Correspondence

Regression of Splenic Lymphoma after Treatment of Hepatitis C Virus Infection

N Engl J Med 2002; 347:2168-2170December 26, 2002

Article

To the Editor:

The report of Hermine et al. (July 11 issue)1 provides important additional evidence as to the possible role of antiviral therapy for hepatitis C virus (HCV) infection in the treatment of patients with HCV-associated mixed cryoglobulinemia and lymphoma. They report regression of splenic lymphoma with villous lymphocytes and loss of HCV RNA in seven patients with mixed cryoglobulinemia and HCV infection after treatment with interferon. In five of these patients, molecular studies were performed, but none of them showed loss of the monoclonal immunoglobulin gene component.

In 1996, we reported complete remission of low-grade types of non-Hodgkin's lymphoma (lymphoplasmocytic or lymphoplasmoid immunocytomas) in three patients with type II mixed cryoglobulinemia and HCV infection after treatment with interferon.2 Remission was also associated with a loss of detectable HCV RNA. Moreover, these patients, as well as those of Zuckerman et al.,3 had complete regression of the monoclonal B-cell component in peripheral-blood mononuclear cells. In contrast to the patients in the study by Hermine et al. who had clinically evident lymphoma, our patients had no clinical evidence of lymphoma. In addition, we were able to genotype the HCV and found that of the patients who had no response to antiviral therapy or had a relapse, all had genotype 2 (1b). It would be interesting to know which HCV genotype was present in the patients included in the study by Hermine et al. Follow-up of our three patients at 60 months showed maintenance of complete remission of non-Hodgkin's lymphoma and nondetectable HCV RNA.

Cesare Mazzaro, M.D.
Pordenone General Hospital, 33170 Pordenone, Italy

D'Anna Little, M.D.
Centro di Riferimento Oncologico, 33081 Aviano, Italy
dlittle@cro.it

Gabriele Pozzato, M.D.
University of Trieste, 34149 Trieste, Italy

3 References

1. 1

   Hermine O, Lefrere F, Bronowicki J-P, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 2002;347:89-94
   Full Text | Web of Science | Medline

2. 2

   Mazzaro C, Franzin F, Tulissi P, et al. Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to α-interferon therapy. Cancer 1996;77:2604-2613
   CrossRef | Web of Science | Medline

3. 3

   Zuckerman E, Zuckerman T, Sahar D, et al. The effect of anti-viral therapy on t(14;18) translocation and immunoglobulin gene rearrangement in patients with chronic hepatitis C virus infection. Blood 2001;97:1555-1559
   CrossRef | Web of Science | Medline

To the Editor:

Hermine and colleagues report that antiviral therapy can result in complete remission of HCV infection and splenic lymphoma with villous lymphocytes in patients with coexisting cryoglobulinemia, but not in patients who have splenic lymphoma without HCV infection. These results and others1-3 argue for prospective trials examining the efficacy of antiviral therapy for HCV-associated lymphomas.

However, the treatment of such patients can be complex. We treated a patient with chronic HCV infection, mixed type II cryoglobulinemia, and indolent B-cell lymphoma with interferon alfa and ribavirin. He presented with a plasma HCV RNA level of more than 10 million copies per milliliter, 25 percent cryoglobulins, and a peripheral-blood leukocyte count of 23,800 per cubic millimeter. Flow cytometry revealed a CD5-dim, CD20-bright, CD23-negative, and cyclin D–negative clonal B-cell population, representing 90 to 95 percent of lymphocytes.

One month after antiviral therapy was initiated, there was complete viral suppression (plasma HCV RNA, <100 copies per milliliter). One month later, small-vessel vasculitis developed, with ischemic necrosis of both index fingers. The cryoglobulin fraction remained at 25 percent, and the peripheral leukocyte count was 7928 per cubic millimeter, with 30 percent monoclonal B cells. The patient required treatment with high-dose corticosteroids, plasmapheresis, and two cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. Interferon alfa and ribavirin therapy was continued. Two years after completing a 12-month course of antiviral therapy, the patient remains free of HCV, cryoglobulinemia, and lymphoma. Antiviral therapy with complete HCV suppression may thus not always control manifestations of the associated B-cell lymphoproliferation, and determination of the optimal sequences of antiviral and cytotoxic therapy could improve the outcomes of disease.

Leisha A. Emens, M.D., Ph.D.
Mark S. Sulkowski, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD 21231
emensle@jhmi.edu

3 References

1. 1

   Mazzaro C, Franzin F, Tulissi P, et al. Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to α-interferon therapy. Cancer 1996;77:2604-2613
   CrossRef | Web of Science | Medline

2. 2

   Zuckerman E, Zuckerman T, Sahar D, et al. The effect of antiviral therapy on t(14;18) translocation and immunoglobulin gene rearrangement in patients with chronic hepatitis C virus infection. Blood 2001;97:1555-1559
   CrossRef | Web of Science | Medline

3. 3

   Patriarca F, Silvestri F, Fanin R, Zaja F, Sperotto A, Baccarani M. Long-lasting complete remission of hepatitis C virus (HCV) infection and HCV-associated immunocytoma with alpha-interferon treatment. Br J Haematol 2001;112:370-372
   CrossRef | Web of Science | Medline

To the Editor:

We previously reported regression of a monoclonal WA cross-idiotype–positive B-cell proliferation after treatment for HCV infection in a patient with features of splenic lymphoma with marginal-zone B-cell phenotypic markers and type II cryoglobulinemia who also had 3q trisomy and overexpression of Bcl-2.1 Monoclonal rheumatoid factors that bear the WA cross-idiotype are the most prevalent monoclonal rheumatoid factors in type II cryoglobulinemia and lymphomas associated with HCV infection.2 Our study raises several questions for Hermine et al. Were the cryoglobulins typed? Were the monoclonal immunoglobulin bands sequenced? Were the monoclonal B cells in the blood monitored by B-cell clonal analysis? Were chromosomal and Bcl-2 studies performed in both HCV-infected patients and noninfected controls?

Vincent Agnello, M.D.
Lahey Clinic, Burlington, MA 01805
vincent.agnello@lahey.org

Cristina Mecucci, M.D.
University of Perugia, 01805 Perugia, Italy

Milvia Casato, M.D., Ph.D.
University of Rome La Sapienza, 00185 Rome, Italy

2 References

1. 1

   Casato M, Mecucci C, Agnello V, et al. Regression of lymphoproliferative disorder after treatment for hepatitis C virus infection in a patient with partial trisomy 3, Bcl-2 overexpression, and type II cryoglobulinemia. Blood 2002;99:2259-2261
   CrossRef | Web of Science | Medline

2. 2

   Knight G, Agnello V. WA monoclonal rheumatoid factors and non-Hodgkin lymphoma. Blood 2001;97:3319-3321
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Our report suggests that patients infected with HCV who have splenic lymphoma with villous lymphocytes have a higher rate of viral clearance and a longer-lasting response (more than 60 months) to interferon than do patients with hepatitis C. In contrast to the findings of Mazzaro et al.,1 one of our patients was infected with the interferon-resistant genotype-1b virus despite having a good response to interferon treatment. Similar good responses were also reported in previous studies in patients with HCV type II cryoglobulinemia treated with interferon alfa.2 Further prospective studies in larger groups of patients are warranted, however, in order to assess the frequency of each virus genotype, to define predictors of responses, and to elucidate the pathophysiology of the association between HCV infection and splenic lymphoma with villous lymphocytes.

In our study, all patients had type II cryoglobulinemia. We agree that in some cases, because of the slow response to antiviral therapy, symptomatic cryoglobulinemia, particularly if there is also glomerulonephritis, peripheral neuropathy, or both, may initially require treatment with corticosteroids, immunosuppressive drugs (e.g., cyclophosphamide), or plasma exchange. In most cases, however, antiviral therapy may lead to the rapid disappearance of symptoms even when cryoglobulinemia and lymphoma are still detectable. Chemotherapy should be used only if the tumor burden is life-threatening. However, by controlling the replication of the virus, antiviral therapy should reduce the risk of worsening hepatitis after the administration of immunosuppressive drugs or chemotherapy.

As others have reported, antiviral therapy may also induce complete remission of lymphoplasmatic lymphoma or immunocytoma1 and leukemic marginal-zone lymphoproliferation with partial trisomy 3.3 We have observed such responses after the failure of chemotherapy in a patient with splenic follicular lymphoma with the t(14;18) translocation (unpublished data). Thus, other subtypes of low-grade lymphoma may also respond to antiviral therapy. In patients with high-grade lymphoma associated with HCV infection, in addition to the protective effect against liver damage, antiviral therapy may actually increase the response rate and reduce the risk of relapse after chemotherapy. Therefore, we believe that screening for HCV should be considered at diagnosis for patients with low-grade B-cell lymphoma as well as those with high-grade B-cell lymphoma. If our data are confirmed in larger groups of patients with HCV infection and various B-cell lymphomas, HCV-related B-cell lymphoproliferation and particularly splenic lymphoma with villous lymphocytes could be classified as a special entity, as has been proposed in the classifications of the World Health Organization for T-cell lymphoproliferation related to human T-cell lymphotropic virus type I.4

François Lefrère, M.D.
Necker University Hospital, 75743 Paris CEDEX 15, France

Xavier Troussard, M.D.
Côte de Nacre University Hospital, 14000 Caen, France

Olivier Hermine, M.D., Ph.D.
Necker University Hospital, 75743 Paris CEDEX 15, France
hermine@necker.fr

4 References

1. 1

   Mazzaro C, Franzin F, Tulissi P, et al. Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to α-interferon therapy. Cancer 1996;77:2604-2613
   CrossRef | Web of Science | Medline

2. 2

   Casato M, Agnello V, Pucillo LP, et al. Predictors of long-term response to high-dose interferon therapy in type II cryoglobulinemia associated with hepatitis C virus infection. Blood 1997;90:3865-3873
   Web of Science | Medline

3. 3

   Casato M, Mecucci C, Agnello V, et al. Regression of lymphoproliferative disorder after treatment for hepatitis C virus infection in a patient with partial trisomy 3, Bcl-2 overexpression, and type II cryoglobulinemia. Blood 2002;99:2259-2261
   CrossRef | Web of Science | Medline

4. 4

   Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting -- Airlie House, Virginia, November 1997. J Clin Oncol 1997;17:3835-3849
   Web of Science

Citing Articles (12)

Citing Articles

1. 1

   Gabriele Pozzato, Francesca Zorat, Stefania Bonetto, Cesare Mazzaro. (2011) Hepatitis C virus and non-Hodgkin’s lymphoma: biology, epidemiology and therapy. Oncology Reviews
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2. 2

   Ajay Nooka, Pareen J. Shenoy, Rajni Sinha, Sagar Lonial, Christopher R. Flowers. (2011) Hepatitis C Reactivation in Patients Who Have Diffuse Large B-Cell Lymphoma Treated With Rituximab: A Case Report and Review of Literature. Clinical Lymphoma Myeloma and Leukemia 11:5, 379-384
   CrossRef

3. 3

   Masahiko Ito, Hideki Kusunoki, Keiko Mochida, Kazunari Yamaguchi, Toshiaki Mizuochi. (2011) HCV Infection and B-Cell Lymphomagenesis. Advances in Hematology 2011, 1-8
   CrossRef

4. 4

   Z. Stamataki, C. Shannon-Lowe, J. Shaw, D. Mutimer, A. B. Rickinson, J. Gordon, D. H. Adams, P. Balfe, J. A. McKeating. (2009) Hepatitis C virus association with peripheral blood B lymphocytes potentiates viral infection of liver-derived hepatoma cells. Blood 113:3, 585-593
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5. 5

   Anna Linda Zignego, Antonio Craxì. (2008) Extrahepatic Manifestations of Hepatitis C Virus Infection. Clinics in Liver Disease 12:3, 611-636
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6. 6

   David Saadoun, Aurelien Delluc, Jean Charles Piette, Patrice Cacoub. (2008) Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Current Opinion in Internal Medicine 7:2, 209-214
   CrossRef

7. 7

   A.L. Zignego, C. Ferri, S.A. Pileri, P. Caini, F.B. Bianchi. (2007) Extrahepatic manifestations of Hepatitis C Virus infection: A general overview and guidelines for a clinical approach. Digestive and Liver Disease 39:1, 2-17
   CrossRef

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   V De Re, D Sansonno, M P Simula, L Caggiari, D Gasparotto, M Fabris, F A Tucci, V Racanelli, R Talamini, M Campagnolo, S Geremia, F Dammacco, S De Vita. (2006) HCV-NS3 and IgG-Fc crossreactive IgM in patients with type II mixed cryoglobulinemia and B-cell clonal proliferations. Leukemia 20:6, 1145-1154
   CrossRef

9. 9

   Manuel Ramos-Casals, Josep Font. (2005) Extrahepatic manifestations in patients with chronic hepatitis C virus infection. Current Opinion in Internal Medicine 4:5, 503-511
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10. 10

    Laura Waters, Justin Stebbing, Sundhiya Mandalia, Anne Marie Young, Mark Nelson, Brian Gazzard, Mark Bower. (2005) Hepatitis C infection is not associated with systemic HIV-associated non-hodgkin's lymphoma: A cohort study. International Journal of Cancer 116:1, 161-163
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11. 11

    M. RAMOS-CASALS, L.-J. JARA, F. MEDINA, J. ROSAS, J. CALVO-ALEN, J. MANA, J.-M. ANAYA, J. FONT, . (2005) Systemic autoimmune diseases co-existing with chronic hepatitis C virus infection (the HISPAMEC Registry): patterns of clinical and immunological expression in 180 cases. Journal of Internal Medicine 257:6, 549-557
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12. 12

    J. P. Gisbert, L. Garcia-Buey, J. M. Pajares, R. Moreno-Otero. (2005) Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection. Alimentary Pharmacology and Therapeutics 21:6, 653-662
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