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II SESSIONE
Moderatori: G. Angarano, A. Di Leo
Complicanze extra-epatiche da HCV
• L'evoluzione futura degli obiettivi terapeutici:
dalla cura alla prevenzione
• L'impatto dei DAAs sull'epidemiologia delle
complicanze extraepatiche: un possibile punto
di svolta?
M. Persico
26 giugno 2014 Bari
COMPLICANZE EXTRA-EPATICHE da HCV
Prof. Marcello Persico
UOC Medicina Interna ed Epatologia
Dipartimento di Specialità Mediche
Università degli studi di Salerno
[email protected]
Questions about HCV+
and NHL
• Is the NHL related with HCV
infection ?
• Which is the best
therapeutic strategy ?
• Is the antiviral treatment
appropriate ?
• Is the chemotherapy safe ?
Is the NHL related with HCV
infection ?
Clinical and histological characteristics:
• Histological subtype:
Lymphoplasmacytic
Primary nodal marginal zone
Splenic marginal zone
MALT marginal zone
• Indolent course
• Presence of mixed cryoglobulinemia
• Presence of autoimmunity
• Presence of monoclonal IgMk component
Biological characteristics:
•
Since the primary target of antibody
responses is the HCV-E2 protein the
antibodies derived from HCV-infected
patients use a restricted IgV gene
repertoire, with a strong bias for VH1-69
(also known as 51p1) and V3-A27 (also
known as 325).
•
The monoclonal IgM component of type II
MC is often encoded by the same set of V
region genes, VH1-69 and Vk3 -A27
•
bcl-2/IgH translocation
•
miRNA (miR-26b) (down regulation in
HCC)
•
Serpins (SERPINB3)
Serum biomarker signature identifies
patients with B-cell non-Hodgkin
lymphoma associated with
cryoglobulinemia vasculitis in chronic HCV
infection
Benjamin Terrier ……. Patrice Cacoub.
Autoimmunity Reviews
Volume 13 (3) March 2014: 319–326
Multiparametric analysis : signature
involving CD27,IL-2R-alpha, gammagloulins and C4 related to hCV/NHL
witn NPV and PPV of 100% and 97%
and sensitivity of 100% and specificity
of 90%.
Which is the best
therapeutic
strategy ?
Factors to be
taken in
consideration:
•
•
•
•
Tumor burden
Disease course
Liver disease
Symptoms
• Comorbidities
High  Chemotherapy
Aggressive  Chemoterapy
Absent  Chemotherapy
Tumor-related  Chemotherapy
Low  Antiviral
Indolent  Antiviral
Present  Antiviral
MC-related  Antiviral
Contra-indication to antiviral therapy  Chemotherapy
Contra-indication to chemotherapy  Antiviral
Which is the ideal
patient ?
Histological subtype typical for HCV-related lymphoma
Molecular characteristics typical for HCV-related lymphoma
Indolent course
Low tumor burden
MC-related symptoms
Presence of chronic hepatitis
No contra-indications to antiviral therapy
The antiviral
therapy in the
indolent
HCV + NHL
Vallisa et al. J Clin Oncol 2005: 13 cases: one follicular lymphoma, 4
lymphoplasmacytoid lymphomas, and 8 marginal-zone lymphomas
Results: 7 CR and 2 PR but all responders relapsed from 2 to 29 months after the
end of the treatment. The hematologic response was related to the disappearance of viremia
Pozzato et al. Br J Hematol 2009: 18 cases: one follicular lymphoma, 10
lymphoplasmacytoid lymphomas, and 7 marginal-zone lymphomas
Results: 9 CR and 3 PR, a fraction (3 cases) of CR relapsed immediately after the
end of treatment. The hematologic response was related to the disappearance of viremia
Hepatitis C-associated B-cell non-Hodgkin lymphomas.
Epidemiology, molecular signature and clinical management
Jan Peveling-Oberhag Luca Arcaini, Martin-Leo Hansmann, Stefan Zeuzem
•
•
•
•
•
•
•
•
Very small number of cases enrolled
Heterogeneous histology
Different treatment schedules
No randomized trials
Scattered presence of mixed cryoglobulinemia
Chronic liver disease of different severity
Difficult interpretation of the results
A fraction of cases previously treated with chemotherapy
At least ….. the treatment is well tolerated. Complete and durable
response is achieved in a small fraction of cases. The complete
response is associated with the clearance of the HCV-RNA.
The splenic
lymphoma with
villous
lymphocytes
CD19+ CD20+ CD22+ CD24+
CD5- CD10- CD23- CD25-
Hermine et al. NEJM 2002
9 cases treated with IFN or IFN+RIBA All cases
responded. After a mean of 27 months 7 cases were
still negative for HCV-RNA
 Kelaidi C et al. Leukemia 2004
8 cases treated with combination therapy: 5 long
term responders
 Saadoun D et al. Blood 2005
18 cases treated with IFN and Riba:14 complete
hematological and virological responders.
 Kanbay M et al Am J Hematol 2006
1 case treated with PEG-IFN: complete responder
 Nunes J et al. Acta Med Port 2010
1 case treated with PEG-IFN+Riba: complete responder
Small number of cases, but very homogeneous for histology, clinical and biological
characteristics. Antiviral treatment safe and effective !
Takahashi et al.
Regression of Hodgkin lymphoma [Nodular
lymphoid proliferative Hodgkin’s lymphoma
(CD30-)] in response to antiviral therapy for
hepatitis Cvirus infection
Intern Med 2012; 51: 2745-7
Coskun A et al.
Lacrimal Gland Marginal Zone Lymphoma:
Regression after Treatment of Chronic
Hepatitis C Virus Infection: Case Report
and Review of the Literature
Intern Med 2013 52: 2615-8
Panfilio et al.
Regression of a case of Multiple Myeloma
with antiviral treatment in a patient with
chronic HCV infection
Leukemia Research Reports 2013; 2: 39-40
Pangalis et al. Recombinant alfa-2binterferon therapy in untreated, stages A
and B chronic lymphocytic leukemia. A
preliminary report.
Cancer 1988; 61(5): 869-72
Rozman C et al. Recombinant alpha 2interferon in the treatment of B chronic
lymphocytic leukemia in early stages.
Blood 1988; 71(5): 1295-8
O'Connell MJ et al. Clinical trial of
recombinant leukocyte alfa- interferon as
initial therapy for favorable histology nonHodgkin's lymphomas and chronic
lymphocytic leukemia. An Eastern
Cooperative Oncology Group pilot study.
J Clin Oncol 1986; 4(2):128-36.
Anti-viral and anti-proliferative properties of
IFN cannot be separated …… until ….
…. until interferon-free regimens
will be available !!!
With new DAAs the anti-
proliferative properties of antiviral
therapy shut down and the “pure”
anti-HCV activities of the new drugs
will responde the question whether
the HCV replication is directly
correlated with the B-cell monoclonal
proliferation
Counting down the final days of interferon
Simeprevir or
Sofosbuvir + PEG-R
Boceprevir or
Telaprevir + PEG-R
2011
IFN + Riba
1991
Standard IFN
1998
GT1
2014 2005
2001
Peg IFN- Riba
GT2/3
2014
Sofosbuvir + Ribavirin
Saadoun D et al.
Ann Rheum Dis 2013
Kinetics of hepatitis C virus RNA (A), cryoglobulins (B) and C4 serum level (C)
Kinetics of virological response to triple antiviral therapy in all HCV+ MC
patients (23) according to the type of therapy. Data are expressed as n (%) of
undetectable HCV RNA.
Grade 3 and 4 adverse events (anemia, neutropenia and thrombocytopenia) were
observed in 10 cases (43%). Twenty patients (87%) received EPO, 9 (39%) had
red cell transfusion and 2 (9%) had granulocyte-stimulating agent.
A role of the antiviral therapy
in the aggressive
HCV+ NHL ?
Evolving Management Strategies in Non-Hodgkin’s Lymphoma
clinicaloptions.com/oncology
Most Common Lymphomas
T lymphoblastic: 2%
Other: 9%
Marginal zone, nodal: 2%
Burkitt: 2%
Anaplastic large cell: 2%
Diffuse large B cell: 31%
Mediastinal large B cell: 2%
Mantle cell: 6%
Small lymphocytic/CLL: 7%
Peripheral T cell: 7%
Follicular: 22%
Marginal zone, extranodal: 8%
Armitage JO, et al. J Clin Oncol. 1998
Molecular
changes
associated with
DLBCL
Gene(s) Affected/Disregulated
Frequency, %
Predominant Causal Genetic
Abnormality
45
Aberrant Immungl somat Hypermut
(SHM)
Bcl-6
35-40
3q27 translocations
Bcl-2
15/24
t(14;18)/amplification
Fas(CD95)
20
10q24 mutations
p53
16
17p mutations/deletions
c-Myc
15
t(8;14)
Potentially c-Rel
14
2p13 amplification
Multiple
Gene expression profiling (GEP) defined
three molecularly and clinically distinct
subgroups of DLBCL
PMBL: primary mediastinal BCL
GCB: germinal center B-like DLBCL
ABC: activated B-cell-like DLBCL
1.0
0.8
PMBCL
0.6
GBC-DLBCL
0.4
ABC-DLBCL
0.2
Yrs
0
0
2
4
6
8
R-CHOP-21
(n = 405*)
R-CHOP-14
(n = 426*)
CR/CRu (P = .183)
63
58
CR/CRu/PR (P = .139)
88
91
 CR
49
40
 CRu
14
18
 PR
24
32
SD
6
5
PD/relapse
6
4
Response (%)
Second-line therapy
• DHAP ± rituximab
ESHAP ± rituximab
• GDP ± rituximab
GemOx ± rituximab
• ICE ± rituximab
miniBEAM ± rituximab
• MINE ± rituximab
Bendamustine ± rituximab
CR: complete response; Cru: undefined CR; PR: Partial R; SD: stable disease; PD: progressive disease
There are some anecdotal
observations reporting successful of
the antiviral treatment in DLBCL or
mantle cell lymphoma.
However, treating aggressive HCVNHL with standard immunochemotherapy, the underlying HCV
infection remains an issue to be
considered and the impact of the
treatment on the HCV replication and on
liver disease should be carefully
monitored.
Different mechanisms may be implicated in the potential higher rates of liver
dysfunction after chemo-immuno-therapy in HCV-NHL
1) aggravation of preexisting liver damage
2) accelerated HCV replication and increase of liver damage
3) increased drug toxicity due to altered drug metabolism
The first paper addressing this topic
showed a worse prognosis in HCV+ vs
HCV– in DLBCL (Besson C et al. J Clin.
Oncol 2006) :
At 2 years, the OS of HCV+ cases was
56% vs 80% of their matched patients and
PFS was 53% vs 75%.
Other papers did not confirm these
observations:
Arcaini et al. Am J Hematolgy
160 patients with NHL and HCV infection. Among 93 patients with normal ALT, 16
patients (17%) had liver toxicity. Among 67 patients with abnormal ALT, 8 (12%) had liver toxicity
Tomita N et al Leukemia Lymphoma 2007
Patients with HCV+ aggressive NHL have a similar prognosis as HCV- At least in noncirrhotic subjects
Visco et al. Ann Oncol 2006
The OS and PFS of HCV+ cases were similar to HCV- cases in DLBCL
In conclusions:
In HCV+ NHL the chemotherapy is safe
and only a small fraction of cases (less
than 10%) develop hepatic toxicity.
Only in a minority of patients (2-5%) the
treatment must be stopped for severe
liver toxicity.
The liver toxicity is rather related with
the underlying chronic liver disease than
an increase of HCV replication.
A role of the antiviral therapy
in the aggressive
HCV+ NHL ?
Concurrent chemo-immuno-therapy and
antiviral therapy is primarily hampered
by the hematological toxicity, but
antiviral therapy following recovery
from NHL has been used with promising
results, leading to improved clinical
outcome and prolonged disease free
survival
La Mura et al. J.Hepatology 2008
A fraction of HCV+ cases with indolent NHL were treated with PEG-IFNRIBA after achieving CR. Responders did not show relapse of the NHL, while
29% of the non-responders/relapsers to antiviral therapy relapsed even for NHL.
Musto P et al Blood 2005 (ASH Meeting Abstract)
44 cases of HCV+ DLBCL were treated with standard R-CHOP. 4 cases
underwent antiviral therapy during chemotherapy, but treatment was withdrawn
for hematological toxicity. Other 12 cases obtained SVR after PEG-IFN-RIBA
after recovery from DLBCL.
A role of the antiviral therapy
in the aggressive
HCV+ NHL ?
We don’t know the impact of the new
DAAs in the context of the NHL
Given the absence of hematological
toxicities, DAAs could be used together
with chemotherapy to prevent the
increase of HCV replication.
Since a fraction of patients develop
secondary MDS after intensive
chemotherapy, these cases are, at
present, excluded from antiviral
therapy, while they might benefit form
new DAAs.
With new drugs new studies are
needed and the necessity of an
interdisciplinaryapproach has to be
emphasized.
Moreover, since these new antiviral
drugs show new side effects, new
drug-drug-interactions require close
monitoring.