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
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
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 !!!
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
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
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
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
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
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)
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
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
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.
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
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
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
Aims
To determine whether the toxicity of RIC allo-SCT is feasible
To establish evidence of efficacy
To identify clinically important prognostic factors
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
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
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
Response after RIST
0 2 4 6 8 10 12 14 16 18 20
Pre-RIST Post-RIST
MR or less PR CR
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%
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
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
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
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.
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
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
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
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
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
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
Cumulative incidence of TRM and DP
PFS
OS
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
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
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
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.
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
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
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
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
Relapse after HSCT a/t type of transplant
Low-grade
High-grade
intermediate-grade
Summary
No evidence of GVL effect Indirect evidence:
1.Tumor contamination: lymphoma relapse 2.Beneficial effect of graft purging
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
Cumulative incidence of TRM and DP
OS a/t type of donor
Probability of DFS & OS
OS a/t disease status at alloHSCT
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
Incidence of TRM, PD,REL
OS a/t clinical subtype
OS & PFS (n=233)
OS a/t histologic subtype of aggressive NHL
OS a/t response to CTx
Adverse prognostic factor
chemoresistance prior autograft
prior radiotherapy Problem; high TRM&
REL
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%
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
Second allogeneic transplantation after failure of first autologous transplantation. Radich, BBMT 2000:279
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.
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%
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
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
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’s’s ++++
Hodgkin
Hodgkin’s ’s +?+?
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
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