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

Reduced-intensity Conditioning Transplantation

He Huang M.D., Ph.D.

Bone Marrow Transplantation Center The First Affiliated Hospital Zhejiang University School of Medicine, China

—Current Role and Future Prospect

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

 Seattle Group: 322 patients  Conditioning Regimen: TBI or TBI + Flu  Only 21 patients experienced graft rejection

Months from transplantation Full T-cell chimerism (%) J Clin Oncol 2005;23:1993-2003

Engraftment

RIC-HSCT is safe and effective

 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.

Immunologic Recovery

Experimental Hematology 2003;941-952

The current role of RIC-HSCT

1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000 9,000 10,000

1998 1999 2000 2001 2002 2003 2004

Reduced Intensity Conditioning Traditional

Allogeneic Transplants Registered with the CIBMTR, 1998-2004

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

• n 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

• n 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

• Pts. receiving

Hematopoietic Stem Cell for nonhematopoietic use Cardiovascular

• 95

95 Neurological 6 88 94 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

 RIC vs myeloablative: older patients, less NRM,

similar survival.

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 y) 33(21-51) 43(25-74) 49(34-72) NS NRM (2 y) 22(13-39) 8(2-31) 8(2-23) 0.05

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

Best Pract Res Clin Haematol 2008;21(4):667-675 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.

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

• ral busulfan (8 to 10 mg/kg).

RIC-HSCT for AML: cGVHD

 The development of chronic GVHD after

transplant improves survival by reducing relapse.

J Clin Oncol 2008;26:577-584

OS

With cGVHD Without cGVHD

P<0.001

relapse

With cGVHD Without cGVHD

P<0.01

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

 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. DFS

P=0.003

OS

P=0.003

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 P=0.05 Grade 2-4 aGVHD P=0.2 cGVHD P=0.02 DFS 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

• thers

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

Patients 3y OS（%） TRM（%） All(n=22) 50 27 CR1 (n=12) 81 8 CR2 or advanced(n=10) 15 50

Bachanova V et al, Blood. 2009

RIC Vs MA in ALL

 A CIBMTR Analyisis  RIC group

 92 patients median age: 45y  Conditioning Regimen: Bu + melphalan

 MA group

 1421 patients median age: 28y  Conditioning Regimen: BuCy or TBI based

 Other major potential prognostic factors were similar

in the two groups.

Marks et al, ASH 2009 abstract-872

RIC Vs MA in ALL

 The only difference between RIC and MA group is age.

RIC MA P value age 45 28 <0.0001

aGVHD(100d,%) 39

46 0.16 cGVHD(3y,%) 34 42 0.16 Relapse(3y,% ) 35 26 0.08 OS(3y, %) 38 43 0.39 TRM(3y, %) 32 33 0.86

Marks et al, ASH 2009 abstract-872

RIC-HSCT for ALL: Summary

 Older patients have poor prognosis.  The experience in ALL is far more limited than

AML.

 Patients underwent HSCT in CR1 had a better

prognosis.

 Similar OS, TRM and relapse rate compare with

MA-HSCT.

Contents

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

CML: the Imatinib Period

 On 7 November 2001, imatinib was licensed for CML.  CR rate was more than 90%  Long time survival was more than 80%  Allo-HSCT was not recommend as a first-line therapy in

NCCN guideline.

Imatinib: CR rate Imatinib: DFS

CML: allo-HSCT?

Data from EMBT

CML: Asia and Western

 CML in the far east

Younger patients: median age: 40 vs 60 Longer time for imatinib gene mutation: resistance Economics ……

RIC-HSCT for CML in our Group

 A clinical research in our group

From June 2005 to October 2007, 28

consecutive patients with Ph+ CML in CP1.

median age of 26 years (range, 17–49 years). median interval from diagnosis to transplant

was 8 months (range, 4–28 months).

Imatinib was administered at a dose of 400

mg/day for 3–6 months before transplantation.

Leukemia 2009;23(6):1171-1174; Int J Hematol 2009;89(4):445-451

 Conditioning regimen:

intravenous Flu 30mg/m2/day (from day–10 to –

5)

oral Bu 4 mg/kg (n=4) or intravenous Bu 3.2

mg/kg (n=24) (from day –6 to –5)

ATG Fresenius 5 mg/kg/day (from day –4 to –1)

 Prevent aGVHD: cyclosporin (CsA), mycophenolate

mofetil (MMF) and short-term methotrexate.

 Imatinib was administered 400–600 mg/day after

transplantation to treat relapsed disease or graft failure.

RIC-HSCT for CML in our Group

Leukemia 2009;23(6):1171-1174; Int J Hematol 2009;89(4):445-451

 Engraftment: 26 cases (92.9%)  Grade I–II aGVHD: 7 cases (26.9%)  None of grade III–IV aGVHD  Limited cGVHD: 10 cases (40%)  Extensive cGVHD: 2 cases (8%)  At a median follow-up of 23 months:

 overall non-relapse mortality was 14.3%  overall survivalwas 82.1%

RIC-HSCT for CML in our Group

Leukemia 2009;23(6):1171-1174; Int J Hematol 2009;89(4):445-451

plateau phase?

RIC-HSCT for CML in our Group

Leukemia 2009;23(6):1171-1174; Int J Hematol 2009;89(4):445-451

 Cause of death

interstitial pneumonia bronchiolitis obliterans Intracranial extramedullary relapse DLI-aGVHD

RIC-HSCT for CML in our Group

Leukemia 2009;23(6):1171-1174; Int J Hematol 2009;89(4):445-451

RIC-HSCT for CML: Summary

 Imatinib changed the place of HSCT.  Difference between Asia and western.  Imatinib plus RIC-HSCT could be a safe

and effective therapy choice for young CML patients.

Contents

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

Allo-HSCT in MM

 Advantages

Stem cells: no contaminated and no damage

(chemo)

GVM effects

 Disadvantages

TRM (20-40%) Age and donor availability (only 10%

candidates)

Auto/RIC vs tandem Auto

 IFM study

Blood 2006;107:3474-3480

Auto/RIC vs tandem Auto

Blood 2006;107:3474-3480

Auto/RIC vs tandem Auto

OS

Blood 2006;107:3474-3480

Auto/RIC vs tandem Auto

 A retrospective study from PETHEMA study  received 6 cycles of VBMCP or VBAD  Failing to achieve CR or nCR after first auto-HSCT  Conditioning regimen: Flu + melphalan Blood 2008;112:3591-3593

Auto/RIC vs tandem Auto

group RIC Auto P value TRM 16% 5% 0.08 DFS Not reached 31months 0.08 OS Not reached 58months 0.9

DFS RIC: plateau? auto OS RIC auto

Blood 2008;112:3591-3593

Auto/RIC vs tandem Auto

 A EBMT cohort study  358 myeloma patients from 26 European centres

 with an HLA-identical sibling: allocated to the ASCT-RIC-arm

(n=107)

 without a matched sibling donor: ASCT (n=251)

 Conditioning regimen

 Auto: melphalan 200 mg/m2  RIC: ludarabine 30 mg/m2 x 3 plus TBI 2 Gy

gahrton, ASH 2009 abst 52

Auto/RIC vs tandem Auto

 RIC group vs auto group(auto + tandem Auto)

group RIC auto P value Relapse(5y,%) 49 75 <0.05 PFS (5y,%) 35 18 <0.05 OS (5y,%) 65 57 >0.05 group RIC auto P value CR rate(%) 51 43 Relapse(5y,%) 45 77 <0.05 PFS (5y,%) 39 19 <0.05 OS (5y,%) 63 60 >0.05

gahrton, ASH 2009 abst 52

 RIC group vs tandem Auto

RIC-HSCT for MM: Summary

 Studies have different conclusions.  Difference in patient characteristics, GVHD

prophylaxis, conditioning regimens may explain these discrepant results.

 Not the upfront choice.  Yes in high-risk patient.  Should go to transplantation with low tumor

burden.

Contents

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

RIC-HSCT: A better future

 Lower TRM

Conditioning regimen anti-infection immunosuppressive agents

 More candidates

Up to 70 years or older? Young patients?

Unresolved issues in RIC-HSCT

 Role of T-cell depletion on relapse and overall

survival.

 Impact of minimal residual disease status at the

time of transplantation on relapse risk.

 Optimal dose and duration of post transplant

immunosuppression.

 Role of donor lymphocyte infusion in patients

with isolated mixed T-cell chimerism in the first 12 months post transplant.

Bone Marrow Transplant 2008;41:415-423

• Blood. 2005;105:1810.

Dana Farber Cancer Institute

Outcome of nonmyeloablative vs myeloablative allo-HSCT for patients older than 50 years

• Figure. Comparison of the causes of treatment failure for patients over the age of

50 receiving either nonmyeloablative or myeloablative transplants.

Conclusions

 RIC-HSCT: based on GVL effect, for older and

weak patients

 RIC-HSCT provide a similar survival rate

compare with myeloablative HSCT.

 Better survival require a complete remission  How can improve outcome due to decrease

relapse after transplantation