Transcript Philadephia - ASIA-PACIFIC HEMATOLOGY CONSORTIUM

Philadephia chromosomal positive
acute lymphoblastic leukemia
Jiong HU
Blood & Marrow Transplantation Center, Rui Jin Hospital,
Shanghai Jiao Tong University School of Medicine
1. Role of TKI: overview
2. Dose of chemotherapy with TKI
3. SCT with TKI:
allo-SCT and pre/post-SCT TKI
auto-SCT
4. Elderly
Background
about 25% adult cases of ALL
- randomized controlled trials of therapy unusual
- poor outcome with standard combination chemotherapy
-Two major developments
- tyrosine kinase inhibitors (TKI)
- myeloablative allogeneic HSCT
Tyrosine kinase inhibitors (TKI)
Agent
FDA approved
dose
Mechanism
Mutation
Imatinib
600mg/day
- ABL inhibitor
-Substrate of Pgp; Uptake by
OCT-1
P loop mutation
Dasatinib
140mg/day
- SRC/ABL inhibitior, more
potent than IM
- Not substrate of Pgp,
penetration across the
blood-brain barrier
T315I
Nilotinib
150-200mg twice
daily
More potent than IM
/
Khan S. US Pharm. 2012;37(5)(Oncology suppl):3-7
Stock W. Leukemia & Lymphoma, 2010; 51(2): 188-198
Tyrosine kinase inhibitors (TKI)
Josep-Maria Ribera Leukemia & Lymphoma, 2012; Early Online: 1–7
Tyrosine kinase inhibitors (TKI)
- Induction:
TKIs added upfront , during or after induction chemotherapy
CR rates based on morphology and conventional cytogenetics
over 90% with major molecular response of 30 ~50%
- Consolidation:
including TKIs and allogeneic HSCT when possible
- Overall outcome
40~60% of patients achieved prolonged remissions
significant improve compare to pre-TKI era
- No rationale for omitting TKIs from treatment though no data
from randomized clinical trials
Josep-Maria Ribera Leukemia & Lymphoma, 2012; Early Online: 1–7
1. TKI in the treatment of ph+ ALL
2. Dose of chemotherapy with TKI
3. SCT with TKI:
allo-SCT and pre/post-SCT TKI
auto-SCT
4. Elderly
Intensity of chemotherapy in TKI era
- Reduction of cytotoxic agents or even increasing dose of TKIs
early studies for patients not eligible for intensive therapy or
SCT due to advanced age
TKIs (imatinib or dasatinib) combined with minimal
chemotherapy achieved 100% CR without induction fatalities
Josep-Maria Ribera Leukemia & Lymphoma, 2012; Early Online: 1–7
TKI + chemotherapy: EWALL study
- EWALL-Ph-01 Study (2007~2010): 71 pts with median age 69.2
(58-83) and FU of 3.3 years
- Treatment:
Induction: Dasatinib 140mg QD (100mg >70y) + weekly VCR
1mg + DEX 40mg 2 days (20mg >70y) x 4 weeks
Consolidation: Dasatinib 100mg/d sequentially with MTX
1g/m² IV d1 (500 mg/m² >70y) + L-ASP 10,000UI/m² IM d2
(5,000 UI/m² >70y) for cycles 1, 3, 5 or cytarabine 1g/m²/12h d1,
d3, d5 (500 mg/m² >70y) for cycles 2, 4 and 6.
Maintenance: Dasatinib sequentially with 6-MP/MTX every
other month and DEX/VCR every 2 months up to 24 months
followed by dasatinib alone until relapse or death
ASH 2012 abstract
TKI + chemotherapy: EWALL study
- CR: 67/71 (94%)
- BCR-ABL/ABL ≤0.1% 54%; undetectable (<4.5 log) 22%
- RFS(censored at HSCT) and OS(non-censored):
42.7% (26.9-58.5) and 44.7% (31.8-57.5)
- Safety:
3 pts died in induction; 60 pts (84%) received consolidation and
8 died in CR
-Relapses:
29 relapsed (median 9 months, range 3-34) and 24 pts died;
T315I in 63%; F317L in 7%; V299L in 4% and no mutation in 7%
ASH 2012 abstract
TKI + chemotherapy: EWALL study
Additional chromosomal abnormality (ACA) at induction
and molecular response were prognostic factors
ASH 2012 abstract
TKI + chemotherapy: EWALL study
- 32 adults Ph+ ALL (18~60 years) with pediatric-based chemo +
imatinib
- CR: 94%
- Toxicity: III-IV infections, neuropathy, myopathy and liver
function abnormalities; major treatment delays and dose
reductions
- Median and 3-year OS: 40.7 months and 53%; Median and 3year EFS: 30.1 months and 50%
- Imatinib + pediatric-based regimen results in high response,
considerable toxicity and high non-relapse mortality post-HSCT
British Journal of Haematology
Volume 158, Issue 4, pages 506–514, 2012
TKI + chemotherapy: Graaph-2005 study
- Prospective randomized study
- Patients: 18-60 years untreated Ph+ ALL
- Induction:
arm A (IM-based): IM 800mg on D1-28 + VCR (2mg, D1, 8, 15, 22)
+ DEX(40mg D1-2, 8-9, 15-16, and 22-23);
arm B (IM/HyperCVAD): IM 800mg on D1-14 + HyperCVAD
- Consolidation: 1 cycle of MTX (1g/m2, D1) + AraC (3g/m2/12h,
D2~3) + IM 800mg D1-14 followed by allo-SCT or autologous SCT
ASH 2012 abstract
TKI + chemotherapy: Graaph-2005 study
- Patients:270 randomized and 265 were evaluable (133 arm A,
132 arm B; median age, 47 years; median follow-up, 40 months)
Arm A n=133
Arm B n=132
P value
cycle 1
98%
89%
0.003
cycle 2
98%
91%
0.006
1
9
0.01
major response
44%
46%
NS
undetectable
10%
10%
NS
Transplantation
80 allo/17 auto
77allo/17 auto
NS
3-year EFS
46%
38%
NS
3-year OS
53%
49%
NS
CR rate
Induction Death
MRD response
ASH 2012 abstract
TKI + chemo: Summary
- Front-line TKIs with chemo yields high response rate
- TKI + reduced dose chemo followed by Allo-HSCT and/or Auto-
HSCT:
.
comparable
outcome to TKI + intensive chemo
- Role of intensified chemo must be reconsidered except for
patients not undergoing SCT
1. TKI in the treatment of ph+ ALL
2. Dose of chemotherapy with TKI
3. SCT with TKI:
allo-SCT and pre/post-SCT TKI
auto-SCT
4. Elderly
Role of stem cell transplantation in TKI era
- Allogeneic transplantation:
considered as the only curative option in the pre TKI era
searching for suitable donor
transplantation mortality
.
- Autologous transplantation:
usually associated with high relapse rate
limited to patients achieved undetectable transcripts
Role of stem cell transplantation in TKI era
- Impact of TKI on leukemia stem cells (LSC):
imatinib and novel TKIs such as nilotinib and dasatinibas
combined with cytotoxic agents improved response, molecular
remission and overall outcome
. vitro experiments suggested that TKIs have antiproliferative
in
but no cytotoxic effect on most primitive ALL LSCs
none TKIs in clinical use are able to kill most primitive LSCs
LSCs lead to relapse
World J Stem Cells 2012 June 26; 4(6): 44-52
Role of stem cell transplantation in TKI era
Therapy with TKI results in the depletion of cycling leukemia cells without
eliminating the Leukemia stem cells (LSCs), then the latter can regenerate
the tumor after that therapy is halted.
World J Stem Cells 2012 June 26; 4(6): 44-52
Allo-SCT in pre TKI era: International ALL
Trial MRC UKALLXII/ECOG2993
267 adult ALL without TKI as front-line therapy
Blood August 1, 2008 vol. 112 no. 3 903-909
Allo-SCT in post TKI era: GMALL study
- Prospective multicenter GMALL study: 335 newly diagnosed
Ph+ ALL
- Treatment: imatinib 600mg daily with chemotherapy
(different starting time and duration)
- CR rate: 85.7~89.4%
- For all patients in CR1, 219 patients (66.4%) underwent SCT
3-year and 7 year OS: 57% and 52%
- For patients did not undergo SCT in CR1:
median OS of 9.4 months; 3-year OS 14%
SCT in CR1 remains the treatment of choice even in patients
who achieve a good molecular response to initial therapy
with TKI and chemo
ASH 2010, 147
ph+ALL: allo-HSCT combined with TKI
- pre-transplantation TKI
improve CR rate and MRD response
- post-transplantation TKI
prevention and treatment of relapse
Leukemia & Lymphoma, 2012; Early Online: 1–7
MDACC study
- Retrospective study: adult 102; pediatric 11
- Sib donor (n=60), unrelated (n=40), cord blood (n=12), haplo
(n=1)
- CR1(n=71),CR2(n=11), NR(n=31)
-TKI as front-line therapy n=67；Post-transplantation TKI
maintenance n=32
- Median FU: 5 years(1.1-20.4)
- OS：CR1 43% vs. other 16%, P=.002
- Pre-transplantation TKI not associated with outcome
(uni/mutlivariate analysis)
Biology of Blood and Marrow Transplantation
Volume 18, Issue 4 , Pages 584-592, 2012
JALSG study
- Retrospective analysis between 2002~2005
- 100 newly-diagnosed adult ph+ALL with imatinib + chemo as
front-line therapy
97 CR achieved and 51 received allo-HSCT vs. historical
control (n=122) allo-HSCT in CR1 without TKI treatment
- 3-year OS: Imatinib+HSCT 65%；control HSCT 44%；P=0.005
- 3-year DFS/3-year RR much improved in Imatinib+HSCT group
P=0.005
- TRM not significantly different (P=0.27)
Leukemia (2011) 25, 41–47
JALSG study
Leukemia (2011) 25, 41–47
Imatinib GRAAPH-2003 Study
Biology of Blood and Marrow Transplantation
Volume 19, Issue 1 , Pages 150-155, 2013
Imatinib GRAAPH-2003 Study
LALA-94
N=103
GRAAPH2003 N=43
4-year OS ,95%CI
4-year DFS ,95%CI
CIR%
TRM in CR
20 (14-26)
20(14-28)
42(34-50)
16
52(36-66) *
43(27-58) *
24(14-40)
11
* p=0.001~0.002
In Ph+ ALL, the addition of
imatinib to chemo followed
by auto or allo-HSCT is
associated with an improved
long-term outcome.
Biology of Blood and Marrow Transplantation
Volume 19, Issue 1 , Pages 150-155, 2013
Pre-SCT IM: GMALL study
- Treatment:
Arm 1: IM starting between IND and conso 1, then after
conso1 (n=51);
Arm 2: IM starting 2nd half of IND and throughout conso1
(n=105);
Arm 3: IM starting and throughout conso1 (n=179) until
SCT
ASH 2010, 147
Pre-SCT IM: GMALL study
No pts
CR rate
ED / NR
A1
N=51
/
/
A2
N=105
89.4%
5.8% / 4.8%
A3
N=179
85.7%
11.3% / 3%
PCR negative *
4.2%
12.5%
33%
OS
Pre-SCT rel
31%
11.8%
40%
8.7%
50%
4%
Post-SCT rel
Post-SCT NRM
30.8%
33.3%
24.3%
25.7%
11.3%
20.8%
earlier and prolonged IM is associated with superior
treatment outcomes after SCT
ASH 2010, 147
PKU Study
- n=82 ph+ALL with allo-HSCT: regimen TBI+Cy or BU-based
- 62 pts received post-transplantation Imatinib starting D+70;
10(16.1%) stop due to AEs
- DFS：IM group 81.5% vs. no IM group 33.5% (p=0.000)
with the median follow-up of 31 months (range, 2.5-76
months) and 24.5 months (range, 4–72 months)
- Multivariate analysis: post-transplantation Imatinib as
independent prognostic factor DFS (p=0.000) and OS
(p=0.000)
J Hematology Oncology 2012
PKU Study
Selection bias: more patients in the non IM group present poor
prognostic factor such as severe gut GVHD, pancytopenia.
J Hematology Oncology 2012
PKU Study
J Hematology Oncology 2012
Post-allo-HSCT TKI: GMALL randomized
study
No pts
Allo-SCT
IM treatment
Median D of IM
Follow-up
Alive in CR
MRD +
Duration of MRD- CR
5-year OS
prophylaxis
26
Pre-emptive
29
P value
CR1 23; CR2 3
24/26
D+ 48
30 months
CR1 27; CR2 2
14/29
D+70
32 months
82%
10/26, 40%
26.5 months
78%
20/29; 69%
6.8 months
0.046
0.065
80%
74.5%
0.84
ASH 2011 abstract
Post-allo-HSCT TKI: GMALL randomized
study
- Prophylactic imatinib treatment significantly reduces the
molecular relapse after SCT
- Both prophylactic / pre-emptive strategies are associated with
a low rate of hematologic relapse, durable remissions and
excellent long-term outcome
- MRD+ prior to and early after SCT in small subset of patients
associated with poor prognosis even with post-transplant
imatinib
ASH 2011 abstract
TKI + allo-HSCT: Summary
• Pre-transplantation TKI
- TKI improve remission rate and improve MRD response
- Pre-transplantation TKI improve post-transplantation
outcome remains to be determined
• Post-transplantation TKI
- Benefit need confirmation in prospective study
- Tolerability of post-transplantation TKI
- Optimal dose, duration of TKI treatment
Autologous SCT
• TKI + sequential chemotherapy would result in significant
leukemia cell cytoreduction leading to molecular remission in
Ph+ ALL
• collection of normal hematopoietic stem cells
uncontaminated by residual BCR/ABL+ lymphoblasts
• reduce the likelihood of relapse after auto-SCT
• Post-transplant maintenance with TKIs
Autologous SCT: CALGB study10001
• 58 ph+ ALL with 3-4 cycels of imatinib (400 mg twice daily)
plus sequential chemotherapy followed auto-SCT or allo-SCT
from a matched sibling donor by TBI/etoposide based
conditioning
• 15 allo-SCT from sib donor, 19 atuo-SCT, other from unrelated
donors or alternative therapy
• Imatinib + chemotherapy resulted RT-PCR negative stem cells:
9/19 complete molecular response(CMR); 4/19 major
molecular response (MMR) and 6 not evaluable.
ASH 2012 abstract
Autologous SCT: CALGB study10001
• RT-PCR status (CMR vs. MMR) had no effect on OS or DFS
after auto-SCT (P=0.77 for DFS and P=0.50 for OS).
• Day +120 MRD auto-SCT: DFS and OS longer in patients with
MMR (n=8) than no MMR (n=6, P=0.045 and P=0.011).
• Median follow up of 5.1 years: 9/19 (47%) auto-SCT and 7/15
(47%) allo-SCT remain alive in continuous CR.
• 10 relapsed (8 with auto-SCT and 2 with allo-SCT)
• DFS (median, 5.5 vs 4.1 years; P=0.84) and OS (median, 6.0
years vs. not reached at >6 years; P=0.90) similar for auto- or
allo-SCT
ASH 2012 abstract
Autologous SCT: EBMT study
•
•
•
•
•
•
•
•
171 auto-SCT in CR1 between 1996-2010
Median patient age 48.3 (19-65) years
Conditioning regimen: TBI (63%) or chemotherapy (37%).
Peripheral blood as source of stem cells in 84%
Median follow-up of 2 years
2-year OS 45% (+/-4%) and LFS 32% (+/-4%)
RI and NRM 54% (+/-4%) and 13% (+/-3%),
2-year LFS increased from 22% (1996-2000) to 32% (20012006) and 54% (2007-2010) p<0.001
• RI decreased from 65% to 47% and 46% (p=0.01)
ASH 2012 abstract
Autologous SCT: EBMT study
ASH 2012 abstract
Autologous SCT: summary
• In the era of TKIs, auto-SCT may be considered potentially
curative option for patients without sibling donors
• Advantage:
more profound responses achieved with TKIs
post-transplant maintenance remains to be determined
1. TKI in the treatment of ph+ ALL
2. Dose of chemotherapy with TKI
3. SCT with TKI:
allo-SCT and pre/post-SCT TKI
auto-SCT
4. Elderly
Elderly ph+ ALL
• TKI + minimal chemo as induction resulted in high initial
response
• Post-remission therapy:
- Myeloablative SCT not feasible
- non-myeloablative or auto-SCT can be considered in
fit patients
- TKI + chemo
Elderly ph+ ALL: PETHEMA study
Prephase
Induction 1
Maintenance
Dexamethasone
Vincristine
Imatinib
Dexamethasone
Mercaptopurine
Methotrexate
Imatinib
Dexamethasone
Reinduction cycles
Vincristine
Maintenance-2
Imatinib
10 mg/m2, i.v., days −5 to −1
1 mg (fixed dose), i.v., days 1, 8, 14, 22
400 mg/d, p.o.
10 mg/m2, i.v., days 1, 2, 8, 9, 15, 16
50 mg/m2, p.o., daily
20 mg/m2, i.m., weekly
400 mg/d, p.o.
40 mg (fixed dose) p.o./i.v., days 1, 2
(every 3 months, 1st year)
1 mg (fixed dose), i.v., day 1 (every
3 months, 1st year)
400 mg/d, p.o. (3rd year)
British Journal of Haematology
Volume 159, Issue 4, pages 485–488, November 2012
Elderly ph+ ALL: PETHEMA study
- 32 newly diagnosed ph+ ALL
- median age 65 (56-82)
- Induction response: 26 CR (84%); ED 4 (13%); NR 1 (3%)
- Post-remission: death in CR 2/26 (8%), relapse 9/26 (35%),
alive in CR1 15/32 (47%)
- CR duration: median 37 months (13~43)
- Median OS: 22 months
- Median EFS: 21 months; 4-year EFS: 38%
British Journal of Haematology
Volume 159, Issue 4, pages 485–488, November 2012
Conclusions
• Use of TKIs resulted in higher CR rate (95~100%) even with
minimal chemotherapy
• TKI-containing therapy followed by myeloablative allo-HSCT
resulted in long-term survival of 50~60% in young adults;
promising results also in non-myeloablative HSCT or alternative
donor
• Auto-HSCT can be reconsidered in case of profound or
complete molecular response without suitable donor
• TKI + chemo without SCT:
- intensified chemo + TKI considered for young/fit patients
- TKI + chemo in elderly remained to be improved
• Optimal dose / duration of TKI remained to be determined