Transcript OUTCOME OF AUTOLOGOUS STEM CELL TRANSPLANT DR.GOH AI SIM CONSULTANT HAEMATOLOGIST HOSPITAL PULAU PINANG.

OUTCOME OF AUTOLOGOUS
STEM CELL TRANSPLANT
DR.GOH AI SIM
CONSULTANT HAEMATOLOGIST
HOSPITAL PULAU PINANG
Autologous Stem Cell Transplant
(ASCT)
 High
dose chemotherapy/radiotherapy with
subsequent stem cell rescue
 Stem cells collected from the patient prior to
transplant
 Conditioning regime: usually a combination of
chemotherapy at near maximal tolerated dose in
terms of other non-haematological toxicities
eg BEAM, BuCy, iv Melphalan
 Stem cells reinfused to hasten marrow recovery
Advantages of ASCT

Autologous stem cell transplant
 Allows
much higher doses of conventional drugs
 No need for donor
 No added risk of GVHD
 Recovery faster
 Immunological reconstitution faster
 Mortality risk is low (<5%)

However, no graft versus tumour effect
INDICATIONS


Multiple myeloma
Lymphoma
 Relapsed Hodgkin’s lymphoma
 Relapsed aggressive Non-Hodgkin’s lymphoma
 1st CR in high/intermediate high risk IPI patients
 Relapsed


follicular lymphoma
Acute myeloid leukaemia
Others
 Solid
tumours, autoimmune disease
Auto-HSCT in multiple myeloma
ASCT in multiple myeloma
Commonest indication for auto-HSCT in
North America and Europe
 Non-curative but prolongs survival
 Melphalan 200mg/m2 gold standard
conditioning regime

ASCT vs standard chemotherapy
Results of randomised studies
ASCT vs standard chemotherapy
Results of randomised studies
Study
# pts
Age (yrs)
CR
EFS
OS
Fermand
2005
190
55-65
CR + VGPR 25m vs 19m 48m vs 47m
42% vs 20%
Blade
2005
164
<65
30% vs 11% 42m vs 33m 61m vs 66m
Barlogie
2006
516
<70
11% vs11% 7yr PFS
17%vs16%
7yr OS
37% vs 42%
ASCT vs standard chemotherapy
Results of randomised studies
ASCT: CR + VGPR increased
 EFS: ASCT is superior to chemo
 Conflicting data on overall survival

 IFM90
57m vs 42m
 MRC7 55m vs 42m
 PETHEMA, French MAG91, SWOG no
difference in OS in spite of improved RR, EFS
ASCT in multiple myeloma

Prognostic factors
 Beta
2 microglobulin
 Chromosome 13 del, t(4,14)
 Chemosensitivity at time of transplant
Strategies to improve the outcome
of ASCT
Tandem transplant
 Maintenance therapy post transplant

 Thalidomide,

lenalidomide
Improved induction regimens
 integration
of novel agents
1)Single vs double auto-transplant
Study
# pts
EFS
OS
IFM 94
Attal NEJM 2003
399
7yr 10% vs 20%
7yr 21% vs 42%
(p <0.01)
Bologna 96
Cavo JCO 2007
321
23m vs 35m
7yr 43% vs 46% NS
HOVON 24
Sonneveld
Hematol 2007
304
21m vs 22 m
6yr 15% vs 7%
50m vs 55m NS
1)Single vs double auto-transplant



Superior CR,RFS and
EFS in double ASCT
No significant
difference in OS
Benefits among
patient who failed to
achieve nCR after 1st
transplant
2) Maintenance therapy post
transplant
Rationale: median duration of response after the
newer chemotherapeutic protocols and ASCT
does not exceed 3 years, and almost all relapse.
 IFM 99 02 (Attal Blood 2006)
 VAD x 3-4 →double ASCT →randomize 3 arms
(no maintenance vs pamidronate vs thalidomide
maintenance)

Arm A Arm B Arm C
Median follow up from
time of enrollment
(months )
40
39
39
Median follow up from
time of randomisation
( months )
3 year probabilities of
event free survival
3 year probablilities of
relapse-free survival
Overall survival ( 4 yrs
after enrollment )
30
29
29
36%
37%
52%
38%
39%
51%
77%
74%
87%
2) Maintenance therapy post
transplant
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Patient who had at least a VGPR did not benefit
from thalidomide maintenance.
Patient who did not achieve at least a VGPR had
a significant benefit from thalidomide ( p<0.004)
Other studies on post-ASCT with thalidomide
shows improved CR, PFS + OS (Barlogie NEJM
2006, Abdelkefi Blood 2007, Spencer IMMW 2007)

Dose and duration not standardized
3) Improved induction therapy prior
to ASCT
Induction regime
VAD
Pre-ASCT
(CR + VGPR)
15%
Post-ASCT
(CR + VGPR)
32%
TD
TAD
27%
33%
42%
49%
VD
40%
57%
VTD
60%
77%
SUMMARY


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ASCT is superior to standard chemotherapy as
first line treatment of MM with improved CR and
EFS and is the backbone of treatment in
younger patients < 60years
Strategies to improve outcome of ASCT eg
tandem transplant and maintenance therapy
have been successful in patients with < VGPR
Better induction therapy gives rise to better posttransplant response rate & outcome
Auto-HSCT in Hodgkin’s lymphoma
ASCT in relapsed Hodgkin’s
lymphoma
Standard of care for relapsed HL
 Results are better with chemo-sensitive relapse
 BNLI study: First randomised trial comparing
ASCT vs salvage CT in HL in 1st relapse
mini-BEAM x3 vs BEAM plus ASCT

 No
significant difference in TRM
 Better 3y EFS (53% vs 10%) and lower relapse with
BEAM (Linch et al. Lancet 1993)
ASCT in relapsed Hodgkin’s
lymphoma

German HD study group / EBMT
 161
pts, 4x DEXA-BEAM vs auto HSCT with BEAM
 3 year FFTF 34% vs 55%
 No difference in OS
 No significant improvement in auto HSCT for small
subgroup of multiple-relapsed patients
(Schmitz et al. Lancet 2002)
ASCT in Hodgkin’s lymphoma with
primary refractory disease (PRD)
PRD – progression during first-line chemo
or within 3 months after the end of therapy
 Prognosis poor
 Cure rate 20-30%with auto HSCT
 EBMT registry, 5yr PFS 32%, OS 36%
 TRM ~10%

ASCT in primary refractory
Hodgkin’s lymphoma
Prognostic factors: B symptoms and Karnofsky score correlated
with survival (Lazarus JCO 1999)
 Response rate with salvage therapy
< 25% vs > 25% response
(10yr EFS 17% vs 60%) Moskowitz CH et al. BJH 2004
 Lines of treatment before ASCT

Sweetenham JCO 1999
ASCT in Hodgkin’s lymphoma

No role for ASCT in CR1
(EBMT HD01 trial - Federico et al JCO 2003,
SNLG HD III - Proctor SJ Eur J Cancer 2002)
Auto-HSCT in Non-Hodgkin’s
lymphoma
ASCT for relapsed aggressive NHL
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Results with conventional salvage
chemotherapy eg. DHAP, ESHAP for relapsed
aggressive NHL are poor
ASCT: Standard of care in chemosensitive
relapsed aggressive NHL
PARMA trial: Benefit of HDT in chemosensitive
relapses over conventional salvage regimens
PARMA trial
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215 relapsed patients
109 patients randomised after DHAP X 2
54 DHAP X 4 + DXT
 RR
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44%, 5y EFS 12%, OS 32%
55 BEAC/HDT + DXT
 RR
84%, 5y EFS 46%, OS 53%
 Median F/u 63m
Time to relapse > or < 12mths most
important prognostic factor
 Second line aaIPI, quality of response to
salvage chemotherapy
 PET/CT may predict outcome and help
identify patients who are best candidates
for transplant. (Haoiun C. Blood 2005)

Auto-HSCT in primary refractory
aggressive NHL
Chemosensitive do better
 Chemoresistant < 10% EFS

Autotransplants for diffuse aggressive
NHL never achieving remission – ABMTR

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184 pt never achieving CR or Cru
>1 salvage regimens
60% sensitive 28% resistant 12% unk
5y PFS 31%
5y OS 37%
Adverse factors
 Chemoresistance

2y survival 13%
Vose et al, JCO (2001) 19:406-413
ASCT in first line therapy of aggressive
NHL

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Conflicting results
4 randomised trials demonstrated benefit in EFS
and OS in high risk patients < 60y (aaIPI score 2
or 3)
LNH 87-2 trial 5yr OS 64% vs 49%
No benefit with GELA LNH 93-3, EORTC and
German High Grade NHL Study Group and
MISTRAL study
Upfront Transplantation: Randomized Trials
Suggesting Benefits
Study
Treatment Arms
Results for HDT
Santini et al,
1998
(Italian)
Full course VOCP-B
followed by DHAP or
HDT
DFS (P = .008) and PFS (P = .08)
better for intermediate-/high+ high-risk groups
Haioun et al,
1997
(GELA)
Full course ACVB or
NCVB followed by
Sequential
Chemotherapy
consolidation or HDT
5 yr DFS (P=0.01) and 5 yr OS
(p=0.06) better for
intermediate-/high- + high-risk
groups
Gianni et al.
1997
(MILAN)
MACOP-B vs.Sequential
HDT
EFS (P=0.004) and OS (p=0.09) favors
HDT
Milpied et al,
2004
CHOP x 8 vs. CEEP x 2
followed by MTX +
Cytarabine
BEAM
5 yr EFS (P=0.003) and 5 yr OS
(P=0.001) better for those with high
intermediate age-adjusted IPI
(GOELAMS)
Upfront Transplantation: Randomized Trials
Suggesting No Benefits
Study
Treatment Arms
Results for HDT
Gisselbrecht et
al, 2002
ACVBP vs. Shortened
initial Chemo +HDT
5 yr EFS (P=0.01) and OS
(P=0.007) higher in conventional
Arm
Kluin
CHVmP/BV x 6 vs.
Nelemans et al, CHVmP/BV x 3 followed
2001 (EORTC) By HDT
No difference in EFS or OS in all
pts, and by IPI subgroups
(GELA)
Martelli et al,
2003
(Italian)
Kaiser et al,
1999
(German)
MACOP-B vs
abbreviated MACOP-B
followed by HDT
No difference in EFS and OS
CHEOP vs. abbreviated No difference in EFS and OS
CHEOP followed by
HDT
Auto-HSCT in first line therapy of
aggressive NHL

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Meta-analysis of 15 randomised trials (2728pts)
was inconclusive but suggested a benefit of
upfront HDT in poor risk patients
Rituximab was not used in any of the studies
ASCT does not appear to benefit those who
received abbreviated courses of chemotherapy
before transplantation
Auto-HSCT in first line therapy of
aggressive NHL

Benefits are most likely to be seen in those who
have maximal response after full course of
conventional chemotherapy.

American Intergroup trial on-going
 R-CHOP
+/- ASCT in HI/high risk patients
Auto-HSCT in first line therapy of
aggressive NHL
Role of HDT as consolidation in PTCL has
not been defined
 Subset analysis of GELA showed no
benefit

Auto-HSCT for relapsed low grade NHL
In spite of improved outcome with
Rituximab based regimens, indolent B-cell
lymphoma is still an incurable disease
 Therapeutic options are needed to
postpone or delay relapse
 Role of auto-HSCT in low grade NHL not
fully established

Auto-HSCT for relapsed low grade NHL
CUP study the only prospective randomised trial
to assess role of auto HSCT in relapsed FL
 Significantly improved PFS
 Survival advantage of auto-HSCT
4yr OS 77% purged, 71% unpurged, 46% chemo

Relapsed Follicular Lymphoma
C U P Trial
Schouten. JCO Vol 21, pp3918-3927
Results
2-year PFS
C 26%, U 58%, P 55%
OS at 4 years
C 46%, U 71%, P 77%
Auto-HSCT as consolidation in 1st CR

3 phase 3 randomised trial
 GLSG: 2 CHOP or MCP followed by auto HSCT or IFN
maintenance
5y PFS 64.7% vs 33.3%, no increase mortality
 GOELAMS: CHVP and IFN or HDT with auto HSCT
Higher response rate 81 vs 69% with transplant,
longer PFS but no survival benefit
 GELF: CHVP vs CHOP x 4 with HDT, TBI and autoHSCT
Similar response rate and long term outcome
SUMMARY
Consider ASCT in younger patient with
high risk relapsed follicular lymphoma (FL)
 ASCT as consolidation in 1st CR only in
the setting of clinical trial

Auto-HSCT in AML
ASCT in Acute myeloid leukaemia


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Most patients with AML who achieve a complete
remission (CR) after induction chemotherapy will
relapse if they do not receive further therapy
ASCT used as post-remission therapy to
eradicate residual disease and prevent relapse
Better outcome when cells are harvested after 2
to 3 cycles of chemotherapy
ASCT in Acute myeloid leukaemia

Disadvantages compared to alloSCT:
 Relapse
rate is much higher, lack of GVL and
contamination of graft with leukaemia cells
 Difficulties to collect sufficient stem cells
 Results dismal in high risk AML
ASCT in Acute myeloid leukaemia
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3 yr leukaemia free survival (LFS) 40-50%
Acute Leukaemia Working Party registry
 2100 patients btw 1996 to 2001
 5yr LFS 43%, OS 51%, relapse 53%,TRM 9%
Reduction in TRM due to better supportive care
Possible in elderly patients >65y
However, poor survival outcome in elderly
ASCT in 2nd CR: durable 2nd remission 25-30%
Auto non-M3 AML (N=39)
Autologous for non-M3 AML - OS(from transplant)
100
90
80
Survival probability (%)
70
60
RemissionStatus
CR 1
CR > 1
50
40
30
20
CR
10 1
CR > 1
Sample size:
270
12
Median survival
17
0
20
26
40
60
P=
Months
80
0.7011
100
120
Median Follow-up from transplant : 66 months(1 - 112)
ASCT in Acute myeloid leukaemia

Indications:
 Younger
patients lacking a HLA matched donor
 Older patients
 APML in 2nd molecular remission

Only 50-60% planned for autoHSCT actually
reach transplant
 Early
relapse
 Insufficient stem cells
Causes of death in ASCT
Early death
 Relapse (70%)
 Infection (8%)
 Organ toxicity (6%)
 Others
Late death
 Relapse (60%)
 Organ toxicity
 Second cancer
(5-20%)
 Others
Relapse after auto-HSCT


Most common cause of treatment failure
Risk factors for relapse
 Disease
status at transplant
 Conditioning
 Graft manipulation

Post HCT relapse has poor prognosis
< 6 months –survival < 10%
 Relapse > 6 months – survival < 20%
 2nd transplant an option for some patients
 Relapse
MDS/AML after auto-HSCT
Incidence 5-15%
 Latency period 2-5 years
 Risk factors:

 Old
age at transplant
 extensive alkylator base chemo pre-transplant
 TBI
SECONDARY SOLID TUMOURS
Latency period: 3-5 years
 Increase with time
 Transplant survivors need surveillance for
2nd cancers
