Hodgkin’s disease (HD)

– Christian Hoffmann –

The incidence of HD is elevated in HIV-infected patients by a factor of 5-15 compared to the HIV-negative population. For particular subtypes, such as lymphocyte-depleted and mixed-cellularity HD, the relative risk is presumably much higher (Frisch 2001). Despite this and the growing realization that these subtypes at least are clearly associated with immunodeficiency, HIV-HD is not included as an AIDS-defining illness.

There is growing evidence that the incidence of HIV-HD is increasing in the setting of improved immunity. Several studies reported on an increased incidence during the last years (Clifford 2005, Biggar 2006, Engels 2008, Bohlius 2011). In our own cohort we found significant differences between NHL and HD (Wyen 2008). Whereas the majority of NHL cases was diagnosed in ART naïve patients, HD mainly occurred in subjects receiving a virologically effective ART. In 54% of the patients with HIV-HD, plasma viremia was below the limit of detection at the time of HD diagnosis (NHL: 21%, p <0.001). The reason for this phenomenon is still under debate. As CD4 T cells usually predominate in the tumor microenvironment of HD, it is speculated that immune reconstitution induced by ART provides an appropriate micro-environment allowing adequate growth signals for proliferation and survival of the neoplastic Reed-Sternberg (RS) cells in HD (Gloghini 2007). In addition, CD40/CD40L interactions and EBV infection may contribute to constitutive activation of NFkB which is an antiapoptotic factor in RS cells. Interestingly, patients whose CD4 T cell counts decline despite suppression of HIV-1 replication, are at risk for HD (Bohlius 2011).

An advanced stage of disease at diagnosis is typical, as is frequent extranodal involvement and a trend towards prognostically poorer subtypes (Tirelli 1995, Rapezzi 2001, Thompson 2004). Mediastinal disease is significantly less frequent than in HIV-negative patients. A further difference to HD in seronegative patients is the predominance of cases with RS cells, as well as the clear association with EBV infection, which is 80-100%, depending on the study. EBV infection is therefore seen as an important etiologic factor for development of HIV-HD.

In comparison to HIV-negative HD, which is a highly treatable tumor, the prognosis of HIV-HD was poor in the pre-HAART era. In nearly all cohorts with more than 20 patients, the median survival was only between 15-20 months, respectively (Andrieu 1993, Tirelli 1995, Errante 1999, Levine 2000). The response to chemotherapy was also moderate compared to the normal population. Complete remission rates were between 40-80%, and hematological and infectious complications were frequent. This gloomy scenario has clearly changed since the introduction of combination ART. In our own multicenter cohort of 56 patients, the median survival was 40 months. In patients with adequate ART, the two-year survival rate was 84%, which was very encouraging (Hoffmann 2004). In the meantime, other groups have also reported better prognoses with ART (Ribera 2002, Gérard 2003, Berenguer 2008).

Signs and symptoms

B symptoms occur in the majority of cases. Extranodal and advanced stages are almost always the rule. Lymphomas are firm, immobile or hardly mobile and painless, and the distinction from HIV lymphadenopathy or tuberculous lymphadenitis is not always possible.

Diagnosis

Staging is necessary as for non-Hodgkin lymphomas (see relevant section). Diagnostic lymph node extirpation is even more important here than with NHL, as puncture only rarely allows diagnosis of Hodgkin’s disease. Single accurate diagnostics are better than half-heartedly bothering the patient with repeated punctures and losing time unnecessarily. Surgical extirpation is possible as an outpatient in many centers. As with NHL, specimens should be sent to reference laboratories if possible. Since bleomycine will be administered, a lung function test should always precede the first chemotherapy.

Treatment

Risk adapted treatment strategy in patients with HIV-HD in accordance with standard treatment procedures established for HIV-negative patients with HD is recommended. The achievement of complete remission (CR) is important. In one larger cohort, the only variable independently associated with overall survival was the achievement of CR (Berenguer 2008).

In limited (Ann Arbor I-II, no risk factors) and intermediate (I-II with risk factors) stages, many clinicians still favor the classical ABVD regimen (four double cycles, see Table 4) for HIV infected patients. ABVD is the abbreviation for the combination chemotherapy with the cytostatics adriamycine, bleomycine, vinblastine and DTIC (dacarbazine). Ambulatory treatment is possible.

Table 4: ABVD regimen (4 double cycles, repeat on Day 29)*
Adriamycine (= doxorubicin) Doxo-Cell®, Adriblastin® 25 mg/m2 i.v. Day 1 + 15
Bleomycine Bleomycin Hexal®, Bleo-Cell® 10 mg/m2 i.v. Day 1 + 15
Vinblastine Velbe®, Vinblastin Hexal® 6 mg/m2 i.v. Day 1 + 15
Dacarbazine (DTIC) Detimedac® 375 mg/m2 i.v. Day 1 + 15
* ABVD regimen. Due to strong emetogenicity of dacarbazine, 5HT3-receptor blocker anti-emetics should always be administered, e.g. granisetron, tropisetron or ondansetron.

In HIV-negative patients with advanced stages (as is almost always the case for HIV-HD) the BEACOPP regimen of the German Hodgkin Study Group has been used in the last years, mainly with escalated dosing. This has proven to be significantly more effective, both with regard to response rates and long-term survival. However, the BEACOPP regimen is more toxic. Whether these positive results can be seen in HIV-HD is still not clear. However, based on initial reports and our own experience, BEACOPP seems to be possible (Hartmann 2003). There is also growing experience to date with the Stanford V protocol, for which there have recently been promising reports (Spina 2002).

References

Andrieu JM, Roithmann S, Tourani JM, et al. Hodgkin’s disease during HIV-1 infection: the French registry experience. French Registry of HIV-associated Tumors. Ann Oncol 1993, 4:635-41.

Berenguer J, Miralles P, Ribera JM, et al. Characteristics and outcome of AIDS-related Hodgkin lymphoma before and after the introduction of highly active antiretroviral therapy. J AIDS 2008;47:422-8.

Biggar RJ, Jaffe ES, Goedert JJ, et al. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 2006, 108:3786-91.

Bohlius J, Schmidlin K, Boué F, et al. HIV-1-related Hodgkin lymphoma in the era of combination antiretroviral therapy: incidence and evolution of CD4+ T-cell lymphocytes. 4. Blood. 2011 Mar 2. [Epub ahead of print]

Cheung MC, Hicks LK, Leitch HA. Excessive neurotoxicity with ABVD when combined with protease inhibitor-based antiretroviral therapy in the treat-ment of AIDS-related Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk 2010, 10:E22-5.

Clifford GM, Polesel J, Rickenbach M, et al. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and HAART. J Natl Cancer Inst 2005;97:425-32.

Engels EA, Biggar RJ, Hall HI, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer 2008;123:187-94.

Errante D, Gabarre J, Ridolfo AL, et al. Hodgkin’s disease in 35 patients with HIV infection: an experience with epirubicin, bleomycin, vinblastine and prednisone chemotherapy in combination with antiretroviral therapy and primary use of G-CSF. Ann Oncol 1999, 10:189-95.

Frisch M, Biggar R, et al. Association of Cancer with AIDS-related immunosuppression in Adults. JAMA 2001, 1736-1745.

Gérard L, Galicier L, Boulanger E, et al.  Improved survival in HIV-related Hodgkin’s lymphoma since the introduction of highly active antiretroviral therapy. AIDS 2003;17:81-7.

Gloghini A, Carbone A. Why would the incidence of HIV-associated Hodgkin lymphoma increase in the setting of improved immunity? Int J Cancer 2007, 120:2753-4.

Hartmann P, Rehwald U, Salzberger B, Franzen C, Sieber M, Wohrmann A, Diehl V. BEACOPP therapeutic regimen for patients with Hodgkin’s disease and HIV infection. Ann Oncol 2003;14:1562-9.

Hoffmann C, Chow KU, Wolf E, et al. Strong impact of highly active antiretroviral therapy on survival in patients with human immunodeficiency virus-associated Hodgkin’s disease. Br J Haemat 2004, 125: 455-462.

Levine AM, Li P, Cheung T, et al. Chemotherapy consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine with granulocyte-colony-stimulating factor in HIV-infected patients with newly diagnosed Hodgkin’s disease: a prospective, multi-institutional AIDS clinical trials group study (ACTG 149). JAIDS 2000, 24:444-50.

Rapezzi D, Ugolini D, Ferraris AM, Racchi O, Gaetani GF. Histological subtypes of Hodgkin’s disease in the setting of HIV infection. Ann Hematol 2001, 80:340-4.

Ribera JM, Navarro JT, Oriol A, et al. Prognostic impact of highly active antiretroviral therapy in HIV- related Hodgkin’s disease. AIDS 2002, 16: 1973-6.

Spina M, Gabarre J, Rossi G, et al. Stanford V regimen and concomitant HAART in 59 patients with Hodgkin disease and HIV infection. Blood 2002, 100:1984-8.

Thompson LD, Fisher SI, Chu WS, Nelson A, Abbondanzo SL. HIV-associated Hodgkin lymphoma: a clinicopathologic and immunophenotypic study of 45 cases. Am J Clin Pathol. 2004, 121:727-38.

Tirelli U, Errante D, Dolcetti R, et al. Hodgkin’s disease and HIV infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors. J Clin Oncol 1995, 13:1758-67.

Wyen C, Faetkenheuer G, Oette M, Plettenberg A, Rockstroh J, van Lunzen J, Mayr C, Esser S, Hentrich M, Hoffmann C. Treatment of AIDS-related lymphoma: rituximab may be beneficial even in severely immunosuppressed patients. Abstract 1026, 14th CROI 2008, Boston.


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Filed under 13. Malignant Lymphomas, Hodgkin's diesease (HD), Part 3 - AIDS

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