Hematologic Disorders
Related to HCV Infection and
their management
By
prof.Rashed Hasan
Extra-hepatic manifestations of HCV
Introduction:
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They are included under extrahepatic manifestations (EHMs) of hepatitis C virus (HCV) infection .
Forty to 75% of patients with chronic HCV infection exhibit at least one clinical EHM .
Many of these extrahepatic manifestations of hepatitis C infection can be grouped into four
types: blood disorders, autoimmune disorders, skin conditions and kidney disease.
• Mechanism:
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1-Direct infection of extrahepatic tissue cells (viral tropism) by HCV .
2-the majority of EHMs are thought to be secondary to immune-mediated mechanisms, infection
results in upregulation of the humoral immune system in patients with chronic disease, which leads
to increases in monoclonal and polyclonal autoantibodies via chronic antigenic stimulation . It has
been postulated that anti-HCV-IgG and HCV lipoprotein complexes may act as B-cell superantigens
inducing the synthesis of non-HCV reactive IgM with rheumatoid factor-like activity . These
autoantibodies, in turn, form immune complexes, which circulate through the body and are
deposited in small to medium blood vessels, resulting in complement activation and extrahepatic
injury.
3-Lymphoproliferative effect of the virus
4-Autoimmune in nature.
The autoimmunity is due to:1-Auto antibodies production to the cellular components
which leak from the persistent destruction of the infected
cells. About 20% with hepatitis C patients are ANA positive .
2-The molecular mimicry between NS5A and NS core
proteins of HCV and auto antigens .
3-Abnormality of lymphocytic cells :
HCV infection and proliferation within lymphocytes leads to
functional alteration of lymphocyte and production of
excessive auto- antibodies and cryoglobulins
1- Peripheral blood cell disorders
• 1-ANEMIA
• The influence of HCV infection on the peripheral blood cell count has not
been well studied. A recent National Health and Nutrition Examination
Survey of HCV-infected individuals in the United States showed that HCV
antibody—positive subjects were more likely to have low neutrophil and
platelet counts than were HCV-negative individuals, but there was no
association between HCV status and anemia .
• However, independent case studies have demonstrated that patients with
chronic HCV infection can develop autoimmune hemolytic anemia in the
absence of treatment with IFN-α .
• In these HCV-infected patients, autoimmune hemolytic anemia was
reversible with prednisolone therapy . In addition, fatigue, a major
symptom of anemia, was recently reported to be the most common
extrahepatic complication in HCV-infected patients, and, in one study, it
was considered by almost one-half (48%) of all untreated HCV-infected
patients to be the initial or worst symptom
• Anemia of chronic disease (ACD) occurs in association with chronic
infections and inflammatory or neoplastic diseases. ACD can be
mild or severe (hemoglobin level of 7–12 g/dL) with
normochromic/normocytic or normochromic/microcytic RBCs . An
inflammatory response, manifesting as increases in levels of TNF-α
and IL-1 (which inhibit erythropoiesis), is common among
patients with ACD . Patients with HIV infection or cancer typically
have bone marrow suppression, which results in ACD . Although it
appears that individuals with chronic HCV monoinfection do not
demonstrate ACD, it has been shown that HCV can replicate
extrahepatically, specifically in the bone marrow —the physiologic
site of erythropoiesis. Replication of HCV in the bone marrow may
also contribute to the etiology of neutropenia and
thrombocytopenia observed in HCV-infected patient.
• Aplastic anemia:May occure several weeks or months following
acute HCV infection.It is usually severe & irreversible.
2-HCV related Thrombocytopenia
• HCV antibodies were identified in 30% of patients with chronic
idiopathic thrombocytopenia purpura .
• Pathogenesis:Thrombocytopenia associated HCV may be present
even in the absence of clinically evident liver disease or
splenomegaly and may be wrongly diagnosed as ITP . The detection
of HCV in platelet and megakaryocytes make HCV related
thrombocytopenia is probable cause. High affinity binding of HCV
to platelet membrane with subsequent binding of anti-HCV
antibody might lead to phagocytosis of platelets . High rate of HCV
RNA in HCV related-thrombocytopenia than non thrombocytopenic
patients was detected.Furthermore, HCV may be causative factor
for the production of platelate associated immunoglobulin G
inducing thrombocytopenia in mechanism similar to idiopathic
thrombocytopenia purpura (ITP)
• Treatment:Classical therapeutic approaches such
as corticosteroid, antiviral therapy and
Intravenous immunoglobulin and splenectomy
can be used. Disappearance of HCV RNA after IFN
α associated with improvement of
thrombocytopenia. Caution is recommended
in thrombocytopenic patients treated with
PEG-IFN α and ribavirin when platelet count less
than 50,000/μl as significant aggravation of
thrombocytopenia may occur
• Platelet count can be decrease from 30-50% in
patient who administrates interferon or
peginterferon, so reduction of the dose must
be if the platelet counts reach 50.000/mm and
discontinuation of the antiviral therapy if the
counts reach 25.000/mm. Peg interferon alpha
2a can reduce the weekly dose from 180μg to
135 or even to 90μg, and peg interferon alpha
2b can reduce from 1.5μg/kg to 1μg/kg or even to
0.5μg/kg
2-Human Recombinant Interleukin –
11(Oprelvekin) :Oprelvekin promoting
proliferation and maturation of megakerocytes
which can be used to stimulate increasing
number of platelet count at dose of 5 μg/kg/day
S.C for 7 days initially and if necessary during
antiviral therapy maintainance by taking 1-3
doses per week
3-Elthrombopag:Active thrombopoietin receptor
agonist (Elthrombopag) may be applied before and
during antiviral therapy in HCV related
thrombocytopenia at dose 30, 50 and 75mg lead to
sustained increase of platelate count and it allows
initiation and/or continuation of antiviral therapy.
4-Rituximab has promising therapeutic
approach,especially in refractory cases or
aggravating thrombocytopenia during the course of
antiviral therapy
2-Bleeding Disorders & Hepatitis C
• “Bleeding disorders” is a general term for a wide range of medical
problems that lead to poor blood clotting and continuous bleeding.
Medical terms referring to bleeding disorders include coagulopathy,
abnormal bleeding and clotting disorders.
• A person with a bleeding disorder has a tendency to bleed longer.
The disorders can result from defects in the blood vessels or from
abnormalities in the blood itself.The abnormalities may be in blood
clotting factors or in platelets. Unfortunately, the liver is intimately
involved in the production of clotting factors and platelets; so
having hepatitis C on top of a blood disorder is not a good thing.
• As we all know,advanced liver disease can cause bleeding disorders
as the liver becomes too diseased to manufacture clotting factors
and hormones to make platelets
3-Clotting Disorders and HCV
• Thrombophilia:
• It is the opposite of hemophilia. While people with
hemophilia have an increased tendency to bleed, people
with thrombophilia have an increased tendency to clot. Just
as hemophilia is caused by an abnormality of a bloodclotting factor, some forms of thrombophilia are also
caused by an abnormality or deficiency of a blood-clotting
factor.
• Chronic hepatitis C and treatment with interferon have
often been associated with a procoagulant state, and may
cause a protein C and S deficiency (natural anticoagulants
synthesised in the liver). This deficiency has been known to
cause mesenteric vein thrombosis, and can be fatal
• Thrombotic Thrombocytopenic Purpura (TTP or Moschcowitz
Syndrome):TPP is a rare disorder of the blood-coagulation system,
causing extensive microscopic thromboses to form in small blood
vessels throughout the body.
• This disorder is associated with both hepatitis C and treatment
with interferon and ribavirin. There are quite a few studies
demonstrating that interferon treatment can trigger TTP, most
probably as a result of heightened immune system response.
• As for blood clotting disorders, hopefully with the advent of new
direct-acting antiviral therapy and interferon-free combinations,
the incidence of thrombophilia and TTP will be greatly reduced
because these new treatments have a greater chance of curing HCV,
thus getting rid of these associated conditions
4-CRYOGLOBULINEMIA
• Definition of Cryoglobulinemia: Cryoglobulinemia refers to the
presence of one (monoclonal) or more (mixed or polyclonal)
immunoglobulins in the serum, which reversibly precipitate in vitro
at temperatures below normal body temperature (less than 37°C).
These immunoglobulins dissolve again when reheating the serum.
Cryoglobulins typically are composed of a mixture of
immunoglobulins and complement components.
• Mechanism of Disease: In HCV-related cryoglobulinemia,
immune complexes that contain HCV particles igG-igM-RF antibody
complex & complement deposit in the walls of capillaries, venules,
or arterioles, causing small vessel inflammation. In patients who
develop cryoglobulinemia, HCV causes chronic stimulation of
lymphocytes, which is thought to induce B-cell clonal expansion and
production of antibodies, including rheumatoid factor.
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1-The common hypothesis regarding HCV-related cryoglobulinemia is the chronic
antigenic stimulation of the humoral immune system, which facilitates clonal Blymphocyte expansion.
2-Other hypotheses:
-Chronic HCV infection of B cells and Bcl-2 activation (protoncogene). Bcl-2 (B-cell
lymphoma 2), encoded in humans by the BCL2 gene, is the founding member of
the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either
inducing (pro-apoptotic) it or inhibiting it (anti-apoptotic). Bcl-2 is specifically
considered as an important anti-apoptotic protein and is thus classified as an
oncogene which increase B cell survival by inhibiting apoptosis .
-Interaction of HCV E2 envelope protein with the cell surface glycoprotein CD81
that is present on B cells as well as on hepatocyte reduces the threshold for B-cell
activation.
HCV-specific proteins also demonstrate molecular mimicry with auto antigens.
NS5A and NS core proteins can simulate host auto antigens, possibly resulting in
B-lymphocyte activation and auto antibody production which may allow cross-
Classification of Cryoglobulinemia: Cryoglobulinemia is classically
grouped into three types according to the Brouet classification system.
• Type 1 cryoglobulinemia consists of isolated monoclonal immunoglobulin
IgM and most commonly occurs in association with lymphoproliferative
disorders; type 1 cryoglobulinemia represents only 10 to 15% of cases of
cryoglobulinemia.
• Type 2 cryoglobulinemia consists of mixed immune complexes, typically
monoclonal IgM and polyclonal IgG. This type of cryoglobulinemia most
often develops in persons who have chronic viral infections, such as HCV,
hepatitis B virus, and cytomegalovirus (CMV), but also occurs in persons
with chronic inflammatory states, such as systemic lupus erythematosus,
rheumatoid arthritis, and Sjögren's syndrome. Type 2 cryoglobulinemia is
the most common type of cryoglobulinemia seen in HCV-infected
patients.
• Type 3 cryoglobulinemia consists of mixed immune complexes, typically
formed by polyclonal IgM, and it represents 25 to 30% of cases of
cryoglobulinemia.
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• Association between HCV and Mixed Cryoglobulinemia: Multiple
reports have shown a close association of HCV and mixed
cryoglobulinemia, most often type 2 cryoglobulinemia. With HCVrelated mixed cryoglobulinemia, immune complexes comprised of
immunoglobulin and HCV particles precipitate in many organs,
including the skin, kidneys, and peripheral nerve fibers.
• Investigators have postulated that expansion of rheumatoid factor
activity and cryoprecipitability is responsible for the vasculitis. Most
patients with mixed cryoglobulinemia have evidence of chronic HCV
infection: studies have shown from 50 to 100% of patients with
mixed cryoglobulinemia cases have HCV infection. Conversely, most
HCV-infected patients do not have mixed cryoglobulinemia, with
estimates ranging from 10 to 50%
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Clinical Syndromes Associated with Cryoglobulinemia: A variety of clinical
syndromes can be associated with cryoglobulinemia. The most common manifestations of
HCV-associated cryoglobulinemia, along with the prevalence of the condition in patients with
HCV and cryoglobulins, are shown in the following list:
Mixed cryoglobulinemia vasculitis (4 to 40%). Cryoglobulinemic vasculitis is considered
a systemic small vessel vasculitis. In this disorder, damage to the small vessels is thought to
result from the deposition of immune complexes on the vessel wall followed by subsequent
activation of the complement cascade. Fewer than 10% of patients with cryoglobulinemia
develop cryoglobulinemic vasculitis. Diagnosis of Cryoglobulinemic Vasculitis: Specific criteria
of cryoglobulinemic vasculitis have not yet been defined. The diagnosis is typically made from
the combination of history, skin purpura, low complement levels, circulating cryoglobulins,
and histology that shows small vessel inflammation with immune deposits found in the
vascular wall.
Fatigue, arthralgia, myalgia (35 to 54%)
Renal disease (27 to 30%)
Palpable purpura (18 to 33%). Palpable purpura is evident in more than 90% of patients with mixed
cryoglobulinemia, and is usually the first sign of cryoglobulinemia. The finding of palpable purpura in a
patient with chronic hepatitis C should raise an immediate suspicion for cryoglobulinemic vasculitis.
Neuropathy (11 to 30%)
Sicca syndrome (10 to 25%).
The majority of HCV-infected patients with cryoglobulinemia have either no symptoms or nonspecific
clinical manifestations. A triad of purpura, myalgia, and arthralgia (Meltzer’s triad) occurs in an
estimated 30% of patients with HCV-related mixed cryoglobulinemia.
• Correlation with Liver Disease:
MC tends to correlate with duration of HCV
infection and older age.
However, cryoglobulinemia in the serum of
HCV patients has been associated with
increased risk of advanced fibrosis, the severity
of hepatic steatosis on liver biopsy and cirrhosis,
irrespective of age or disease duration
Treatment of HCV-related
Cryoglobulinemic Vasculitis
• 1-Interferon alfa: In patients with cryoglobulinemic vasculitis, experience
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with HCV treatment regimens that include interferon or peginterferon has shown
that HCV RNA levels decrease to an undetectable range before cryoglobulin levels
substantially decline. There is no evidence that patients with cryoglobulinemia
have different SVR rates than patients without cryoglobulinemia. Low HCV RNA
levels alone predict a favorable response of cryoglobulins to interferon
monotherapy, but approximately 80% of these responders will relapse within 6
months after completion of interferon therapy.
The combination of peginterferon alfa with ribavirin enhances and improves the
response. Use of interferon or peginterferon in this setting remains controversial
since treatment may precipitate and aggravate neuropathies, induce renal failure,
and delay ulcer healing. Insufficient data exist regarding the treatment of hepatitis
C-related cryoglobulinemia using regimens that include or consist entirely of new
direct acting antiviral agents. Interferon-free regimens would theoretically provide
an advantage by avoiding the interferon-related complications associated with
treatment of cryoglobulinemia.
• Corticosteroids, Cytotoxic Agents, and Plasmapheresis: Some experts have
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used corticosteroids in combination with cytotoxic agents and plasmapheresis to
treat rapidly progressive cryoglobulinemic vasculitis. Treatment with these agents
should be administered by an expert (or in consultation with an expert) who has
experience with treating this disorder.
Monoclonal Antibodies: B-cell clonal expansion is a key finding in mixed
cryoglobulinemia. Rituximab (Rituxan), an anti-CD20 monoclonal antibody,
modifies the dynamics of B cells by deleting expanded clones in cryoglobulinemic
patients. This treatment may provide protection against factors potentially
involved in the pathogenesis of malignant B-cell transformation. Patients with HCV
infection may have increased HCV RNA levels detected after treatment with
rituximab. A few studies have investigated the use of rituximab in combination
with peginterferon and ribavirin and have shown an improvement in results when
compared with peginterferon and ribavirin alone. Treatment with rituximab should
be administered by an expert (or in consultation with an expert) who has
experience with use of rituximab.
LAC-diet(low antigen content)
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The rationale of the use of LAC-diet in the treatment of patients with mixed cryoglobulinemia is to
reduce the input of food antigens to the mononuclear phagocytic system which is satured by large
amounts of endogenous immune-complexes (chiefly the cryoglobulins).
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The administration of the restricted diet (LAC-diet) for 10-15 days every month should maintein the
efficiency of mononuclear phagocytic system in the clearance of cryoglobulins.
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The following foods must be avoided during the LAC-diet treatment:
dairy products
eggs
fish
meats (except turkey, rabbit, lamb)
legumes
alcohol
additives, preservatives
tomatoes
5-Lymphoproliferative disorders (LPD)
&HCV:
• Lymphoproliferative disorders (LPDs) are neoplasms of the blood and
encompass lymphoma, multiple myeloma, and leukemia.The associated
lymphoma include Hodgkin & non- Hodgkin lymphoma(NHL).
• NHL include diffuse large B-cell lymphoma, marginal zone lymphoma,
lymphoplasmacytic lymphoma{Waldenström
macroglobulinemia(WM)}, splenic lymphoma with villous
lymphocytes, and extranodal marginal zone B cell lymphoma of
mucosa-associated lymphoid tissue(MALT lymphoma).
• Diffuse large B-cell lymphomas is aggressive lymphoma. Indolent
lymphomas include: follicular lymphoma, small lymphocytic
lymphoma, marginal zone lymphomas, splenic marginal zone
lymphoma, primary nodal marginal zone lymphoma and extranodal
marginal zone lymphoma of mucosa-associated tissue (MALT), and
lymphoplasmacytic lymphoma. Indolent lymphomas are defined from
a clinical point of view as scarcely symptomatic lymphomas, growing
and spreading slowly.
• Relationship: Chronic hepatitis C infection has been associated with the
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development of B-cell non-Hodgkin lymphoma, HCV RNA has been isolated in the
gastric mucosa of patients with MALT lymphoma , raising the possibility that HCV
may play a role in its pathogenesis as well as primary hepatic lymphoma. There is
a high prevalence of HCV seropositivity (15%) in patients with B-cell
lymphoproliferative disorders, especially B-cell non-Hodgkin lymphoma. Primary
hepatic diffuse large B-cell lymphoma (DLBCL) is also associated with HCV. DLBCL
may present on histology as large lymphoid cells with vacuolated nuclei in a diffuse
infiltrating pattern intermingled with small lymphoid cells. The large cells typically
stain positively for CD20, CD10, and CD25.
Low grade lymphomas are more frequently associated with HCV . The
association between HCV and NHL is strongest in geographic areas with the
highest prevalence of the viral infection.
Overall, marginal zone lymphoma appears to be the most frequently encountered
low-grade B-cell lymphoma in HCV patients. HCV infection is documented in
approximately 35% of patients with nongastric B-cell marginal zone lymphoma.
Splenic marginal zone lymphoma, in particular has a high prevalence of HCV
infection and is often associated with type II cryoglobulinemia
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Other hematologic disorders in the course of HCV infection are gammopathies of uncertain
significance (MGUS): usually they are gammopathies IgM/Kappa.MGUS are present in up to
11% patients with HCV infection without cryoglobulins. Some authors reported an
association with HCV genotype 2a/c. These monoclonal gammopathies have to be
monitorized in order to exclude the possibility of an evolution to multiple myeloma.
Waldenström macroglobulinemia(WM), one of the malignant monoclonal gammopathies, is
a chronic, indolent, lymphoproliferative disorder. It is characterized by the presence of a high
level of a macroglobulin (immunoglobulin M [IgM]), elevated serum viscosity, and the
presence of a lymphoplasmacytic infiltrate in the bone marrow. A clonal disease of B
lymphocytes, Waldenström macroglobulinemia is considered to be a lymphoplasmacytic
lymphoma. No definite etiology exists for Waldenström macroglobulinemia. Environmental,
familial, genetic, and viral factors have been reported. IgM monoclonal gammopathies of
undetermined significance (MGUS) are considered a precursor of Waldenström
macroglobulinemia. Hepatitis C, hepatitis G, and human herpesvirus 8 have been implicated,
but as yet, no strong data support a causative link between these viruses and Waldenström
macroglobulinemia.
Results from a few studies show that people who have the Hepatitis C virus may have an
increased risk of Hodgkin’s lymphoma.
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Pathogenesis: The mechanism may be due to long term HCV infection, resulting in clonal
B cell expansion of immunoglobulin (cryoglobulin) secreting lymphocytes, also a
combination of a mutation agents like factors (genetic, environmental, immunological) result
in activation of oncogenes and resulting in NHL. Another possibility is the inhibition of
apoptosis of HCV infected lymphocytes by over-expression of the bcl2, and a second
mutation (myc oncogene) may lead to the development of lymphoma . This data suggest
that the multi step lymphomagenetic cascade may have points of no-return, making LPD
progressively independent from HCV infection . The pioneering work of Bishop and
colleagues established that v-myc was the oncogene captured by the avian MC29
myelocytomatosis transforming virus
According to the currently more accepted pathogenetic model, the role of HCV infection in
lymphomagenesis may be related to the chronic antigenic stimulation of B-cell immunologic
response by the virus , similarly to the well-characterized induction of gastric MALT
lymphoma development by Helicobacter pylori chronic infection . In a similar way, chronic
HCV infection may possibly sustain a multistep evolution from type II mixed cryoglobulinemia
to overt low-grade NHL and eventually to high-grade NHL . The most convincing argument in
favour of a causative link between HCV and lymphoproliferation is represented by
interventional studies demonstrating that in HCV-positive patients affected by indolent NHL
eradication of HCV with antiviral treatment (AT) could directly induce lymphoma regression .
• Moreover, the upcoming novel antiviral anti-HCV agents as boceprevir and
telaprevir, whose addition to standard treatment has already
demonstrated an increased rate of viral eradication also in more resistant
genotypes (i.e., genotype 1b) , will possibly further improve the efficacy of
this treatment for HCV-positive indolent NHL in the near future
• Treatment and Prognosis:
• Survival outcomes for patients with diffuse large B-cell lymphoma with
HCV infection are worse than in patients without HCV infection. This may
be due to hepatotoxicity of chemotherapy for the lymphoma. Limited data
suggest that low-grade B-cell lymphomas might regress with HCV
clearance induced by antiviral therapy with IFN ; however high-grade B cell
malignancies still require systemic chemotherapy.
• he use of rituximab in HCV-associated NHL, in monotherapy or in
combination with
antiviral treatment and/or chemotherapy, appears
very promising, especially in the setting of low-grade NHL, where
rituximab monotherapy has been proposed as first-line treatment.
• Interestingly, Hainsworth et al showed that the use of rituximab in lowgrade NHL with scheduled maintenance at 6-mo intervals produced high
overall and complete response rates and a longer progression-free
survival than has been reported with a standard 4-wk reatment
• In patient with aggressive lymphoma, antiviral therapy must be
delayed until the NHL is under control. Rituximab-based
chemotherapy has become the first-line approach to treating
aggressive B cell lymphomas.
• Although hepatotoxicity has been reported at higher frequency in
patients treated for HCV-related NHL, some of the data are hard to
interpret because of the definitions for hepatotoxicity used.
• Although there have been infrequent reports of HCV ‘flares’ during
chemotherapy, most data suggest that HCV does not ‘reactivate’
like HBV and chemotherapy should be well tolerated in HCVinfected individuals without cirrhosis.
• As antiviral therapy improves, it may even be possible to combine
HCV treatment with treatment for NHL
Multiple myeloma (MM)
• Itis a B-cell malignancy characterized by the proliferation of clonal
plasma cells in the bone marrow. Clinically, it often presents with
hypercalcemia, renal dysfunction, anemia, and bone disability.
• . Extensive analysis revealed that the risk of developing MM was
significantly increased among patients with HCV. Some results
showed a prevalence of HCV of 32% in the myeloma patients
compared with a prevalence of 9% in the control . Many people
with monoclonal gammopathy of undetermined significance
(MGUS) or solitary plasmacytoma will eventually develop multiple
myeloma.
• Regression of a case of Multiple Myeloma with antiviral treatment
(Pegilated alpha-Interferon 180 μg/week and Ribavirin 1000 mg
p.o./day)in a patient with chronic HCV infection(Panfillo et al
20013). The clear response obtained in this case suggests a possible
role of chronic HCV infection in MM
Treatment for Multiple Myeloma
• Multiple myeloma treatment depends on several factors, including the
stage of the disease and the overall health and age of the patient. The goal
of treatment is to reduce symptoms and prolong survival (called palliative
treatment). Treatment for multiple myeloma may involve radiation
therapy, chemotherapy and other medications (e.g., targeted therapy,
corticosteroids), stem cell transplantation, and additional treatments.
• Patients with early stage multiple myeloma (i.e., smoldering myeloma) or
slow-growing (indolent) myeloma usually do not require treatment.
Instead, these patients are closely monitored and receive regular testing
(called watchful waiting.
• Radiation therapy usually is administered once daily (e.g., 5 days per
week) for several weeks. Treatment sessions usually last about 30
minutes.
• Some patients with multiple myeloma receive chemotherapy prior to
undergoing stem cell transplantation
•Many thanks