Gavrilina Olga National Research Center for Hematology, Moscow, Russian Federation High-dose chemotherapy with autologous stem cells transplantation in the treatment of patients with diffuse large B-cell lymphoma with bone marrow involvement.

1. High-dose chemotherapy with autologous
stem cells transplantation in the treatment of
patients with diffuse large B-cell lymphoma
with bone marrow involvement.
Rapporteur: Gavrilina Olga
National Research Center for
Hematology, Moscow, Russian Federation.
Moscow, 2013

2. Epidemiology
• DLBCL is the most common type of NHL, 30-40%
• Bone marrow involvement- 10-20% of DLBCL
• Mean age 60 years
• About 2,500 new cases of DLBCL in the year in
Russia
• OS (10 y) <50%, RFS (10y) ~ 40% with standard
chemotherapy (CHOP +-R)
• OS (5 y) DLBCL with bone marrow involvement
does not exceed 10% (* concordant)
Coiffier B, Blood, 2010

3. CHOP and high-dose therapy in 1st-line
treatment of NHL
Fisher R, Blood, 1993
CHOP: the toxicity of grade 5
or fatal 1% ! (Other courses:
3, 5, 6%)

4. Concordant bone marrow involvement is predictor
of poor response to chemotherapy.
Chung, Blood, 2007
5-year overall survival rate in the group with bone marrow involvement
(34.5%) and without BM involvement (46.9%)
5-year overall survival rate in the group with discordant
bone marrow involvement (61.5%), with concordant
bone marrow involvement (10.3%) and without BM
involvement (46.9%)
489 DLBCL patients, of which 55 with bone marrow
(29 - concordant, 26 - discordant).

5. Bone marrow involvement in patients
with DLBCL
Concordant Discordant
Bone
Bone marrow
Intestine
Bone marrow

6. Intensification of induction therapy
Modified NHL-BFM-90
• 86 patients with progressive adverse factors (bulky
disease, tumor invasion into adjacent organs / tissues in all
its dimensions, III-IV stage of the disease at Ann -Arbor
classification, and LDH above normal)
• OR 64 patients (86%)
• OS and 5y PFS 74.4% and 65%, respectively.
• Patients without bone marrow involvement with III-IV
stage (5y OS 84%)
• Patients with bone marrow involvement 5y OS 12%
Magomedova A.U., Ther. archive, 2011

7. DLBCL with bone marrow involvement
Magomedova A.U., Ther. archive, 2008
Overall survival of patients with DLBCL
chemotherapy with CHOP-21 ± R
Overall survival of patients with DLBCL
with bone marrow involvement
Without BMI
BMI
month month

8. Scheme modified NHL-BFM-90
preparation dose day
Ifosfamide 800 mgm2 1-5
Methotrexate 1500 mgm2 1
Vincristine 2 mg 1
Doxorubicin 25 mgm2 1-2
Ara-C 100 mgm2
twice a day
4-5
Etoposide 100 mgm2 4-5
Dexamethasone 10 mgm2 1-5
preparation dose day
Cyclophosphamide 200 mgm2 1-5
Methotrexate 1500 mgm2 1
Vincristine 2 mg 1
Doxorubicin 25 mgm2 4-5
Dexamethasone 10 mgm2 1-5
preparation dose day
Methotrexate 1500 mgm2 1
Vinblastine 10 mg 1
Ara-C 2000 mgm2
twice a day
2-3
Etoposide 100 mgm2 3-5
Dexamethasone 20 mg 1-5
Block A Block B Block C

9. ASCT in the treatment of relapsed
chemosensitivity DLBCL
Philip T, N Engl J M, 1995
N = 215 (109 patients responded to induction therapy were separated by arm with ASCT (n = 55) and
standard 2-line chemotherapy (n = 54).
Event-free survival in groups with ASCT (46%)
and standard chemotherapy (12%)
Overall survival in groups ASCT (53%) and
standard chemotherapy (32%)

10. Nademanee A, Blood, 1992
ASCT in first-line therapy in young
patients with high IPI
Induction
therapy:
CHOP-like
courses (3-10)
Conditioning:
Vp16 + Cycl +
TBI or BCNU

11. Conditioning regimens before
autologous stem cell transplantation
regimen characteristic
BEAM "Gold standard", the mortality rate of 3-5%
131 I Tositumomab +BEAM Toxicity does not exceed BEAM, perhaps
more effectively
90 Y Ibritumomab tiuxetan+ BEAM Toxicity does not exceed BEAM, perhaps
more effective
Busulfan+ Cyclophosphomide+ Vp-16 Most of the toxicity, no "+" compared with
BEAM
TBI containing regimens Most of the early and delayed toxicity,
there is no difference in survival
BeEAM Toxicity does not exceed BEAM,
? efficiency
Gascoyne R, Biology of Blood and Marrow Transplantation, 2012

12. High-dose sequential chemotherapy:

13. Patients with bone marrow involvement.
Treatment on the modified program NHL-BFM-90, high-dose
sequential chemotherapy(HDSC) and ASCT.
IPI Bone marrow
involvement
Induction
therapy
Response to
induction
therapy
Response
to HDSC
OS,
month
EFS,
month
R., 38 HI Discordant А-С-А-С CR CR 45 6
G., 48 H Concordant А-С-А-С с R PR CR 63+ 50+
А., 23 LI Discordant А-С-А-С PR CR 56+ 44+
Т., 41 H Concordant А-С-А-С PR CR 49+ 40+
B., 52 LI Discordant А-С-А-С-А-В с R PR CR 18+ 4+
S., 57 HI Discordant А-В-А-В-А-В с R CR - 25+ 12+
All patients were treated at the National Research Center for Hematology at the Department Chemotherapy
hematological diseases and intensive care from 2007 to 2012.
Mean observation time: 46 months (18-65 months)
Mean overall survival: 42 months (18-63 months)
Mean event-free survival: 26 months (4-50 months)

14. Patients with bone marrow involvement.
Treatment on the modified program NHL-BFM-90, high-
dose sequential chemotherapy(HDSC) without ASCT.
IPI Bone marrow
involvement
Induction therapy Response to
induction
therapy
Response to
HDSC
OS EFS
S., 31г HI Discordant А-С-А-С CR CR + Dexa-BEAM 38+ 32+
SH., 55 л HI Concordant А-С-А-С PR CR 26+ 19+
S., 33 л LI Discordant А-С-А-С+R CR CR 24+ 17+
S., 48 л H Discordant А-С-А-С-А PR CR 58+ 50+
D., 54 г HI Discordant А-С-А-С CR CR+ Dexa-BEAM 44+ 34+
К., 40 л HI Concordant А-С-А-С+R PR CR 32 6
К ., 36 г H Concordant А-С-А-А PR CR+ Dexa-BEAM 43+ 36+
D., 73 г HI Discordant А-В-А-В CR CR 27 20
S., 67 л H Discordant В-А-С-А PR PR 21+ 8
YA., 55 л HI Discordant А-С PR CR+ Dexa-BEAM 92+ 87+
Mean observation time and overall survival: 40 months (21-92 months)
Mean event-free survival: 30 months (6-87 months)

15. The results of treatment of DLBCL with
bone marrow involvement
0%
25%
50%
75%
100%
Overallsurvival
0 12 24 36 48 60 72 84
Months after start of treatment
0%
25%
50%
75%
100%
Relapse-freesurvival
0 12 24 36 48 60 72 84
Months after start of treatment
5-year overall survival rate is 72% ± 14%. 5-year disease-free survival rate is
80% ± 10%.

16. Acknowledgments:
Director of National Research Center for Hematology, academician VG Savchenko
Head. Dep. VHL, MD Zvonkov EE
Head. Dep. HGZiIT, MD Kravchenko, SK
MD Magomedova AU
MD Lorie YY
k.m.n Gabeeva NG
K.m.n Mangasarova JK
VI Vorobiev
Employees department VHL and HGZiIT National Research Center for
Hematology Russian Ministry of Health