SLIDE DECK MabThera NHL CHEMO 2023.ppt

Non Hodgkin's Lymphoma

1. OPTIMIZING TREATMENT OF
MALIGNANT B CELL LYMPHOCYTES
(NON HODGKIN”S)
MAB/OTH/Q4/15/68
DR. Dr. Tutik Harjianti, SpPD, K-HOM, FINASIM
Sub Div. of Hematology & Medical Oncology
Dept. of Internal Medicine, Medical Faculty,
Hasanuddin University
September 2023

2. NON-HODGKIN’SLYMPHOMA
•Non-HodgkinLymphoma(NHL)isthemostcommon
hematologiccancerinadults,withincidenceofNHLis66.120
casesinUS(2008)
1
•DiffuselargeB-celllymphoma(DLBCL)isthemostcommon
formoflymphomaandcomprisesmorethan30%ofpeoplein
theUSwithNHL
2
•Follicularlymphoma(FL)isthemostcommontypeofindolent
NHLandrepresents~70%ofindolentlymphomasandupto
25%ofallcasesofNHL
3
1
Jemal, A., et al. (2008). Cancer Statistics, 2008. Cancer J Clin, 58, 71-96. doi: 10.3322/CA.2007.0010
2
ASCO. 2014. Lymphoma –Non-Hodgkin: Subtypes. http://www.cancer.net/cancer-types/lymphoma-non-
hodgkin/subtypes, accessed on 2/12/15
3
Sousou, T. & Friedberg, J. (2010). Rituximab In Indolent Lymphomas. Semin Hematol, 47(2), 133-142. doi:
10.1053/j.seminhematol.2010.01.003

3. WHO CLASSIFICATION FOR NHL
1
1
Harris, N.L. (1997). Principles of The Revised European-American Lymphoma Classification (from the
International Lymphoma Study Group). Annals of Oncology 8 (Suppl. 2), S11-S16. Retrieved from:
http://annonc.oxfordjournals.org/
NON-HODGKIN LYMPHOMA
Indolent
(Low Risk)
CLL/
SLL
Lympho-plasmacytic
MCL FL MZL
Aggressive
(Intermediate Risk)
DLBCL
Anaplastic Large
Cell
Peripheral T-cell
Very Aggressive
(High Risk)
Precursor
B-Lym-
phoblastic
Burkitt’s
Lymphoma
Notes:CLL(SLL):Chronic(small)lymphocyticleukemia,DLBCL:DiffuselargeB-celllymphoma,FL:Follicularlymphoma,MCL:Mantlecelllymphoma,MZL:
Marginalzonelymphoma(includingmucosa-associatedlymphoidtissue).

4. IgVH, 13,17,11

6. DIAGNOSIS OF NHL

7. RISK FACTORS FOR NHL
•Age
•Gender
•Bacterial Infections
•Viruses
•Autoimmune disorders
•Immune Deficiency Disorder
•Genetic Factors
•Organ Transplantations
ASCO. 2014. Lymphoma –Non-Hodgkin: Risk Factors. http://www.cancer.net/cancer-types/lymphoma-non-
hodgkin/risk-factorsaccessed on 7 October 2015

8. SIGN AND SYMPTOMS
The symptoms of NHL depend on where the cancer started and the organ that is involved.
General symptoms:
•Enlarged lymph nodes in the abdomen, groin, neck, or underarms
•Fever that cannot be explained by an infection or other illness
•Weight loss with no known cause
•Sweating and chills
•Enlarged spleen or liver
•Fatigue
Examples of symptoms related to a specific tumor location:
•A tumor in the abdomen can cause a stretched belly or pain in the back or abdomen.
•A tumor in the center of the chest may press on the trachea and cause chest pain,
difficulty breathing, or other respiratory problems.
ASCO. 2014. Lymphoma –Non-Hodgkin: Risk Factors. http://www.cancer.net/cancer-types/lymphoma-non-
hodgkin/risk-factorsaccessed on 7 October 2015

9. DIAGNOSIS REQUIRES AN ADEQUATE BIOPSY
•Fortheinitialdiagnosisoflymphoma,anFNAorcorebiopsyaloneisnot
generallysuitable
1
•AcombinationofcorebiopsyandFNAbiopsiesinconjunctionwithappropriate
ancillarytechniquesforthedifferentialdiagnosismaybesufficientfor
diagnosis
1
•BasedonESMODLBCLclinical2015,surgicalexcisionbiopsyremainsthe
optimalmethodofdiagnosis.AmorphologicaldiagnosisofDLBCLshouldbe
confirmedinimmunohistochemistry(IHC),orflowcytometryoracombination
ofbothtechniques
2
•AccordingtoESMODLBCLclinicalguidance2012,diagnosisofNHLrequires
immunohistochemistry(IHC)tests(CD-20,CD-45,CD-3)asmandatory
3
1
NCCN ver.2 2015. Non-Hodgkin’s Lymphomas. Page 31
2
Tilly, H., et al. (2015). Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis,
treatment, and follow-up. Annals of Oncol 26 (Supplement 5), v116-v125. doi:10.1093/annonc/mdv304
3
Tilly, H., et al. (2012). Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis,
treatment, and follow up. Annals of Oncology 23 (Supplement 7): vii78–vii82. doi:10.1093/annonc/mds273

10. NCCN 2015: DIAGNOSIS DLBCL
1
CD20
BIOPSY
FNAB & Core Needle Biopsy is
not recommended as a single
biopsy for lymphoma diagnosis
1
NCCN ver.2 2015. Non-Hodgkin’s Lymphomas. Page 59

11. NCCN 2015: DIAGNOSIS FL
1
CD20
BIOPSY
FNAB & Core Needle Biopsy is
not recommended as a single
biopsy for lymphoma diagnosis
1
NCCN ver.2 2015. Non-Hodgkin’s Lymphomas. Page 31

12. NCCN 2015: DIAGNOSIS CLL
1
CD20
BIOPSY
FNAB & Core Needle Biopsy is
not recommended as a single
biopsy for lymphoma diagnosis
1
NCCN ver.2 2015. Non-Hodgkin’s Lymphomas. Page 12

14. NCCN2023

15. CD20
•CD20antigenisahydrophobictransmembraneprotein
withamolecularweightapproximately35kD
1
•Itislocatedonpre-BandmatureB-lymphocytes,
butnotfoundonhematopoieticstemcells,pro-Bcells,normalplasma
cells,orothernormaltissues
2
•Theantigenisexpressedon>95%ofB-cellNHL
2
1
Pescovitz, M. (2006). Rituximab, an Anti-CD20 Monoclonal Antibody: History and Mechanism of Action. American
Journal of Transplantation 6: 859-866. doi: 10.1111/j.1600-6143.2006.01288.x
2
BPOM. 2015. Mabthera (Rituximab) Product Information

16. TREATMENT FOR NHL

17. TREATMENT IN NHL
Before Rituximab was discovered, standard treatment for NHL
was 6–8 cycles of cyclophosphamide, doxorubicin, vincristine
and prednisone (CHOP)
Other regimens studied failed to show any advantage over
CHOP
1
AdditionofRituximabtostandardchemotherapyhasresulted
asignificantimprovementinpatientssurvival
2
RituximabhasbeenastandardofcareforCD20+Non-Hodgkin
LymphomaPatientsandusedformorethan15years
3-6
1
Fisher R.I, et al. (1993). Comparison of a Standard Regimen (CHOP) with Three Intensive Chemotherapy Regimens for
Advanced Non-Hodgkin’s Lymphoma. N Engl J Med328: 1002–1006. Retrieved from: nejm.org
2
Cartron, G., et al. (2011). Interindividual Variability of Response to Rituximab: From Biological Origins to Individualized
Therapies. J Clin Cancer Res 17: 19-30. doi: 10.1158/1078-0432.CCR-10-1292
3
NCCN ver.2 2015. Non-Hodgkin’s Lymphomas
4
Tilly, H., et al. (2012). Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment,
and follow up. Annals of Oncology 23 (Supplement 7): vii78–vii82. doi:10.1093/annonc/mds273
5
Dreyling, T., et al.(2014). Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practicr Guidelines for
diagnosis, treatment, and follow-up. Annals of Oncology,25 (Supplement 3): iii76–iii82. doi:10.1093/annonc/mdu200
6
Eichhorst, B., et al.(2011). Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment, and
follow-up. Annals of Oncology, 22 (Supplement 6): vi50–vi54. doi:10.1093/annonc/mdr377

18. •Anti-CD20 antibody IDEC-2B8 with murine variable regions.
1,2
•Linked to human IgG1 and kappa constant regions.
1
•Apparent affinity: 5 x 10
-9
mol/L.
2
•Causes complement-mediated lysis and ADCCof CD20-positive tumor cells in
vitro.
1
V
L
C
V
H
C1
Human constant Fc region
Human constant region
Murine variable regions
RITUXIMAB: CHIMERIC ANTI-CD20
MONOCLONAL ANTIBODY
1
Maloney, D., Smith, B., & Rose, A. (2002). Rituximab: Mechanism of Action and Resistance. Semin Oncol 29 (suppl
2): 2-9. doi:10.1053/sonc.2002.30156
2
Maloney, D.G., et al. (1997). IDEC-C2B8 (Rituximab) Anti-CD20 Monoclonal Antibody Therapy in Patients With
Relapsed Low-Grade Non-Hodgkin’s Lymphoma. Blood 9(6), 2188-2195. Retrieved from: www.bloodjournal.org

19. MECHANISM OF ACTION RITUXIMAB
BPOM. 2015. Mabthera (Rituximab) Product Information, p. 28-29
ADCC antibody dependent cellular cytotoxicity. MAC MEMBRANE ATTACK COMPLEX

20. AGGRESSIVE LYMPHOMA
DIFFUSE LARGE B-CELL
LYMPHOMA (DLBCL)

21. NCCN 2023: IPI

22. NCCN 2023:TREATMENT FOR DLBCL

27. GELA LNH-98.5 study:
1
8xR-CHOP in patients aged 60–80 years
1
Coiffer, B., et al. (2010).Long-term outcome of patients in the LNH-98.5 trial, the first randomised study
comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe
dÉtudes des Lymphomes de l’Adulte. Blood 116, 2040–2045. doi: 10.1182/blood-2010-03-276246.
CHOP
R-CHOP
Time (years)
0.0
0.2
0.4
1.0
0.6
0.8
0 2 4 6 8 10 12
Log-rank p< 0.0001Survival probability
PFS

28. GELA LNH-98.5 study –10 years f.u.
1
Overall Survival
27.6%
1
Coiffer, B., et al. (2010).Long-term outcome of patients in the LNH-98.5 trial, the first randomised study
comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe
dÉtudes des Lymphomes de l’Adulte. Blood 116, 2040–2045. doi: 10.1182/blood-2010-03-276246.

29. MInTstudy: 6-year follow-up
1
R-CHOP-like chemo
CHOP-like chemoEFS (%)
0
20
40
100
60
80
Log-rank p< 0.0001
EFS
0 24 48 72 96 120
Time (months)
1
Pfreundschuh, M., et al. (2011). CHOP-like chemotherapy with or without rituximab in young patients with good-
prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera
International Trial (MInT) Group. Lancet Oncol 12, 1013–1022. doi: 10.1016/S1470-2045(11)70235-2
*Design method: eligible patients were aged 18-60 years

30. Safety Profile of Rituximab
8 x Rituximab + 6–8 x CHOP:
•No clinically significant increase in toxicity
1,2
Rituximab
in DLBCL
10-year follow-up demonstrates
the long-term safety of Rituximab
in the treatment of DLBCL
3
GELA LNH-98.5; RiCOVER-60
8 x Rituximab in combination
with chemo (ACVBP, CHOP-21
or CHOP-14):
•Adverse events can be managed
4
•ACVBP represents an alternative
chemo partner for Rituximab
4
4
Récher, C.,et al. (2011). Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the
treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet 378, 1858–1867.
Retrieved from: thelancet.com
5
Pfreundschuh, M., et al. (2011). CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis
diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT)
Group. Lancet Oncol 12, 1013–1022. doi: 10.1016/S1470-2045(11)70235-2
In young*, low-risk patients:
•No increase in toxicity compared
to chemo alone
5
MInT
Recheret al
4
GELA LNH-98.5
1
Coiffier, B., et al. (2002). CHOP Chemotherapy Plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma.N Engl J Med346, 235–242.
Retrieved from: nejm.org
2
Pfreundschuh, M., et al. (2008). Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+B-cell lymphomas: a randomised
controlled trial (RICOVER-60). Lancet Oncol 9, 105–116. doi: 10.1016/S1470-2045(08)70002-0
3
Coiffer, B., et al. (2010).Long-term outcome of patients in the LNH-98.5 trial, the first randomised study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients:
a study by the Groupe dÉtudes des Lymphomes de l’Adulte. Blood 116,2040–2045. doi: 10.1182/blood-2010-03-276246
*Design method: eligible patients were aged 18-60 years

31. INDOLENT LYMPHOMA
FOLLICULAR LYMPHOMA (FL)
CHRONIC LYMPHOCYTIC LEUKIMIA(CLL)

32. FOLLICULAR LYMPHOMA (FL)

37. Single-agent
bendamustine
produced a high rate of
objective responses
with acceptable toxicity
in patients with
recurrent, rituximab-
refractory indolent B-
cell lymphoma
Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a
multicenter study. Cancer. 2010;116:106-114.

38. Robust responses in patients previously
treated with and resistant to rituximab-
containing regimens
Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a
multicenter study. Cancer. 2010;116:106-114.

39. Single-agent bendamustine provided
durable responses that lasted a median of
9 months
Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a
multicenter study. Cancer. 2010;116:106-114.. www.treanda.com

40. Flinn IW, et al. Blood. 2014;123(19):2944-2952)
The overall response rates for BR and R-CHOP/R-CVP were
97% and 91%, respectively (P=.0102).

41. Randomized trial
of bendamustine-
rituximab or R-
CHOP/R-CVP in
first-line
treatment of
indolent NHL or
MCL: the BRIGHT
study
Flinn IW, et al. Blood. 2014;123(19):2944-2952)

42. THANK YOU

43. www.thelancet.com Published online February 20,
2013 http://dx.doi.org/10.1016/S0140-6736(12)61763-
2
Bendamustine plus
rituximab can be considered
as a preferred first-line
treatment approach to R-
CHOP because of increased
progression-free survival and
fewer toxic effects

44. Grade 3–4 neutropenia was 2.25 times less
frequent with bendamustine and rituximab
than with R-CHOP.
Neurotoxic effects were also four times less
frequent with bendamustine and rituximab
than with R-CHOP
www.thelancet.com Published online February 20, 2013 http://dx.doi.org/10.1016/S0140-
6736(12)61763-2

45. Brugger W, Ghielmin M. The Oncologist 2013;18:954
Bendamustine treatment is associated with a better
therapeutic index and offers an improved quality of life
compared to R-CHOP or R-CVP.

46. Brugger W, Ghielmin M. The Oncologist 2013;18:954

47. PD
SD
off study
Maintenance
12 x Rituximab
(375 mg/m
2
q2mo for 24 mo)
Observation
Untreated
follicular NHL
High tumour
burden
Induction
8 x Rituximab
+
Chemotherapy
(8 x CVP
or 6 x CHOP
or 6 x FCM)
CR
CRu
PR
1,217 patients
1,018 patients
1
Salles, G., et al. (2011). Rituximab maintanance for 2 years in patients with high tumour burden follicular lymphoma
responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet377, 42–51. doi:
10.1016/S01406736(10)62175-7
PRIMA STUDY DESIGN
1

48. Rituximab-based induction and maintenance therapy
almost doubles the chance of living life progression free
RITUXIMAB MAINTENANCE THERAPY
IMPROVES THE BENEFITS OF INDUCTION
1
1
Salles, G., et al. (2011). Rituximab maintanance for 2 years in patients with high tumour burden follicular lymphoma
responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet377, 42–51. doi:
10.1016/S01406736(10)62175-7

49. Rituximab maintenance (n = 501)
Observation (n = 508)
Any adverse
event
Grade 3/4
neutropenia
Grade 3/4
infections
Grade ≥2
infections
Patients (%)
100
80
60
40
20
0
56
14
Grade 3/4
adverse events
37
39
24 24
17
14
RITUXIMAB MAINTENANCE DOSAGES
ARE GENERALLY TOLERATED
1
1
Salles, G., et al. (2011). Rituximab maintanance for 2 years in patients with high tumour burden follicular lymphoma
responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet377, 42–51. doi:
10.1016/S01406736(10)62175-7

50. CHRONIC LYMPHOCYTIC
LEUKIMIA(CLL)

51. NCCN GUIDELINES 2015 –1
ST
LINE
1
1
NCCN ver.2 2015. Non-Hodgkin’s Lymphomas. Page 23

52. NCCN GUIDELINES 2015 –RELAPSE
1
1
NCCN ver.2 2015. Non-Hodgkin’s Lymphomas. Page 24

56. ESMO CLL GUIDELINES 2015
1
1
Eichhorst, B., et al. (2015). Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis,
treatment, and follow-up. Annals of Oncology 26 (Supplement 5): v78–v84. doi:10.1093/annonc/mdv303

57. Bendamustine offers
significantly greater
efficacy than
chlorambucil, and a
manageable toxicity
profile, when used as
first-line therapy in
patients with
advanced CLL.

58. More than doubled overall
response rate(ORR)
ORR: 31
%
P<0.0001
Overall response rate was higher in bendamustine-treated
patients (68%) compared to chlorambucil-treated patients
(31%)
More patients showed complete responses with bendamustine
than with chlorambucil
Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previouslyuntreated patients with chronic
lymphocytic leukemia.J Clin Oncol. 2009;27:4378-4384

59. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previouslyuntreated patients with chronic
lymphocytic leukemia.J Clin Oncol. 2009;27:4378-4384
Efficacy bendamustine in CLL
More than doubled longer in median duration of
response(DR)
The median duration of
response in the bendamustine
and chlorambucil groups was
21.8 months and 8.0 months

60. Cramer P, et al. Haematologica 2015; 100(11); 1451
The 3-year overall survival rate was higher after first-line treatment with
chemoimmunotherapies such as fludarabine/cyclophosphamide/rituximab (87.9%) or
bendamustine/rituximab (90.7%) compared to chemotherapies without an antibody
(fludarabine/cyclophosphamide: 84.6%; fludarabine: 77.5%; chlorambucil: 77.4%).

61. R
A
N
D
O
M
I
S
E
R
E
S
T
A
G
E
R-FC q4wk 3
FC q4wk 3
R-FC
q4wk 3
FC q4wk 3
SD, PD off study
CR, PR
Untreated CLL
Binet B requiring
treatment or
Binet C
ECOG PS 0–1
N = 817
CIRS 6
1
Hallek, M., et al. (2010). Addition of rituximab to fludarabine and cyclophosphamide in
patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial.
Lancet 376, 1164–1174. Retrieved from: www.thelancet.com
Rituximab: 375 mg/m
2
cycle 1, 500 mg/m
2
cycles 2–6
Fludarabine: 25 mg/m
2
Cyclophosphamide: 250 mg/m
2
CLL-8: Study Design
1

62. Cumulative survival
0 1 2 3 4 5
Time (years)
1.0
0.8
0.6
0.4
0.2
0.0
R-FC 87%
FC 83%
HR 0.67
(95% CI: 0.48−0.92)
p = 0.012
CLL-8: OVERALL SURVIVAL AT 3 YEARS
1
1
Hallek, M., et al. (2010). Addition of rituximab to fludarabine and cyclophosphamide in patients with
chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376, 1164–1174.
Retrieved from: www.thelancet.com

63. HR 0.56
(95% CI: 0.46−0.69)
p < 0.0001
Progression
-
free rate
0 1 2 3 4 5
Time (years)
1.0
0.8
0.6
0.4
0.2
0.0
R-FC 51.8 mo
FC 32.8 mo
CLL-8: PFS AT 3 YEARS
1
1
Hallek, M., et al. (2010). Addition of rituximab to fludarabine and cyclophosphamide in patients with
chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376, 1164–1174.
Retrieved from: www.thelancet.com

64. Patients (%)
80
60
40
20
100
0
CR
44%
CR
22%
R-FC
(n = 408)
FC
(n = 409)
ORR 90%
ORR 80%
p < 0.0001
CLL-8: CR R-FC IS DOUBLE FROM CR FC
1
p < 0.0001
1
Hallek, M., et al. (2010). Addition of rituximab to fludarabine and cyclophosphamide in
patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial.
Lancet 376, 1164–1174. Retrieved from: www.thelancet.com

65. TAKE HOME MESSAGES
•Fortheinitialdiagnosisoflymphoma,anFNAorcorebiopsyalone
isnotgenerallysuitable
.
AcombinationofcorebiopsyandFNA
biopsiesinconjunctionwithappropriateancillarytechniquesforthe
differentialdiagnosismaybesufficientfordiagnosis
1
•CD20statusineveryNHLpatientshavetobetestedbefore
definethetreatment
2
.CD20isexpressed>95%ofallBcellNon-
Hodgkinlymphoma
3
.
•RituximabhasbeenastandardofcareforCD20+Non-Hodgkin
LymphomaPatientsandusedformorethan15yearsandbeen
recommendedbyESMO&NCCN
1,2,4,5
1
NCCN ver.2 2015. Non-Hodgkin’s Lymphomas
2
Tilly, H., et al. (2012). Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis,
treatment, and follow up. Annals of Oncology 23 (Supplement 7): vii78–vii82. doi:10.1093/annonc/mds273
3
BPOM. 2015. Mabthera (Rituximab) Product Information, p. 1-49
4
Dreyling, T., et al.(2014). Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practicr Guidelines
for diagnosis, treatment, and follow-up. Annals of Oncology,25 (Supplement 3): iii76–iii82.
doi:10.1093/annonc/mdu200
5
Eichhorst, B., et al.(2011). Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis,
treatment, and follow-up. Annals of Oncology, 22 (Supplement 6): vi50–vi54. doi:10.1093/annonc/mdr377

66. THANK YOU

67. PRODUCT INFORMATION MABTHERA®
•CONTRAINDICATIONS
•Hypersensitivity to the active substance or to any of the excipients of this product or to murine
proteins.
•WARNING & PRECAUTIONS
•Infusion/administration-relatedreactions,severecytokinereleasesyndrome.Patientswitha
hightumourburdenorwithahighnumber(≥25x10
9
/l)ofcirculatingmalignantcells,should
onlybetreatedwithextremecautionandbeverycloselymonitoredthroughoutthefirst
infusion.
•Hypersensitivityreactions/anaphylaxis.Epinephrine,antihistaminesandglucocorticoids
shouldbeavailableforimmediateuseintheeventofahypersensitivityreactiontoMabThera
IV.
•Pulmonaryevents;Patientsexperiencingpulmonaryeventsorothersevereinfusion-related
symptomsshouldbecloselymonitoreduntilcompleteresolutionoftheirsymptomsoccurs.
BPOM. 2015. Mabthera (Rituximab) Product Information, p. 1-49

68. PRODUCT INFORMATION MABTHERA®
•WARNING&PRECAUTIONS(cont’d)
•Rapidtumourlysis;ProphylaxisforTLSshouldbeconsideredforpatientsatriskofdevelopingrapid
tumourlysis.
•Cardiovascular;patientswithahistoryofcardiacdiseaseand/orcardiotoxicchemotherapyshould
bemonitoredclosely.
•Monitoringofbloodcounts;Considerationshouldbegiventotheneedforregularfullbloodcounts,
includingplateletcounts,duringmonotherapywithMabTheraIV.WhenMabTheraIVisgivenin
combinationwithCHOPorCVPchemotherapy,regularfullbloodcountsshouldbeperformed
accordingtousualmedicalpractice.
•Severeactiveinfections;MabTheraIVtreatmentshouldnotbeinitiatedinpatientswithsevere
activeinfections.
•HepatitisBInfections.PatientswithahistoryofhepatitisBinfectionshouldbecarefullymonitored
forsignsofactivehepatitisBinfectionwhenrituximabisusedinassociationwithcytotoxic
chemotherapy.
•
BPOM. 2015. Mabthera (Rituximab) Product Information, p. 1-49

69. PRODUCT INFORMATION MABTHERA®
•WARNING&PRECAUTIONS(cont’d)
•Progressivemultifocalleukoencephalopathy(PML).PhysicianstreatingpatientswithNHLor
CLLshouldconsiderPMLinthedifferentialdiagnosisofpatientsreportingneurological
symptomsandconsultationwithaneurologistshouldbeconsideredasclinicallyindicated.
•SkinReactions.SevereskinreactionssuchasToxicEpidermalNecrolysisandStevens-
JohnsonSyndrome,somewithfataloutcome,havebeenreported.Incaseofsuchanevent,
treatmentshouldbediscontinued.Re-administrationmustbecarefullyassessedbasedonthe
individualpatient`sbenefit–riskprofile.
•Immunizations.PatientstreatedwithMabTheraIVisnotrecommendedtogetvaccinationwith
livevirusvaccines.PatientstreatedwithMabTheraIVmayreceivenon-livevaccinations.
However,withnon-livevaccinesresponseratesmaybereduced.
BPOM. 2015. Mabthera (Rituximab) Product Information, p. 1-49

70. PRODUCT INFORMATION MABTHERA®
•UNDESIRABLEEFFECTS
•Verycommon(≥10%):Bacteriinfections,virusinfections,neutropenia,leucopenia,angioedema,
nausea,pruritis,rash,fever,chills,asthenia,headache,decreasedIgGlevels.
•Common(≥1%-<10%):sepsis,
+
pneumonia,
+
febrileinfection,
+
herpeszoster,
+
respiratorytract
infection,fungalinfections,infectionsofunknownaetiology,anaemia,thrombocytopenia,hypersensitivity,
hyperglycaemia,bodyweightloss,peripheraledema,faceedema,increasedLDH,hypocalcemia,
paresthesia,hypoesthesia,agitation,insomnia,vasodilatation,dizziness,anxiety,lacrimationdisorder,
conjunctivitis,tinnitus,earpain,
+
myocardialinfarction,arrhythmia,
+
atrialfibrillation,tachycardia,
+
cardiac
disorder,hypertension,orthostatichypotension,hypotension,bronchospasm,respiratorydisease,chest
pain,dyspnoea,cough,rhinitis,vomiting,diarrhea,abdominalpain,dysphagia,stomatitis,constipation
dyspepsia,anorexia,throatirritation,urticaria,
+
alopecia,sweating,nightsweats,hypertonia,myalgia,
arthralgia,backpain,neckpain,tumourpain,flushing,malaise,coldsyndrome.
BPOM. 2015. Mabthera (Rituximab) Product Information, p. 1-49

71. PRODUCT INFORMATION MABTHERA®
•UNDESIRABLEEFFECTS
•Uncommon(≥0.1%-<1%):coagulationdisorders,transientaplasticanaemia,haemolytic
anaemia,lymphadenopathy,depression,nervousness,dysgeusia,
+
leftventricularfailure,
+
supraventriculartachycardia,
+
ventriculartachycardia,
+
angina,
+
myocardialischaemia,
bradycardia,asthma,bronchiolitisobliterans,lungdisorder,hypoxia,infusionsitepain.
•Note:Foreachterm,thefrequencycountwasbasedonreactionsofallgrades(frommildto
severe),exceptfortermsmarkedwith"+“wherethefrequencycountwasbasedonlyon
severe(≥grade3NCIcommontoxicitycriteria)reactions.Onlythehighestfrequency
observedineithertrialisreported.
BPOM. 2015. Mabthera (Rituximab) Product Information, p. 1-49

72. PRODUCT INFORMATION MABTHERA®
•INTERACTIONS
•InteractionswithOtherMedicinalProductsandOtherFormsofInteraction
•Atthepresent,therearelimiteddataonpossibledruginteractionswithMabThera.InCLLpatients,co-
administrationwithMabTheradidnotappeartohaveaneffectonthepharmacokineticsoffludarabineor
cyclophosphamide,inaddition;therewasnoapparenteffectoffludarabineandcyclophosphamideonthe
pharmacokineticsofMabThera.Co-administrationwithmethotrexatehadnoeffectonthe
pharmacokineticsofMabTherainrheumatoidarthritispatients.Patientswithhumananti-mouseantibody
(HAMA)orhumananti-chimericanti¬body(HACA)titersmaydevelopallergicorhypersensitivityreactions
whentreatedwithotherdiagnosticortherapeuticmonoclonalantibodies.IntheRAclinicaltrialprogram,
373MabThera-treatedpatientsreceivedsubsequenttherapywithotherDMARDs,ofwhom240receiveda
biologicDMARD.InthepatientstherateofseriousinfectionwhileonMabtThera(priortoreceiving
biologicDMARD)was6.1per100patientsyearscomparedto4.9per100patientsyearssubsequent
treatmentwiththebiologicDMARD.
“Before prescribing, please refer to updated Product Information, for additional important safety information.”
BPOM. 2015. Mabthera (Rituximab) Product Information, p. 1-49

73. Reporting Channels :
1.Email : [email protected]
2.Phone : [phone]
3.Fax : [phone]
Anyuntowardmedicaloccurrenceinapatientorclinicalinvestigationsubject
administeredapharmaceuticaldrugandwhichdoesnotnecessarilyhaveacausal
relationshipwiththistreatment.
Example:anyunfavorableandunintendedsign(includinganabnormallaboratoryfinding),
symptom,pregnancy.
REPORTINGADVERSEEVENTISMANDATORYACCORDINGTOINDONESIANREGULATORY
AUTHORITY(REGULATIONHEADOFBPOMRINoHK.03.1.23.11.10690Year2011ON
PHARMACOVIGILANCEIMPLEMENTATIONBYPHARMACEUTICALS)
REPORTING ADVERSE EVENT
Adverse Event
ALL THE DATA COLLECTED
WILL BE USED FOR ADVERSE
EVENT PROCESSING ONLY
OTH-OTH-Q4-15-169

74. KontakPelaporanAdverse event:
•Email : [email protected]
•Phone : [phone]
•Fax : [phone]
Adverseevent(KejadianTidakDiinginkan/KTD)adalahsemuakejadianmedisyangtidakdiinginkan
yangdialamiolehpasienatausubyekujiklinikselamaterapimenggunakanobattetapibelumtentu
disebabkanolehobattersebut.
Contoh:tanda/gejalayangtidakdiinginkan(termasukhasillaboratoriumyangabnormal)dankehamilan.
PELAPORANADVERSEEVENTDIWAJIBKANSESUAIPERATURANKEPALABPOMRINo
HK.03.1.23.11.10690Tahun2011TENTANGPENERAPANFARMAKOVIGILANSBAGIINDUSTRI
FARMASI
PELAPORAN KEJADIAN TIDAK DIINGINKAN
KejadianTidakDiinginkan(KTD)
DATA YANG DILAPORKANHANYAAKANDIGUNAKANUNTUKPEMANTAUAN
KEAMANANOBAT

75. ESMO DLBCL GUIDELINES 2015
1
Age
<60
>80
Fit, 60-
80
(aaIPI= 0) + no bulk
(aaIPI= 0) + bulk aaIPI= 1 R-ACVBP +
sequential consolidation
R-CHOP21 ×6 +
IF-RT on bulk
(aaIPI= 2, 3)
R-CHOP21 ×6
R-CHOP / R-ACVBP +
HDCT with ASCT
R-CHOEP14 ×6
R-CHOP14 ×6 with 8 R
R-CHOP21 ×6–8
(aaIPI= 0) R-CHOP21 ×6
R-CHOP14 ×6 with 8 R
(aaIPI>1)
With cardiac dysfunction
Unfit or frail
>60
without cardiac dysfunction R-miniCHOP21 ×6
R-C(X)OP21 ×6
+
palliative care
Consider CNS prophylaxis in patients at risk
1
Tilly, H., et al. (2015). Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis,
treatment, and follow-up. Annals of Oncol 26 (Supplement 5), v116-v125. doi:10.1093/annonc/mdv304

76. Thank you