies from Minnesota  22 adult patients, median age: 49 (24-68)  12 in CR1, 14 were Ph+  Conditioning Regimen: Flu + CTX 3y OS （ % ） TRM （ % ） Patients All(n=22) 50 27 CR1 (n=12) 81 8 CR2 or advanced(n=10) 15 50 Bachanova V et al, Blood. 2009