Treatment of aggressive lymphomas in HIV+patients: result of a multicenter cooperative study

1. Treatment of aggressive lymphomas in
HIV+ patients: result of a multicenter
cooperative study
Saint-Petersburg ● 9 April 2017
Первый Санкт-Петербургский государственный
медицинский университет им. акад. И. П. Павлова
First Pavlov State Medical University of Saint-Petersburg
НИИ детской онкологии, гематологии и трансплантологии
им. Р.М. Горбачевой
Raisa Gorbacheva Memorial Institute of Children Oncology,
Hematology and Transplantation, CIC725
Marina Popova
MD, PhD

2.  The number of people living with HIV has been increasing
Background
http://aidsinfo.unaids.org
Source: UNAIDS Estimates 2016
Global: 36 700 000

3.  People living with HIV are at the high risk of cancer
Background
Eric A. et al. AIDS 2006, 20:1645–1654
Shiels M. et al. Ann Intern Med 2010, 153(7):452-60;
Tumor SIR*
Kaposi sarcoma Greater than
1000
Primary CNS lymphoma 1020
Non-Hodgkin lymphoma 23
Cancer of the anus 20
Hodgkin lymphoma 14
Cancer of the cervix 5
Cancer of the penis 8
Liver cancer 3
Cancer of the larynx 3
Lung cancer 3
Cancer of the mouth or pharynx 2
All non-AIDS-associated cancers 2
*SIR - Standardizd incidence ratio

4.  Cancer is the second cause of death in HIV patients
Background
http://www.cdc.gov/hiv/library/slideSets/index.html

5.  Lymphomas are a second cause of cancer related morbidity in HIV+
Background
Shiels M., et al. J Natl Cancer Inst 2011;103:753–762
31037
26038
4140
2540
2004
1276
Kaposi sarcoma
non-Hodgkin lymphoma
lung cancer
anal cancer
Hodgkin lymphoma
cervical cancer
0 10000 20000 30000 40000
79 657 cancers in the US AIDS population

6.  Lymphomas & HIV = cure from HIV is hidden here
Background
Saint-Petersburg experience with
allo-HSCT in patients with high risk acute leukemia and HIV
sex age diagnosis Disease
status
HIV
status
cART Donor /
CCR5
CR GvHD Follow
up
outcome
1 f 50 AML relapse PCR + no MRD RIC no 7
years
alive
2 f 29 ALL remissio
n
PCR - yes MUD
wt/wt
RIC no 41
days
died
3 f 26 AL, mixed
phenotype
remissio
n
PCR - yes MUD
del 32/wt
RIC yes 3,5
years
alive
B. Afanasyev , et al.
Saint-Petersburg experience of allogeneic hematopoietic stem cell transplantation in
patients with acute leukemia and human immunodeficiency virus // Cellular Therapy and
Transplantation (CTT). Vol.4, No.1-2, 2015. doi: 10.18620/1866-8836-2015-4-1-2-24-30.

7. Aim
to determine an epidemiological characteristics and the outcome of
lymphomas in HIV infected patients in Russian Federation

8. Methods
 First in Russian Federation retrospective multicenter study
 Inclusion criteria
 diagnosed lymphoma in HIV infected patients
 The data was collected for patients from May 2006 to Jan 2016 [..going-on]
 The data analysis of medical history, test results and treatment

9. 26%
12%
3%
6%
34%
3%
2%
3%
1%
1% 1%
8%
city hospital #31, hematology dept., SPb
hematology dept., Surgut
oncology dept., Volgograd
hematology dept., Petrozavodsk
hematology dept., Leningrad region hospital, SPb
hematology dept., Tyumen
RGMICOHT, SPb
city hospital #15, hematology dept., SPb
hematology dept., Saratov
hematology dept., Vologda
hematology dept., NWMU, SPb
others in SPb
Participants

10. Patients
73 patients
The median age was 32 [19-65]
The median follow-up was 24 [15-106] months
 Primary end-points
 epidemiological characteristics
 overall survival (OS) and time to progression (TTP) at 2 years
 Secondary end-points
 factors associated with OS and TTP at 2 years

11. Results
epidemiological characteristics: diagnosis
NHL
83%
HL
14%
MM
3%
28
18
4
4
3
2
2
02040
Follicular Ly
Primary CNS Ly
Unclassified Ly
Plasmoblastic Ly
Gray Zone between BL
and DLBCL
Burkitt Ly
DLBCL

12. Results
epidemiological characteristics: HIV and Lymphoma status
HIV status % pts
HIV before the diagnosis of lymphoma 50%
CD4+ cell and viral load at the diagnosis known 40%
HAART at the moment of lymphoma diagnosis 25%
Co-infection with hepatitis C or B virus 42%
Lymphoma status % pts
Ann Arbor 4 stage with extra nodular involvements 78%
B-symptoms 55%
ECOG 3-4 17%
IPI (3>) 51%
One of c-MYC, bcl2, bcl6 tested by FISH 8.7%
EBV tested 26%

13. Results
epidemiological characteristics: treatment
diagnosis CT % pts
HL
BEACOPP 60%
ABVD 40%
NHL
CHOP 36%
EPOCH (SC-/DA-) 32%
Hyper-CVAD / BFM 32%
MM VAD 50%
all diagnosis No CT of steroids 12.3%
CT with HAART 89% of all Ly
CT with Rituximab 72% of CD20+ Ly

14. Results
OS and TTP at 2 years
TTP at 2 years of all patients was 17%OS at 2 years in patients with HIV and
lymphomas was 64%
Overall survival Time to progression

15. Results
OS and TTP at 2 years: risk factors
40%
76,6%
p=0.006
63,5%
37,5%
p=0.02
Prognostic factors for OS (<0.05)
Favorable
CT in combination with HAART
Adequate CT to type and stage of lymphoma
Adverse
LDH level greater than 500 U/l
B-symptoms
Prognostic factors for TTP (<0.05)
Favorable
Adequate CT to type and stage of lymphoma
Adverse
LDH level greater than 500 U/l
B-symptoms

16. Results
OS and TTP at 2 years: type of lymphoma
16,7%
Type of NHL pts OS
DLBCL 28 59.3%
Burkitt Ly 18 66.7%
Unclassified Ly 3 33.3%
Plasmoblastic Ly 4 75%
Grey Zone between BL and DLBCL 4 25%
Follicular Ly 2 50%
Primary CNS 2 100%
Time to progression NHL
Diagnosis OS TTP
Multiple myeloma 100% 0%
Hodgkin lymphoma 80% 20%
Non-hodgkin lymphoma 60% 16.7%

17. Results
OS and TTP at 2 years: CD20+ Ly (n=56)
CT + Rituximab
significant reduced the probability of progression of CD20+ B-cell lymphoma
p=0,01
8%
37%
p=0,07
42%
67,6%
Overall survival Time to progression

18. n=1546
Barta SK, Xue X, Wang D, et al. Blood 2013;122(19):3251-3262
A recent meta-analysis on 1546 pts, from 19 prospective clinical trials, found
the use of Rituximab, infusional EPOCH and concurrent cART as main
beneficial factors influencing outcome in HIV-lymphomas
Chemotherapy of lymphomas in HIV
the role of Rituximab and intensive CT

19. n=1546
vc
n=73
Barta SK, Xue X, Wang D, et al. Blood 2013;122(19):3251-3262
A recent meta-analysis on 1546 pts, from 19 prospective clinical trials, found
the use of Rituximab, infusional EPOCH and concurrent cART as main
beneficial factors influencing outcome in HIV-lymphomas
Chemotherapy of lymphomas in HIV
the role of Rituximab and intensive CT
42%
67,6%
2 года

20. Diez-Martin JL, Balsalobre P, Re A, et al. Comparable survival
between HIV+ and HIV– non-Hodgkin and Hodgkin lymphoma
patients undergoing autologous peripheral blood stem cell
transplantation. Blood. 2009;113(23):6011–6014.
Krishnan A, Palmer JM, Zaia JA, et al. HIV status does
not affect the outcome of autologous stem cell
transplantation (ASCT) for non-Hodgkin lymphoma
(NHL). Biol Blood Marrow Transplant.
2010;16(9):1302–1308.
High dose chemotherapy with auto-HSCT
in relapse / refractory HIV+ lymphomas in the HAART era
HAART has allowed to use auto-HSCT to rescue relapsed and partially
responding patients, or even to consolidate “high risk” 1st CR HIV-lymphomas,
similarly to non-HIV lymphomas

21. R Gorbacheva Memorial Institute of Children
Oncology, Hematology and Transplantation
experience
auto-HSCT in patients with lymphoma and HIV
n s
e
x
age Ds Indication
to HSCT
HIV status ART CR
Date D-0
Graft
source
HCS
10*6/kg
engraft
ment
Follo
w up
outcom
e
VL CD4
1 m 35 HL Chemo
sensitive
relapse
- 265 + BeEAM
23.03.2016
BM 2,7 D+30 12
mo
alive
2 m 56 HL
(3th
cancer)
Primary
resistance
- 331 + BeEAM
07.07.2016
PBSC 2,6 D+18 9
mo
alive
3 m 26 NHL,
plasmo
blastic
Primary
resistance
+
297
380 + BeEAM
06.07.2016
PBSC 3,4 D+16 9
mo
alive
4 m 59 BL Primary
resistance
- 575 + BeEAM
12.09.2016
PBSC 3,2 D+12 7
mo
alive
5 m 42 HL Chemo
sensitive
relapse
- 468 + BeEAM
13.12.2016
BM
PBSC
6,0 D+14 4
mo
alive
CIC 725, unpublished data

22.  Estimated N of pts with new diagnosed lymphomas* in HIV population
– 1692 in Russia per year
 Estimated N of pts with lymphomas* in HIV population, who need to be
transplanted – 790 in Russia per year
*two types only: HL+DLBCL
Marina Popova
marina.popova.spb@gmail.com
+79117113977

23. High precision disruption of CCR5 gene
with our site specific nuclease
Auto-HSCT* in pts with lymphoma and HIV
edited HSC by CCR5-Uco-TALEN Targeting the CCR5 Locus
genome editing
in HSC
Hematopoietic
stem cells
apheresis
Auto-HSCT =
chemotherapy
+ infuse edited HSC
Generation of
HIV-resistant immune
system
TAL Effector DNA
Binding Domain
CIC 725, unpublished data

24. Genome editing of autologous HSC and
transplantation is a innovation & safe platform for
new generation of gene therapy
Type Disease
Hemoglobinopathies β-thalassemia, sickle-cell disease
WBC Disorders Severe combined immunodeficiency
Wiskott-Aldrich syndrome
Leukocyte adhesion deficiency
Hyper - IgM syndrome
Hemophagocytic lymphohistiocytosis
IPEX Syndrome
Сhronic granulomatous disease
Chediak-Higashi syndrome
Shwachman–Diamond syndrome
Platelet Disorders Congenital amegakaryocytic thrombocytopenia
Trombastenii Glantsmana
Stem cells disorders Fanconi anemia
Diamond–Blackfan anemia
Cyclic neutropenia
Kostmann syndrome
Inborn error
Metabolic disorder
Adrenoleukodystrophy
Metachromatic leukodystrophy
Mucopolysaccharidosis type I and II
Gaucher's disease
Other single-gene disorders Haemophilia
Cystic Fibrosis
Tay sachs disease
Fragile X syndrome
Huntington's disease

25. Conclusions
 Aggressive DLBCL in HIV positive patients was diagnosed more often than other
lymphoma types
 2 year OS in patients with HIV and lymphomas was 64%
 Adequate CT in regards to the type and stage of lymphoma in combination with
HAART improved overall survival
 LDH level greater than 500 U/l, B-symptoms were adverse prognostic factors
 Usage of Rituximab for CD20 B-cell lymphomas reduced the probability of
progression
 Auto-HSCT is safe and feasible procedure in HIV lymphomas
 Gene therapy (genome editing + HSCT) might be a key strategy to cure from HIV
 Prospective studies are needed

26. CIC725
Raisa Gorbacheva Memorial Institute of Children
Oncology, Hematology and Transplantation,
First Pavlov State Medical University of Saint-Petersburg
Students' scientific society
Special thanks to
Dr. Prof. Boris Afanasyev
Prof. Boris Fehse
Russian study team
Мясников А.,
Мошнина С.,
Евсеев А.,
Капланов К.,
Ксензова Т.,
Карягина Е.,
Столыпина Ж.,
Медведева Н.,
Климович А.,
Потапенко В.,
Котова Н.,
Зинина Е.,
Павлюченко Е.,
Попова Н.,
Журба Ю.,
Шнейдер Т.,
Карягин И.,
Пономаренко О.,
Зюзгин И.,
Рябыкина О.,
Ружинская О.,
Успенская О.,
Дзола С.,
Леванов А.,
Ксезонова Т.,
Капланов К.
Acknowledgements
HIV lymphomas program
Natalia Mikhaylova
Anastasia Nekrasova
Genome Editing program
Vladislav Sergeev
Kirill Lepik
Alena Shakirova
Ildar Barkhatov