HIV Case Conference: HIV Associated Lymphoma

Transcription

1 F/C AETC Faculty General HIV Tuesday, July 22, :30 1:30pm (EDT) Facilitator Todd S. Wills, MD University of South Florida Didactic Presenter Jose Castro, MD University of Miami Case Discussant(s) Maribel Gonzalez, RN, ARNP University of South Florida Joanne Orrick, PharmD, AAHIVP University of South Florida HIV Case Conference: HIV Associated Lymphoma Jose Castro, MD University of Miami Division of Infectious Diseases Associate Professor Faculty Member, Florida/Caribbean AIDS Education and Training Center 1

2 Lymphomas NHL most common malignancy associate HIV post cart era. AIDS-related lymphoma are of B lymphocyte origin in 95%. AIDS-associated lymphoma: AIDS-associated Hodgkin AIDS-associated Non-Hodgkin (NHL) Systemic non-hodgkin lymphoma (most common) (~ 80%) Primary CNS lymphoma (PCNSL) (~ 15-10%) Primary effusion ("body cavity") lymphomas (rare) Most common (80%): diffuse large B-cell lymphoma; 20% remaining: small noncleaved cell (such Burkitt) Majority of AIDS-NHL clinically aggressive. HIV immunosuppression and coinfection with EBV seem to drive B cell clonal expansion thus consider marrow biopsy if no other sites 80% present with Stage IV disease Knowles DM. Etiology and pathogenesis of AIDS related non Hodgkin lymphoma. Hematol Oncol Clin North Am. 2003;17(3): Levine AM. Acquired immunodeficiency syndrome related lymphoma: clinical aspects. Semin Oncol. 2000;27: Lymphoma Presentations NHL and HL different HIV+ HIV infected are more likely Intermediate or high grade Extranodal, GI, bone marrow and CNS involvement CNS involvement in NHL: More common than non-hiv, lymphomatous meningitis (CSF: few cells, low glucose, high protein). 20% No symptoms Levine et al. Evolving characteristics of AIDS-related lymphoma. Blood 2000;96: Navarro WH, et al. AIDS-related lymphoproliferative disease. Blood : Taiwo B. AIDS-related primary CNS lymphoma. A brief review. AIDS Reader. 2000;10(8):

3 Before ART era: Lymphoma Good correlation decreasing CD4 and risk of NHL After ART: Decreased lesser degree. One of the most common AIDS defining illness PCNSL rare CD4 > 200, dramatic decline. HL and CD4 cells Incidence increases as CD4 increases with ART HL require certain cytokine milieu Kirk et al. NHL in HIV infected patients in the HAART era. Blood 2001;98: Biggar et al. HL and immunodeficiency in patients with HIV. Blood;2006; 08: Primary CNS Lymphomas in HIV Infected Patients Form of NHL arising and confined to CNS About 15% of AIDS-associated Lymphomas, now rare. Worse prognosis, more likely in younger and black Diagnostic approaches Cranial CT or MRI scan Most important differential diagnosis: toxoplasmosis Stereotatic brain biopsy essential for diagnosis If biopsy not possible, EBV PCR of CSF is useful, 100% sensitive, 80% specific Therapeutic approaches Traditional: radiation ( cgy) 10% 1yr survival High dose methotrexate based chemotherapy Non AIDS patients: shows promise High dose ZDV + GCV +/ IL 2 may have benefit (JAIDS 1999;15:713 19) 3

4 Lymphomas Primary Efusion Lymphoma (PEL) PEL or body cavity lymphoma, rare aggressive HHV 8 driven variant of HIV related lymphoma. Most cases are dually infected with HHV8 and EBV Effusions in serosal cavities: pleural, pericardium, and peritoneum and no solid tumor. Lymphoproliferative disorder 1% to 5% HIV related lymphomas Increased levels of IL 6 and HHV 8 (PML s) Poor prognosis, median survival 5 months. Cesarman E et al. Kaposi s sarcoma associated herpesvirus like DNA sequences in AIDS related body cavity based lymphomas. N Engl J Med. 1995;332: Carbone A. et al. HIV associated lymphomas and gamma herpesvirus Blood 2009:113:

5 Castleman s Disease Multicentric Castleman Disease in HIV infected people is associated with HHV 8 Increases IL 6 and endothelial growth factor Fever, splenomegaly, wasting, respiratory symptoms, low albumin, renal failure Increase angiogenesis and B cell proliferation. Co existence with KS Diagnosis: biopsy Poor prognosis: 70% fatality rate, median survival: 14 months. Casper C. The aetiology and management of catleman s disease at 50 years: translation pathophysiology to patient care. Br J Haematol. 2005;129:3:3 17. Oksenhendler E et al. Multicentric Catleman s disease in HIV infection: a clinical and pathological study of 20 patients. AIDS ;61 7 Bower M. How I treat HIV associated multicentric Castleman disease. Blood 2010; 116:4415. Hodgkin s Disease Association with HIV-infection Hodgkin s disease: RR: 5 to 30 Non-Hodgkin s disease: RR: 24 to 165 Patients with HIV present with: B symptoms (70% to 96%), worse histology, higherstage tumor (74% to 92% are III or IV), bone marrow involvement (40% to 50%), pancytopenia Good response to MOPP/ABV Complete response: 74.5% 2-year disease-free survival: 62% Early better results with Stanford V and BEACOPP Mauch PM, Kalish LA, Kadin M, et al. Patterns of presentation of Hodgkin disease. Implications for etiology and pathogenesis. Cancer 1993; 71:2062. Kaplan HS. Hodgkin's Disease, 2nd ed, Harvard University Press, Cambridge, MA

6 Risk of Hodgkin lymphoma by CD4 count Clifford and Franceschi, 2009 Treatment HIV associated Lymphoma Management of patients with HIV and lymphoma considerably more complex Historically, doses of chemotherapy were restricted: cellular immunodeficiency and limited bone marrow reserve Concomitant ART may improve bone marrow function, thereby allowing for full dosing of chemotherapy. Chemotherapy produces a significant and sustained reduction in CD4 cell counts and an increased risk of OI s. Medications taken to control the HIV infection may have side effects that overlap with chemotherapy side effects. Straus DJ. Human immunodeficiency virus associated lymphomas. Med Clin North Am 1997; 81:495. Kasamon YL, Swinnen LJ. Treatment advances in adult Burkitt lymphoma and leukemia. Curr Opin Oncol 2004; 16:429. Weiss R, Huhn D, Mitrou P, et al. HIV related non Hodgkin's lymphoma: CHOP induction therapy and interferon alpha 2b/zidovudine maintenance therapy. Leuk Lymphoma 1998; 29:103. 6

7 Therapeutic Approaches for AIDS Related NHL Outgrowth of lymphoma treatment in general Multiple agent, non cross resistant chemotherapy Increase dose intensity (infusional therapy, high dose or multiple drugs) Central nervous system treatment or prophylaxis Supportive antibiotics and hematopoietic growth factors Importance of HAART Standard regimen: CHOP Dose adjusted EPOCH Mounier N, Spina M, Gisselbrecht C. Modern management of non Hodgkin lymphoma in HIV infected patients. Br J Haematol 2007; 136:685. Weiss R, et al. Acquired immunodeficiency syndrome related lymphoma: simultaneous treatment with combined cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy and highly active antiretroviral therapy is safe and improves survival results of the German Multicenter Trial. Cancer 2006; 106:1560. Prophylaxis for opportunistic infections During treatment with combination chemotherapy, ART should be continued along with prophylaxis for PCP. Mycobacterium avium complex (MAC) prophylaxis may be appropriate for selected patients with severe immunocompromise (ie, CD4 <50/microL). Antibiotic prophylaxis for enteric organisms during neutropenia is strongly encouraged. Given the high incidence of recurrent HSV, VZV, and Candida infections in this population, antiviral and antifungal prophylaxis is also recommended Sparano JA, Hu X, Wiernik PH, et al. Opportunistic infection and immunologic function in patients with human immunodeficiency virus associated non Hodgkin's lymphoma treated with chemotherapy. J Natl Cancer Inst 1997; 89:301. 7

8 AIDS NHL Survival: Impact of HAART and EPOCH Percent Survival Months (n=63) (n=42) AMC R-EPOCH NCI EPOCH Besson et al. Blood. 2001; 98: Little et al Blood. 2003; 101: Sparano et al: 2006,10th ICMAOAI, Bethesda Phase II trial 149 patients Median CD4 count: 133 cells/mm 3 Regimens Rituximab (day 1) + CHOP (day 3) CHOP Patients restaged every 2 cycles Median F/U 137 wk AMC: Study 010. CHOP with and without Rituximab *P=0.035 vs CHOP alone. Kaplan LD, et al. Blood 2005;106:

9 Response to Dose Adjusted EPOCH in HIV Patients Median follow up 53 months Median CD4 190 cells/mm 3 Not prognostic Tumor proliferation p53 overexpression Little RF, et al. Blood. 2003;101: Summary: Treatment of HIV Asssociated Lymphoma Over the past 10 years, significant progress has been made in understanding HIV associated lymphomas and improving the prognosis of these diseases. With the advent of combination antiretroviral therapy and the development of novel therapeutic strategies, most patients with HIV associated lymphomas are cured. The outcome for the majority of patients with HIV associated diffuse large B cell lymphoma and Burkitt lymphoma in particular, is excellent, with recent studies supporting the role of rituximab in these diseases. Indeed, in the combination antiretroviral therapy era, the curability of many patients with HIVassociated lymphoma is similar to their HIV negative counterparts. New treatment frontiers need to focus on improving the outcome for patients with advanced immune suppression and for those with adverse tumor biology, such as the activated B cell type of diffuse large B cell lymphoma and the virally driven lymphomas. Lanoy E. et al. HIV associated Hodgkin lymphoma during the first months on combination antiretroviral therapy Blood :44 49 Dunleavy K. How to treat HIV associated lymphoma. Blood 2012;119(14): Spina M et al. Rituximab plus infusional cyclophosphamide, doxorubicin, and etoposide in HIV associated non Hodgkin lymphoma: pooled results from 3 phase 2 trials. Blood. 2005;105(5):1891 9

10 Incidence rates of NHL and KS U.S. Adult Spectrum of Disease/HOPS Studies Patel et al. Ann Intern Med 2008, 148, 728 Trends in Hodgkin lymphoma and anal cancer Patel et al. Ann Intern Med 2008, 148,

11 Questions? Question & Answer Session 11