The role of allo-BMT in CML patients in the era of TKI

1. The role of allo-BMT in CML
patients in the era of TKI
R.M.Gorbacheva Memorial Institute of
Children Hematology, Oncology and
Transplantation
I.P. Pavlov First State Medical University
Morozova E.
V Eurasian Hematology Forum
St. Petersburg
April 6-9 2017

2. Chronic phase
First line
Imatinib or nilotinib or dasatinib
HLA type patients and siblings only in case of baseline warnings (high risk, major route CCA/Ph+)
Second line, intolerance to the first TKI
Anyone of the other TKIs approved first line (imatinib, nilotinib, dasatinib)
Second line, failure of imatinib first line
Dasatinib or nilotinib or bosutinib or ponatinib
HLA type patients and siblings
Second line, failure of nilotinib first line
Dasatinib or bosutinib or ponatinib
HLA type patients and siblings; search for an unrelated stem cell donor; consider alloSCT
Second line, failure of dasatinib first line
Nilotinib or bosutinib or ponatinib
HLA type patients and siblings; search for an unrelated stem cell donor; consider alloSCT
Third line, failure of and/or intolerance to 2 TKIs
Anyone of the remaining TKIs; alloSCT recommended in all eligible patients
Any line, T315I mutation
Ponatinib
HLA type patients and siblings; search for an unrelated stem cell donor; consider alloSCT
Acceleration phase / Blast crisis
AP and BP in newly diagnosed, TKI-naïve patients
AlloSCT is recommended for all BP patients and for the AP patients who do not achieve an optimal response.
AP and BP as a progression from CP in TKI-pretreated patients
AlloSCT in all patients
ELN recommendations for allogeneic stem cell transplantation
Baccarani M. et al, Blood, 2013,122(6)
About 20% of
patients with CML
should be referred to
HSCT center!

3. Number of HSCTs in hematologic malignancies
Introduction of imatinib
Although an absolute number of CML patients receiving allo-HSCT
generally decreases, among the patients with advanced phased CML
there is a stable increase of transplant activity from 32% to 53%.
Passweg J. R. et al. Hematopoietic stem cell
transplantation in Europe 2014: more than 40 000
transplants annually. Bone Marrow
Transplantation 2016EBMT transplant activity survey,
2013

4. 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
>CP1
CP1
Changes in transplant activity in patients with CML:
Chronic phase vs. advanced phase
CIC 725

5. Overall survival of patients with blast crisis CML
German CML I, II and III-A studies (n = 605) Dasatinib therapy in patients with myeloid blast crisis
Saglio et al. Blood (ASH Annual Meeting) 2008; 112: Abst. 3226.
Hehlmann R.et al. Haematologica 2008; 93: 1765-1769
Gratwohl A.et al. Leukemia (2016) 30, 562–569
FJ Giles et al., Leukemia, 2012
Overall survival of patients with BC CML
after allo-HSCT and best therapy
Months after BC
Nilotinib therapy in patients with myeloid blast crisis

6. Gratwohl A et al., 1998
Overall survival after allo-НSCT in CML patients
depending on EBMT risk score
Jirí Pavlu et al. Three decades of transplantation
for chronic myeloid leukemia: what have we learned?
Blood, 2011 117: 755-763

7. Общаявыживаемость
Years after HSCT
Apperley J., Curr Hematol Malig Rep (2013) 8:43–51
Improvement of allo-HSCT outcomes over time
Saussele S et al. Blood. 2010 Mar 11;115(10):1880-5.

8. Overall and event-free survival after allo-НSCT in CML patients
according to Gratwohl score and Euro score
A Gratwohl et al. Long-term outcome of patients with newly diagnosed chronic
myeloid leukemia: a randomized comparison of stem cell
transplantation with drug treatment ,Leukemia (2016) 30, 562–569

9. OS
OS
os
Годы
Годы
Годы
AP
CP2
BC
Khoury et al. Bone Marrow Transplant. 2012 June ; 47(6): 810–816.
Effect of prior therapy with nilotinib or dasatinib on the outcome after
allogeneic stem cell transplantation
for patients with chronic myeloid leukemia;
a non-interventional prospective study by the CML subcommittee
of the chronic leukemia Working Party
M.Schleuning, A.van Biezen, J.Hoek, J.Apperley, M.Aljurf, L.Volin, M.Markiewicz,
B.Afanasyev, J.Finke, M.Michallet, P.Browne, A.Nagler, T.de Witte, E.Olavarria on
behalf of the CML subcommittee of the of the chronic leukemia Working Party of the EBMT
WP14: BM transplant
Overall survival of chronic phase 2, accelerated phase,
blast crisis CML patients according to prior TKI therapy

10. Overall and event-free survival after allo-НSCT in CML patients
according to disease stage(n=101)
N=101
CP1n=23
CP≥ 2 n=45
AP n=23
BC n=10
CIC 725
AP
CP1
BC
AP
CP1
BCCP≥ 2 CP≥ 2

11. “The method of transplant at this point remains
wherever possible myeloablative.
In elderly patients and in patients with
concomitant diseases,
reduced intensity conditioning
transplantation offers an acceptable alternative.
Reduced intensity conditioning procedures,
perhaps with maintenance with a TKI
and/or pre-emptive use of donor lymphocyte
infusions, reduce the transplant related toxicity with compromising long term disease
free survival.”
РКСИД при ХМЛ
Месяцы
Topcuoglu Р., Case-matched comparison with standard versus
reduced intensity conditioning regimen in chronic myeloid
leukemia patients,Ann. Hematol., (2012) 91:577–586
Measures to improve survival of
CML patients after allo-HSCT
● Improving conditioning regimens
● Improving graft-versus-host disease prophylaxis
● Post-transplant therapy

12. Intensity of the conditioning and overall and event free survival
(n=107)
RIC
МАС
CIC 725
RIC
RIC
MAC MAC
n=92
n=15

13. Reducing non-relapse mortality with
post-transplantation cyclophosphomide (PTCy)(n=98)
PTCy (+) N=39
PTCy (-) N=59
CIC 725
PTCy (+)
Conventional GVHD prophylaxis

14. Factors effecting the outcome of HSCT:
aGVHD and chGVHD (n=107)
•
CIC 725
aGVHD (+) N=71
aGVHD(-) N=36
cGVHD(1) N=79
cGVHD(0) N=24

15. After HSCT in AP and BC the recurrence rate
is 28% and 38% ACC.
Post-transplant relapse therapy
1-Gratwohl<3(N=12)
2-Gratwohl>3 (N=46)
Relapse treatment
Hematologic
Cytogenetic and
molecular-biological
CT
INF
Donor’s lymphocytes infusion( DLI )
TKI
CumSurvival
CumSurvival
Time from transplant, months
Time from transplant, days
Molecular relapse (n=6)
Hematological relapse (n=19)
All relapses (26%)
Post transplant relapses
80% in the 1st year
Hematological (19%)
Molecular (4%)

16. Post-transplant therapy in CML
Donor lymphocyte infusions (DLI)
Diagnosis /
Indications
ALL+MPAL
n=74
NHL
n=24
AML+MDS
n=121
HD
n=17
CML
n=22
Overall
n=258
Overall
response
rate
39%
29/74
42%
10/24
44%
53/121
53%
9/17
59%
13/22
44%
114/258
Preemptive
DLI
(MRD/
failing
chimerism)
50%
13/26 2/2
32%
9/28 No
78%
7/9
48%
31/65
Therapeutic
DLI
(relapse/
progression)
33%
16/48
36%
8/22
47%
44/93
53%
9/17
46%
6/13
43%
83/193
Efficacy
Courtesy to Olga Slesarchuck

17. Overall and event-free survival in patients
with chronic myeloid leukemia
receiving TKIs after allo-HSCT (n=107)
TKI (+)
TKI (-)
TKI (+)
TKI (-)
TKI (+)
TKI (-)
(n=37)
(n=68)

18. Results of alternative donor HSCT
Ma YR et al.; Clin Transplant. 2016, Transplantation from haploidentical donor is not inferior to that from
identical sibling donor for patients with chronic myeloid leukemia in blast crisis or chronic phase from blast crisis.
.
Patient С.Е.С., 26.11.1988
CML, Ph(+), BCR/ABL p210(+), b2a BC (07.2015)
CT «HyperCVAD+Imatinib» since 14.08.2015.
CHR 09.2015.
Dasatinib 140 mg 09.2015.CHR, CCR 01.10.2015.
Allo-BMT (25.11.2015).
RIC( FluBu)
Tx+MMF+Cy)
Graft failure
Allo-BMT (04.01.2016).
RIC(Flu-Су)
Tx+MMF+Cy
CHR, CCR, CMO(25.01.2016).
Dasatinib 100 mg

19. Conclusions
Allogeneic bone marrow transplantation is
an effective treatment method for patients
with advanced stages of CML
TKI 2,3 may be “bridge” therapy before allogeneic HSCT

20. Thank you for your attention
Moiseev Ivan Sergeevich
Vlasova J.