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(1)

Perspectives on allogeneic hematopoietic stem cell transplantation in Myeloma

Seok-Goo Cho M.D.,PhD.

Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary’s Hospital, The Catholic University of Korea

(2)

Evolution of therapeutic approach in myeloma

Tandem HSCT: Auto- + Allo-NST Single or double HDT

Myeloablative allo-HSCT Conventional CTx

Improvement of CR, OS & PFS

(3)

Autologous transplantation for myeloma

Higher CR rates

Better survival compared with conventional Rx

Applicable to older patients

Applicable to patients with renal failure Low mortality (<5%)

However, not curable !!!

(4)

Conventional CTx vs HDT IFM90 phase III trial

Stage II-III, age <65

VMCP/BVAP (x18) n=100

VMCP/BVAP (x4-6) n=100 → MEL 140/TBI 8Gy, n=74

Attal NEJM 1996;335:91

(5)

MEL vs TBI+MEL

IFM 9502 randomized trial

VADx3 >> radomized n=298 Arm A:TBI 8Gy+MEL 140mg/m2 Arm B:MEL 200 mg/m2

Moreau Blood 2002;99:731

(6)

Single vs double auto-HSCT; IFM trial

TRM 6%

TRM 4%

Arm A: TBI 8 Gy+MEL 140 mg/m2 Arm B: MEL 140 mg/m2 > TBI+MEL

Attal NEJM 2003;349:26

(7)

The established role of high-dose therapy and autologous PBSCT for myeloma

Myeloma is sensitive to alkylating agents such as melphalan in a dose dependent fashion

High-dose therapy followed by autologous PBSCT induces high response rate

High dose therapy and transplant is

superior to conventional chemotherapy Double HSCT improves PFS & OS

(8)

Limitations of autologous SCT

High rates of relapse

Rarely achieved molecular remission

Tandem auto-SCT showed a long term remission of 21%.

Patients with karyotype abnormalities (13 deletion or hypodiploidy) are associated with poor response

(9)

Myeloablative allo-HSCT compared with auto-HSCT

A tumor free graft

Graft-versus-myeloma (GVM) effect Higher rate of molecular remissions Higher TRM (17-60%)

Acute and chronic GVHD Lower risk of relapse

May allow DLI

Restricted to younger pts (median ages 43-44)

(10)

Clinical experience with myeloablative allo-HSCT

Long-term PFS for a minority of pts

Higher TRM & lower relapse rate vs auto- HSCT

TCD: ATG > Campath-1H, low potential cure rate

MEL+TBI > CY+TBI

Strategies with less toxicity than myeloablative HSCT need to be evaluated: RIST

Bensinger Blood 1996;88:2787 Lockhorst JCO 2003;21:1728 Hunter Br J Haematol 2005;128:496

(11)

Support evidence of a GVM effect following allo-HSCT in myeloma

T cell depletion of the graft: reduced PFS In pts with chronic GVHD: low relapse rate

DLI efficacy in patients relapsing after allo-HSCT

Alyea Blood 2001;98:934 Alyea BMT 2003;32:1145 Huff BBMT 2003;32:1145 Badros Blood 2001;97:2574

(12)

Considerations of allo-NST

Allow allogeneic engraftment with minimal conditioning.

Low early TRM.

Minimal direct anti-tumor effects.

Relies on GVM immune response to eliminate disease.

Not effective in pts with rapidly progressive tumors.

(13)

Tandem HSCT in myeloma;

auto-HSCT & allo-NST

To reduce TRM of myeloablative allo-HSCT To retain the cytoreductive effect of HDT To separate GVHD from GVT effect

To decrease the detrimental impact of

pro-inflammatory cytokines due to tissue damage

(14)

Tandem auto vs. auto-allo HSCT

IFM9903 IFM9904 median F/U 24 m Auto+Allo Tandem

Auto

OS 31.7 35

EFS 35 47.2

Not superior to tandem dose- intensified MEL-based HSCT !!!

Garban Blood 2006;107:3474

(15)

A comparison of allografting with

autografting for newly diagnosed myeloma

Tandem autografts (n=80) vs. auto + allo-NST from MSD (n=82).

VAD x3 + PBSC mobilization with CY 3-4 g/m2 MEL 200 mg/m2 + TBI 2 Gy

OS EFS

Bruno, NEJM, 2007

(16)

Aims

To determine whether the toxicity of RIC allo-SCT is feasible

To establish evidence of efficacy

To identify clinically important prognostic factors

(17)

Patients and methods

Eighteen MM patients received an allograft with RIC regimens

Median time from diagnosis to transplant was 14 months (7-28)

Conditioning regimens

- Fludarabine (30 mg/m2) i.v. x 4 days - Melphalan (70 mg/m2) i.v. x 2 days

± Antithymocyte globulin

All patients were transplanted with G-CSF mobilized peripheral blood progenitor cells

- med. CD34 cells 5.4(0.8-27)x106/kg - med. CD3 cells 3.3(1.5-11.4)x108/kg

(18)

Transplant characteristics (n=18)

Age(yr), median, range 46 (34-57)

Sex, M/F 10/8

IgG/IgA/IgD/LCD/NS 8/4/1/4/1

Sibling/unrelated 17/1

GVHD prophylaxis

CsA+MTX/CsA+MMF 9/9

No. of prior ASCT, 0/1/2 1/16/1

Sex match/mismatch 11/7

ABO match/mismatch 12/6

Disease status at transplant

CR/PR/MR or less 10/5/3

(19)

Outcome of RIST (n=18)

Full donor chimera 18 (100%)

Response after RIST

CR/PR/MR or less 15/1/2

Acute GVHD ≥ II 4 (22.2%)

Chronic GVHD limited/extensive

12/16 (75.0%) 1/11

CMV reactivation 6 (33.3%)

Relapse or progression 6 (33.3%) Death

within 1yr/1yr or more

4 (22.2%) 2/2

(20)

Response after RIST

0 2 4 6 8 10 12 14 16 18 20

Pre-RIST Post-RIST

MR or less PR CR

(21)

OS and PFS

med. FU 21 (2-46) mo.

0 10 20 30 40 50

0 25 50 75 100

Months

Percent survival

0 10 20 30 40 50

0 25 50 75 100

Months

Percent survival

3 year 3 year-estimated OS

67.8%

-estimated PFS 42.7%

(22)

PFS according to disease status at RIST

0 10 20 30 40 50

0 25 50 75 100

Months

Percent survival CR at RIST(n=10)

PR or less at RIST

(n=8)

P=0.02

(23)

OS according to disease status at RIST

0 10 20 30 40 50

0 25 50 75 100

Months

Percent survival

CR at RICT (n=10) PR or less

at RICT (n=8)

P=0.07

(24)

Summary

RIC allo-SCT is feasible and safe

- Two out of 18 patients (11.1%) died from multiorgan failure and infection, respectively - Two deaths due to disease progression

Chronic GVHD was a major morbidity.

Five of 8 patients without CR before

transplant obtained a CR after RIC allo-SCT.

Disease status at RIC allo-SCT is critical

- Five out of 8 patients without CR relapsed - DLI seems to be an good option

(25)

Conclusion

Tandem transplants are superior to single transplant.

If MSD or MUD are absent, double auto- HSCT schedule is the best standard Tx.

If MSD or MUD are present, tandem auto- HSCT+allo-NST will be the most promising Tx for cure.

Longer F/U and more results from randomized trials is required.

(26)

Perspectives on allogeneic hematopoietic stem cell transplantation in Lymphoma

Seok-Goo Cho M.D.,PhD.

Catholic Hematopoietic Stem Cell Transplantation Center, St. Mary’s Hospital, The Catholic University of Korea

(27)

Lymphoma: outcome after initial therapy

Diffuse large B-cell: Many cured, most will relapse Follicular: Few cured, most will relapse

Mantle Cell: Few cured, most will relapse T-NHL: Few cured, most will relapse

Hodgkin’s: Most cured, some will relapse

(28)

Rituximab in front-line therapy

(4-year Update of the GELA Study)

R-CHOP

CHOP

R-CHOP

CHOP

Low risk: P < 0.001

High risk: P < 0.01

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 Years

0.0 0.2 0.4 0.6 0.8 1.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 Years

0.0 0.2 0.4 0.6 0.8 1.0

ASH, 2003

(29)

Summary of clinical trials

Author Randomization Age F/U

<50 8 y +16 +15

+10 +5

+12

+8

+30

+13

- +22

+10

+18

+11

+12 8 y

4 y

5 y

5 y Pfreundschuh

(Elderly)

3 wk-CHOP 2wk-CHOP

61-

75 5 y 32.5/43.8 P=0.03

40.6/53.

3 p<0.001

Blood 2004 5 y

Linch CHOP

PACEBOM

16- 60

49/59 P=0.09

60/65 P=0.65

AnnOnco 2000 60-

80 61-

69 15-

60

18- 60 ACBV+consol

ACBV+CBV

Coiffier CHOP R-CHOP

29/51 P=.00001

47/59 P=0.01

ASH 2003

Tilly CHOP

ACVBP+consol

29/39 P=0.05

38/46 P=0.36

Blood 2003 Milpied N CHOP

Initial HDT

37/55 P=0.037

44/74 P=0.001

NEJM 2004

CHOP CHEOP

EFS (%) OS (%) Reference

Haioun 39/55

P=0.02

49/64 P=0.04

JCO 2000

Pfreundschuh (Young)

57.6/69.2

P=0.004 - Blood

2004

(30)

Autologous Stem Cell Transplant Autologous Stem Cell Transplant

Improves PFS/OS in relapsed DLBCL Improves PFS/OS in relapsed DLBCL11

Improves PFS/OS in relapsed FL Improves PFS/OS in relapsed FL22

Improves PFS in relapsed HD Improves PFS in relapsed HD33

Improves PFS in 1st CR MCL Improves PFS in 1st CR MCL44

11Philip NEJM 333: 1540, 1995; Philip NEJM 333: 1540, 1995;

22Schouten et al. Schouten et al. ClinClin OncolOncol. 2003 Nov 1;21(21):3918. 2003 Nov 1;21(21):3918--27; 27;

33SchmitzSchmitz N, et al. Lancet 2002 Jun 15;359(9323):2065N, et al. Lancet 2002 Jun 15;359(9323):2065--71; 71;

44Dreyling et al. Blood. 2005 Apr 1;105(7):2677Dreyling et al. Blood. 2005 Apr 1;105(7):2677--84 84 DLBCL=diffuse large B

DLBCL=diffuse large B--cell lymphoma, FL=follicular lymphoma, HD=cell lymphoma, FL=follicular lymphoma, HD=hodgkinshodgkins disease, MCL= mantle cell lymphoma

disease, MCL= mantle cell lymphoma

(31)

Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission

significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the

European MCL Network. Dreying, Blood 2005:105;2677

(32)

Cumulative incidence of TRM and DP

PFS

OS

(33)

Summary

Auto-HSCT vs IFN

3-year PFS 54% vs. 25% (p=0.018) 3-year OS 83% vs. 77% (p=0.18) Limitation of auto-HSCT efficacy

(34)

Other disadvantages of auto HSCT

Chemoresistant disease

Inability to collect stem cells Tumor contaminated graft

Less effective in some diseases (eg CLL/SLL) Less effective after prior transplant

(35)

Advantages of Conventional (myeloablative) Allogeneic Transplantation for NHL

Tumor free graft Tumor free graft

Immune mediated graft

Immune mediated graft--vsvs--tumor activitytumor activity Replaces damaged host

Replaces damaged host hematopoiesishematopoiesis (less risk (less risk of of myelodysplasiamyelodysplasia))

Lower risk of relapse Lower risk of relapse

DLI may provide augmented anti

DLI may provide augmented anti--tumor activitytumor activity

(36)

Evidence of graft-versus-lymphoma effect

Increased relapse rates after auto-HSCT vs allo- HSCT.

Increased relapse rates after syn-HSCT vs all- HSCT.

Lower relapse rates in the presence of GVHD.

Disease response to immunosuppression withdrawal

Disease response to DLI.

(37)

Prospective comparative trial of autoBMT vs. alloBMT in high-risk NHL;

Priority of allo-HSCT (n=31) 1.Less than 55 yrs

2.MHC-matched or 1 Ag-mismatched sibling donor

3.Preference was given to allograft when patients were candidate for both types of grafts

Priority of auto-HSCT (n=35) 1.Over 60 yrs

2.Without BM involvement at the time of BM harvest 3.No MSD

Ratanatharathorn, Blood 1994;1050

(38)

Prospective comparative trial of autoBMT vs. alloBMT in NHL

Probability of disease progression Autograft Allograft

No. of pt 35 31

Conditioning

CVB 8 7

CY-TBI 27 24

Resp. to last CTx

sensitive 21 15

resistant 14 16

PFS (median F/U

14 m) 24% 47%

prob. of PD 69% 20%

Probability of PFS

Ratanatharathorn, Blood 1994;1050

(39)

Summary

Probability of disease progression was significantly higher in the autologous

group than allogeneic group: GVL effect Chemosensitivity: significant influence on PFS

Allogeneic BMT should be preferable to autologous BMT in younger patients with lymphoma.

Ratanatharathorn, Blood 1994;1050

(40)

Syngeneic vs. Auto vs. Allo-HSCT for NHL

IBMTR + EBMTR

Syngeneic HSCT: n=89

Auto-HSCT: unpurged (n=2018), purged (n=376)

Allo-HSCT: T-cell-replete (n=774), T- cell-depleted (n=119)

Bierman JCO 2003:21:3744

(41)

Relapse after HSCT a/t type of transplant

Low-grade

High-grade

intermediate-grade

(42)

Summary

No evidence of GVL effect Indirect evidence:

1.Tumor contamination: lymphoma relapse 2.Beneficial effect of graft purging

(43)

Myeloablative allo-HSCT in pts who experience relapse after auto-HSCT for lymphoma; a report of IBMTR:

114 pts, 1990-1999 TRM (3 yr): 22%

3 yr OS/DFS: 33%/25%

5 yr OS/DFS: 24%/5%

Freytes Blood 2004: 104:3797

(44)

Cumulative incidence of TRM and DP

OS a/t type of donor

Probability of DFS & OS

OS a/t disease status at alloHSCT

(45)

Myeloablative alloHSCT for NHL:

nationwide survery in Japan.

N=233 NHL with allo-HSCT

MSD 154 (66%), MUD 60 (26%)

TBI-based vs non-TBI-based; 83% vs 17%

aGVHD (II-IV) 39%, (III-IV) 16%

TRM n=98 (48%), GVHD 68% of TRM

2-yr OS indolent, agg., LL; 57%, 42%, 41%

Kim SW Blood 2006; 108:382

(46)

Incidence of TRM, PD,REL

OS a/t clinical subtype

OS & PFS (n=233)

OS a/t histologic subtype of aggressive NHL

(47)

OS a/t response to CTx

Adverse prognostic factor

chemoresistance prior autograft

prior radiotherapy Problem; high TRM&

REL

(48)

Auto- vs Allo-HSCT in FL: Besien, Blood, 2003:3521

TRM a/t type of transplant

DFS a/t type of transplant

Relapse a/t type of transplant

OS a/t type of transplant 30%

14%

8% 43%

58%

21%

62%

55%

51%

39%

31%

45%

(49)

OS by year of auto-HSCT OS by year of sibling allo-HSCT

Summar

y

• Auto-HSCT: Benefit!

Graft purging in auto-HSCT.

• Allo-HSCT

No correlation between GVHD and recurrence.

Decreased recurrence offset by increased TRM in allo-HSCT.

Besien, Blood, 2003: 102:3521

(50)

Second allogeneic transplantation after failure of first autologous transplantation. Radich, BBMT 2000:279

(51)

Summary:

Summary:

Myeloablative

Myeloablative allo transplant for NHLallo transplant for NHL

Compared to ASCT Compared to ASCT

Lower risk of relapse Lower risk of relapse

High TRM (20

High TRM (20-80*%) -80*%)

Higher morbidity (GVHD, infection) Higher morbidity (GVHD, infection)

Limited to healthy, younger patients Limited to healthy, younger patients

Limited data if prior high

Limited data if prior high--dose therapydose therapy Inferior results with

Inferior results with chemoresistantchemoresistant diseasedisease

*78% TRM in Radich et al. Biol Blood Marrow Transplant. 2000;6(3):272-9.

(52)

Chemoresistant or aggressive NHL predicts for a poor outcome following RIST: Lymphoma working Party

of EBMT group. Robinson, Blood 2002:4310 N=188 NHL, Median age: 40 yrs

Median No. of prior Tx: 3 Previous Auto-HSCT: 48%

Full donor chimerism: 71%

Acute GVHD 37%, chronic GVHD 17%

OS 1 yr/2 yr: 62%/50% (median F/U 283 d) TRM 100 d/1-yr: 12.8%/25.5%

Probability of dis progression 1-yr/2-yr:

75%/25%

PFS at 1 yr: 46%

(53)

EBMT group Blood 2002:4310

OS of all Pts OS a/t sensitivity OS a/t histology

TRM of all Pts PD a/t sensitivity PD d/t histology

(54)

PFS of all Pts PFS a/t sensitivity at RIST PFS a/t histology

Summary

1. Reduced TRM

2. Controlable in LG-NHL, advanced HD

3. Poor outcome: HG-NHL, chemoresistant group, MCL

EBMT group Blood 2002:4310

(55)

Non-ablative Allogeneic Transplants:

Advantages

Compared to ablative allogeneic transplants Compared to ablative allogeneic transplants

Lower TRM (20

Lower TRM (20--30% at 2 years)30% at 2 years)

Can treat patients with advanced age, co Can treat patients with advanced age, co--

morbidities, prior therapies morbidities, prior therapies

LongLong--lasting graft versus lymphoma effectlasting graft versus lymphoma effect GVL by histology

GVL by histology

MCL/CLL/FL

MCL/CLL/FL ++++++

DLBCL/

DLBCL/BurkittBurkitt’ss ++++

Hodgkin

Hodgkin’s s +?+?

(56)

NonNon--ablative Allogeneic Transplants: ablative Allogeneic Transplants:

Limitations Limitations

Tumor control Tumor control

Less effective for bulky, rapidly progressive, Less effective for bulky, rapidly progressive,

chemoresistant

chemoresistant diseasedisease

Less effective for DLBCL/HD Less effective for DLBCL/HD Toxicity

Toxicity

Infections and GVHD Infections and GVHD

(57)

NonNon--ablative Allogeneic Transplants: ablative Allogeneic Transplants:

Improving Tumor Control Improving Tumor Control

Selected options:

Selected options:

1.1. Intermediate intensity regimens (Intermediate intensity regimens (egeg BEAM, BEAM, Melphalan

Melphalan, etc), etc)

2.2. Tandem ablative autologousTandem ablative autologous--nonnon-ablative -ablative allogeneic transplants

allogeneic transplants

3.3. RadioimmunotherapyRadioimmunotherapy--based nonbased non--ablative ablative allogeneic transplants

allogeneic transplants

(58)

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