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Hodgkin Lymphoma Among Patients Infected with HIV in Post-HAART Era
Original Contribution Hodgkin Lymphoma Among Patients Infected with HIV in Post-HAART Era Paula Yurie Tanaka,1,2 Vicente Porfírio Pessoa, Jr,1 Luis Fernando Pracchia,3 Valeria Buccheri,3 Dalton Alencar Fisher Chamone,3 Edenilson Eduardo Calore4
Abstract Background: Hodgkin lymphoma is considered a common type of non-AIDS defining tumor among patients infected with HIV, commonly presenting as a widespread disease and with different pathologic features compared with Hodgkin lymphoma in the general population. Despite that, the best treatment option is undefined. Patients and Methods: The authors present a retrospective study of 31 patients with Hodgkin lymphoma–HIV attended at 3 Brazilian centers, 2 of them considered reference centers for HIV treatment. Chemotherapy schemes used were ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) or hybrid MOPP-ABV (mechlorethamine/vincristine/ procarbazine/prednisone-doxorubicin/bleomycin/vinblastine), with prophylactic granulocyte colony-stimulating factor. Results: Treatment response could be evaluated in 22 patients (70.9%) who completed initial treatment: 20 (91%) reached complete remission, 1 had partial remission, and 1 did not exhibit a response. The overall response rate was 95.5% (95% confidence interval, 91.2%-99.8%). After a median follow-up of 3 years, the overall survival (OS) rate among all patients was 80.3%; median OS was not reached. On univariate analysis, only CD4 cell count at diagnosis was significantly related to survival. Conclusion: This retrospective study shows that for patients with Hodgkin lymphoma development in the HIV setting in these 3 Brazilian centers, there was high complete remission and satisfactory OS rates, comparable with results found for Hodgkin lymphoma in patients without HIV.
Clinical Lymphoma & Myeloma, Vol. 7, No. 5, 364-368, 2007 Key words: AIDS, CD4 cell count, Complete remission, Granulocyte colony-stimulating factor
Introduction Hodgkin lymphoma is actually considered the most common type of non-AIDS defining tumor among patients infected with HIV.1,2 The risk of Hodgkin lymphoma development in the HIV setting (HL-HIV) is described to be 8-10–fold higher compared with the general population.3 Among patients with HIV, Hodgkin lymphoma generally presents with widespread disease, with a high frequency of B symptoms and involvement of extranodal sites. The pathologic features are different from those of Hodgkin lymphoma in the general population, and the most frequent histopathologic subtypes are mixed cellularity and lymphocyte depletion.4
1Hematology
Section, Emílio Ribas Infectology Institute de Referência e Treinamento em DST-AIDS 3Hematology Department, Hospital das Clínicas, University of São Paulo 4Pathology Section, Emílio Ribas Infectology Institute São Paulo, Brazil 2Centro
Submitted: Oct 20, 2006; Revised: Dec 27, 2006; Accepted: Jan 18, 2007 Address for correspondence: Paula Yurie Tanaka, MD, Hematology Section, Emilio Ribas Infectology Institute, Av. Dr. Arnaldo n. 165 – 9. andar, São Paulo, Brazil, 01255-010 Fax: 55-11-38911038; e-mail: [email protected]
Before highly active antiretroviral therapy (HAART) introduction, tolerance to chemotherapy was poor, and opportunistic infections were described in a substantial number of patients; most of these episodes were fatal.5,6 The complete remission (CR) rate was below that of patients without HIV, with an overall median survival time of approximately 1.5 years.7-9 With the HAART regimen, better outcomes with chemotherapy were reported, with an increase in CR rate and median survival.10 The largest public distribution program of antiretroviral agents for HIV treatment is in Brazil, but the incidence and results of treatment in patients with HL-HIV are not exactly known. The authors describe a retrospective analysis of 31 patients with HIV and Hodgkin lymphoma attended in 3 centers in São Paulo, Brazil; 2 of them are considered reference centers for HIV treatment (Emilio Ribas Infectology Institute and Centro de Referência e Treinamento em DST-AIDS).
Patients and Methods Patient Management and Treatment Regimen This retrospective study includes 31 patients with HIV with Hodgkin lymphoma diagnosed by tissue biopsy and confirmed by immunohistochemical reactions, according to the World Health Organization classification of neoplasms.
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
364 • Clinical Lymphoma & Myeloma March 2007
All patients were treated at Emílio Ribas Infectology Institute (n = 19), Centro de Referência e Treinamento em DST-AIDS (n = 6), and Hospital das Clínicas (n = 6) between January 1999 and June 2006. All patients have been submitted, before any lymphoma treatment, to conventional staging procedures that included computed tomography scans (cervical, thoracic, abdominal, and pelvic) and bilateral bone marrow biopsy. The stage was classified according to the Cotswold staging system. Patients were treated with standard-dose ABVD (doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2, all given intravenously [I.V.] on day 1 and 15 of each 30-day cycle) or hybrid MOPP-ABV (nitrogen mustard 6 mg/m2 and vincristine 1.4 mg/m2 I.V. on day 1; procarbazine 100 mg/m2 orally on days 1-7; prednisone 40 mg/m2 orally on days 1-14, and doxorubicin 35 mg/m2, bleomycin 6 mg/m2, and vinblastine 6 mg/m2 I.V. on day 8 of each 30-day cycle). Seven patients were treated with low-intensity ABVD or MOPP-ABV (50% dose reduction) according to the judgment of the treating physician. Proposed treatment was 6-8 cycles, 2 after achievement of CR. Subcutaneous granulocyte colony-stimulating factor (300 μg per day) was added to the regimen after each chemotherapy cycle until neutrophil counts exceeded 1.5 × 109/L. Subcutaneous epoetin alfa (300 UI/kg) was given to patients that, at diagnosis or during treatment, had hemoglobin levels ≤ 10 g/dL. All patients received Pneumocystis carinii pneumonia prophylaxis, and other antibiotics as needed. HAART had been prescribed to all patients who had AIDS before lymphoma diagnosis. Antiretroviral schemes that included zidovudine were avoided or changed before chemotherapy institution. Toxicity was obtained by review of medical records and was graded according to World Health Organization common toxicity criteria, version 3.0.
Response Assessment Response to lymphoma treatment was assessed after 4, 6, and 8 cycles and classified as CR, partial response, unconfirmed CR, or progressive disease, according to the Cotswold criteria. Follow-up procedures include physical examination every 3 months for the first 2 years, then every 6 months for 3 years, and then annually. Computed tomography scans (thoracic, abdominal, and pelvic) were performed every 4 months during the first 2 years, every 6 months during the next 2 years, and afterward if a new lesion is suspected.
Statistical Analysis Overall survival (OS) was measured from the date of diagnosis to death from any cause or last follow-up. Diseasefree survival (DFS) was measured from the date of CR or unconfirmed CR to the date of disease progression or last follow-up. Median OS, OS rate at 3 years, mean DFS, and DFS rate at 3 years were estimated by the Kaplan-Meier method and compared by the log-rank test. All P values are 2tailed and α error was defined as 5%. Statistical analyses were performed using SPSS 10.0 for Windows.
Table 1
Patient Characteristics Characteristic
Median Age, Years (Range)
N = 31 43 (27-57)
Sex (%) Female
4 (12.9)
Male
27 (87.1)
Ethnicity (%) White
18 (58.1)
Mixed (white/black) HIV Risk
13 (41.9)
Factors* (%)
Homosexual
16 (53.3)
IVDU
4 (13.3)
Heterosexual
10 (33.3)
Time of HIV Diagnosis (Years)* Median (range) CD4 Cell
7 (0-15)
Count*
Median cells/mm3 (range)
183 (7-522)
CD4 Categories (%) < 100 cells/mm3
8 (26.7)
* 100 cells/mm3
22 (73.3)
HIV Viral Load* Median (range)
17,900 (3400-281,000)
HAART Use* (%) Yes
25 (83.3)
No
5 (16.7)
Pathologic Type (%) Nodular sclerosis
4 (12.9)
Mixed cellularity
22 (71)
Lymphocyte depletion
3 (9.7)
Unclassified
2 (6.5)
Stage* (%) I
1 (3.3)
II
11 (36.7)
III
6 (20)
IV
12 (40)
B Symptoms (%) No
5 (16.1)
Yes
26 (83.9)
Bulky Disease (%) No
24 (77.4)
Yes
7 (22.6)
IPI† (%) Low-risk
10 (38.5)
High-risk
16 (61.5)
*Data not known in 1 patient. †Data not known in 5 patients.
Abbreviations: IPI = International Prognostic Index (high-risk denotes the presence of > 2 risk factors); IVDU = I.V. drug user
Clinical Lymphoma & Myeloma March 2007 • 365
Hodgkin Lymphoma in Patients with HIV Figure 2 Overall Survival of Patients with HIV with Hodgkin Lymphoma According to CD4 Cell Count at Diagnosis
Figure 1 Overall Survival of 31 Patients with HIV with Hodgkin Lymphoma 100
100 80
CD4 r 100 cells/mm3
60 Survival (%)
Survival (%)
80
40
60 CD4 < 100 cells/mm3 40
20 20
0
Table 2
20
40 Months
60
0
Treatment Toxicity Toxicity
Frequency n = 31 (%)
Anemia
4 (12.9)
Neutropenia
18 (58)
Thrombocytopenia
3 (9.6)
Neuropathy Mucositis
80
1 (3) 2 (6.5)
Any World Health Organization grade toxicity observed for each patient during chemotherapy.
Results Characteristics of patients are shown in Table 1. Twentyseven patients (87.1%) were men and 4 women (12.9%), with a median age of 43 years (range, 27-57 years). Risk factors for HIV infection included homosexual contact in 16 (53.3%), heterosexual contact in 10 (33.3%), and I.V. drug use in 4 (13.3%) cases. Twenty-five patients (83.3%) received HAART during lymphoma treatment; the other 6 did not receive any antiretroviral therapy. HAART consisted of 2 nucleoside reverse transcriptase inhibitors (NRTI) with 1 protease inhibitor in 14 patients (56%) or 2 NRTI with 1 non-NRTI (efavirenz) in 11 patients (44%). The median CD4 lymphocyte count at lymphoma diagnosis was 183/μL (range, 7-522/μL). Viral load data were available in 30 patients; 13 patients had undetectable viral load (< 400 copies/μL, according to the local test sensibility), and 17 patients had a median viral load of 17,900 copies/mL (range, 3400-281,000 copies/mL). Median time from the diagnosis of HIV and the onset of Hodgkin lymphoma was 7 years (range, 0-15 years). Only 1 patient had the diagnosis of HIV infection and Hodgkin lymphoma at the same time. First site of Hodgkin lymphoma involvement included cervical nodes on 19 patients (67.9%) and axillary nodes on 4 patients (14.3%). Mixed cellularity
366 • Clinical Lymphoma & Myeloma March 2007
20
40 Months
60
80
subtype was observed in 22 patients (71%) and nodular sclerosing Hodgkin lymphoma in 4 (12.9%). B symptoms were present in 26 patients (83.9%) and bulky disease in 7 patients (22.6%). Eighteen patients (60%) presented with stage III/IV disease. Of the 12 stage IV patients, 9 (75%) had bone marrow involvement and 3 (25%) had lung involvement. High-risk international prognostic index for Hodgkin disease (> 2 adverse prognostic factors) was seen in 16 patients (61.5%). Two patients had other viral infection at diagnosis, 1 had hepatitis C virus, and another had hepatitis B virus. Treatment included full-dose chemotherapy in 24 patients (77.4%) and reduced-intensity chemotherapy in 7 (22.6%). Median chemotherapy cycles delivered to all patients was 8 (range, 1-8 cycles). Radiation therapy to initial bulky sites was performed in 5 patients (16.1%). Treatment response could be evaluated in 22 patients (70.9%) who completed initial treatment; 20 (91%) reached CR, 1 had partial response, and another did not have a response. The overall response rate was 95.5% (95% confidence interval, 91.2%-99.8%). Nine patients (29.1%) were not available for response evaluation: 2 patients died because of sepsis during treatment, 5 abandoned treatment for unknown reasons, and 2 are still receiving treatment. Although all patients were treated with prophylactic granulocyte colony-stimulating factor, neutropenia of any grade was seen in 58% of patients during chemotherapy (Table 2). Ten patients (32%) had infectious episodes during treatment, which included sepsis in 2 patients, disseminated tuberculosis in 2 patients, infectious diarrhea in 2 patients, pneumonia in 2 patients, and cutaneous herpes virus infection in 1 patient. The mortality rate during treatment for the 22 patients who completed therapy was 9%. After a median follow-up of 3 years, the OS rate among all patients was 80.3% (Figure 1); median OS was not reached. On univariate analysis, only CD4 cell count at diagnosis was significantly related to survival (Table 3 and Figure 2). The OS
Paula Yurie Tanaka et al Table 3
Figure 3 Disease-Free Survival of Patients with HIV with Hodgkin Lymphoma 100
Characteristic
3-Year OS Rate (%)
P Value
Sex
80
Survival (%)
Overall Survival of the 31 Patients with HIV with Hodgkin Lymphoma
60
Female
100
Male
77.3
0.45
Ethnicity White
40
84.5
Mixed (white/black)
0.49
72
HIV Risk Factors 20
0
20
40 Months
60
80
Homosexual
69.7
IVDU
100
Heterosexual
100
CD4 Categories < 100 cells/mm3 * 100
rate was not significantly different according to the full-dose chemotherapy scheme used (AVBD vs. MOPP-ABV; P = 0.51). Median DFS among patients who exhibited CRs was not reached (> 33 months), with a mean DFS of 50 months (95% confidence interval, 39-62 months) and DFS rate in 3 years of 74% (Figure 3).
Discussion The best chemotherapy option for HL-HIV remains undefined. Many studies have been performed in pre-HAART era, using different kinds of treatment, with high-grade toxicity and poor outcome in this population.6,9 Spina et al, using Stanford V scheme, performed one of the studies in HL-HIV patients with concomitant HAART in 59 patients. Complete remission was observed in 81% of patients, with an estimated 3-year OS of 51%. The probability of OS was significantly higher (76%) in the group with International Prognostic Score of ≤ 2.11 Hoffmann et al analyzed the outcome of 57 patients with HL-HIV and the use and efficacy of HAART and other prognostic factors. The only factors independently associated with OS were HAART response, CR, and age (≤ 45 years). The median survival in patients who did not respond to HAART was comparable with those described in pre-HAART era. An improvement of survival was related to patients who have a response to HAART.10 Recently, Biggar et al linked the nationwide HIV/AIDS and cancer registry from 1980 through 2002, showing that incidence of HL-HIV was significantly higher in 1996 to 2002, especially for mixed cellularity type. Compared with the general population, the risk of Hodgkin lymphoma was 9.4-fold higher in patients with HIV/AIDS. For each subtype of Hodgkin lymphoma, the incidence decreased with lower CD4 counts than with moderate immunosuppression, suggesting that the increased incidence of Hodgkin lymphoma might be related to HAART use.12 In our study, 71% of patients had mixed cellularity subtype, and 73.3% had CD4 counts ≥ 100/μL. Twenty-five patients
0.28
cells/mm3
55
0.01
89.5
HAART Use Yes
79.3
No
77.8
0.28
Stage I/II
100
III/IV
63
0.06
B Symptoms No
100
Yes
75.2
0.29
IPI Low risk
85.7
High risk
75.6
0.36
Chemotherapy Type Full-dose
86.5
Reduced intensity
59.5
0.08
Abbreviations: IPI = International Prognostic Index (high-risk denotes the presence of > 2 risk factors); IVDU = I.V. drug user
(83.3%) received HAART during chemotherapy, with an overall response treatment rate of 95.5% and OS rate of 80.3% after a median follow-up of 3 years; on univariate analysis, only CD4 cell count at diagnosis was significantly related to survival, suggesting that the worst immunologic status would be related to poor outcome in our patients. We did not observe differences in survival according to the type of treatment received by the patients (ABVD vs. MOPP-ABV or full-dose vs. reduced-dose chemotherapy) or according to other previously described risk factors, such as disease stage and HAART use. It is important to point out that because of the small number of patients included in each of these groups, it is not possible to draw any firm conclusion about the best treatment option or the impact of those risk factors in HL-HIV.
Clinical Lymphoma & Myeloma March 2007 • 367
Hodgkin Lymphoma in Patients with HIV Conclusion This retrospective study shows that for patients with Hodgkin lymphoma–HIV in these 3 Brazilian centers, there were high CR and satisfactory OS rates using ABVD or hybrid MOPPABV scheme, comparable with results observed with more aggressive treatment regimens or for Hodgkin lymphoma in patients without HIV.
References 1. Franceschi S, Dal Maso L, Arniani S, et al. Risk of cancer other than Kaposi’s sarcoma and non-Hodgkin’s lymphoma in persons with AIDS in Italy. Cancer and AIDS Registry Linkage Study. Br J Cancer 1998; 7:966-970. 2. Engels EA, Goedert JJ. Human immunodeficiency virus/acquired immunodeficiency syndrome and cancer: past, present, and future. J Natl Cancer Inst 2005; 6:407-409. 3. Lim ST, Levine AM. Recent advances in acquired immunodeficiency syndrome (AIDS)-related lymphoma. CA Cancer J Clin 2005; 4:229-241. 4. Dolcetti R, Boiocchi M, Gloghini A, et al. Pathogenetic and histogenetic features of HIV-associated Hodgkin’s disease. Eur J Cancer 2001; 10:1276-1287. 5. Errante D, Tirelli U, Gastaldi R, et al. Combined antineoplastic and antiretroviral therapy for patients with Hodgkin’s disease and human immunodeficiency virus infection. A prospective study of 17 patients. The Italian Cooperative Group on AIDS and Tumors (GICAT). Cancer
368 • Clinical Lymphoma & Myeloma March 2007
1994; 2:437-444. 6. 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). J Acquir Immune Defic Syndr 2000; 5:444-450. 7. Tirelli U, Errante D, Dolcetti R, et al. Hodgkin’s disease and human immunodeficiency virus infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors. J Clin Oncol 1995; 7:1758-1767. 8. Rubio R. Hodgkin’s disease associated with human immunodeficiency virus infection. A clinical study of 46 cases. Cooperative Study Group of Malignancies Associated with HIV Infection of Madrid. Cancer 1994; 9:2400-2407. 9. Vaccher E, Spina M, Tirelli U. Clinical aspects and management of Hodgkin’s disease and other tumours in HIV-infected individuals. Eur J Cancer 2001; 10:1306-1315. 10. 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 Haematol 2004; 4:455-462. 11. 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; 6:1984-1988. 12. Biggar RJ, Jaffe ES, Goedert JJ, et al. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 2006; 108:37863791.
Abstract Background: Hodgkin lymphoma is considered a common type of non-AIDS defining tumor among patients infected with HIV, commonly presenting as a widespread disease and with different pathologic features compared with Hodgkin lymphoma in the general population. Despite that, the best treatment option is undefined. Patients and Methods: The authors present a retrospective study of 31 patients with Hodgkin lymphoma–HIV attended at 3 Brazilian centers, 2 of them considered reference centers for HIV treatment. Chemotherapy schemes used were ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) or hybrid MOPP-ABV (mechlorethamine/vincristine/ procarbazine/prednisone-doxorubicin/bleomycin/vinblastine), with prophylactic granulocyte colony-stimulating factor. Results: Treatment response could be evaluated in 22 patients (70.9%) who completed initial treatment: 20 (91%) reached complete remission, 1 had partial remission, and 1 did not exhibit a response. The overall response rate was 95.5% (95% confidence interval, 91.2%-99.8%). After a median follow-up of 3 years, the overall survival (OS) rate among all patients was 80.3%; median OS was not reached. On univariate analysis, only CD4 cell count at diagnosis was significantly related to survival. Conclusion: This retrospective study shows that for patients with Hodgkin lymphoma development in the HIV setting in these 3 Brazilian centers, there was high complete remission and satisfactory OS rates, comparable with results found for Hodgkin lymphoma in patients without HIV.
Clinical Lymphoma & Myeloma, Vol. 7, No. 5, 364-368, 2007 Key words: AIDS, CD4 cell count, Complete remission, Granulocyte colony-stimulating factor
Introduction Hodgkin lymphoma is actually considered the most common type of non-AIDS defining tumor among patients infected with HIV.1,2 The risk of Hodgkin lymphoma development in the HIV setting (HL-HIV) is described to be 8-10–fold higher compared with the general population.3 Among patients with HIV, Hodgkin lymphoma generally presents with widespread disease, with a high frequency of B symptoms and involvement of extranodal sites. The pathologic features are different from those of Hodgkin lymphoma in the general population, and the most frequent histopathologic subtypes are mixed cellularity and lymphocyte depletion.4
1Hematology
Section, Emílio Ribas Infectology Institute de Referência e Treinamento em DST-AIDS 3Hematology Department, Hospital das Clínicas, University of São Paulo 4Pathology Section, Emílio Ribas Infectology Institute São Paulo, Brazil 2Centro
Submitted: Oct 20, 2006; Revised: Dec 27, 2006; Accepted: Jan 18, 2007 Address for correspondence: Paula Yurie Tanaka, MD, Hematology Section, Emilio Ribas Infectology Institute, Av. Dr. Arnaldo n. 165 – 9. andar, São Paulo, Brazil, 01255-010 Fax: 55-11-38911038; e-mail: [email protected]
Before highly active antiretroviral therapy (HAART) introduction, tolerance to chemotherapy was poor, and opportunistic infections were described in a substantial number of patients; most of these episodes were fatal.5,6 The complete remission (CR) rate was below that of patients without HIV, with an overall median survival time of approximately 1.5 years.7-9 With the HAART regimen, better outcomes with chemotherapy were reported, with an increase in CR rate and median survival.10 The largest public distribution program of antiretroviral agents for HIV treatment is in Brazil, but the incidence and results of treatment in patients with HL-HIV are not exactly known. The authors describe a retrospective analysis of 31 patients with HIV and Hodgkin lymphoma attended in 3 centers in São Paulo, Brazil; 2 of them are considered reference centers for HIV treatment (Emilio Ribas Infectology Institute and Centro de Referência e Treinamento em DST-AIDS).
Patients and Methods Patient Management and Treatment Regimen This retrospective study includes 31 patients with HIV with Hodgkin lymphoma diagnosed by tissue biopsy and confirmed by immunohistochemical reactions, according to the World Health Organization classification of neoplasms.
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
364 • Clinical Lymphoma & Myeloma March 2007
All patients were treated at Emílio Ribas Infectology Institute (n = 19), Centro de Referência e Treinamento em DST-AIDS (n = 6), and Hospital das Clínicas (n = 6) between January 1999 and June 2006. All patients have been submitted, before any lymphoma treatment, to conventional staging procedures that included computed tomography scans (cervical, thoracic, abdominal, and pelvic) and bilateral bone marrow biopsy. The stage was classified according to the Cotswold staging system. Patients were treated with standard-dose ABVD (doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2, all given intravenously [I.V.] on day 1 and 15 of each 30-day cycle) or hybrid MOPP-ABV (nitrogen mustard 6 mg/m2 and vincristine 1.4 mg/m2 I.V. on day 1; procarbazine 100 mg/m2 orally on days 1-7; prednisone 40 mg/m2 orally on days 1-14, and doxorubicin 35 mg/m2, bleomycin 6 mg/m2, and vinblastine 6 mg/m2 I.V. on day 8 of each 30-day cycle). Seven patients were treated with low-intensity ABVD or MOPP-ABV (50% dose reduction) according to the judgment of the treating physician. Proposed treatment was 6-8 cycles, 2 after achievement of CR. Subcutaneous granulocyte colony-stimulating factor (300 μg per day) was added to the regimen after each chemotherapy cycle until neutrophil counts exceeded 1.5 × 109/L. Subcutaneous epoetin alfa (300 UI/kg) was given to patients that, at diagnosis or during treatment, had hemoglobin levels ≤ 10 g/dL. All patients received Pneumocystis carinii pneumonia prophylaxis, and other antibiotics as needed. HAART had been prescribed to all patients who had AIDS before lymphoma diagnosis. Antiretroviral schemes that included zidovudine were avoided or changed before chemotherapy institution. Toxicity was obtained by review of medical records and was graded according to World Health Organization common toxicity criteria, version 3.0.
Response Assessment Response to lymphoma treatment was assessed after 4, 6, and 8 cycles and classified as CR, partial response, unconfirmed CR, or progressive disease, according to the Cotswold criteria. Follow-up procedures include physical examination every 3 months for the first 2 years, then every 6 months for 3 years, and then annually. Computed tomography scans (thoracic, abdominal, and pelvic) were performed every 4 months during the first 2 years, every 6 months during the next 2 years, and afterward if a new lesion is suspected.
Statistical Analysis Overall survival (OS) was measured from the date of diagnosis to death from any cause or last follow-up. Diseasefree survival (DFS) was measured from the date of CR or unconfirmed CR to the date of disease progression or last follow-up. Median OS, OS rate at 3 years, mean DFS, and DFS rate at 3 years were estimated by the Kaplan-Meier method and compared by the log-rank test. All P values are 2tailed and α error was defined as 5%. Statistical analyses were performed using SPSS 10.0 for Windows.
Table 1
Patient Characteristics Characteristic
Median Age, Years (Range)
N = 31 43 (27-57)
Sex (%) Female
4 (12.9)
Male
27 (87.1)
Ethnicity (%) White
18 (58.1)
Mixed (white/black) HIV Risk
13 (41.9)
Factors* (%)
Homosexual
16 (53.3)
IVDU
4 (13.3)
Heterosexual
10 (33.3)
Time of HIV Diagnosis (Years)* Median (range) CD4 Cell
7 (0-15)
Count*
Median cells/mm3 (range)
183 (7-522)
CD4 Categories (%) < 100 cells/mm3
8 (26.7)
* 100 cells/mm3
22 (73.3)
HIV Viral Load* Median (range)
17,900 (3400-281,000)
HAART Use* (%) Yes
25 (83.3)
No
5 (16.7)
Pathologic Type (%) Nodular sclerosis
4 (12.9)
Mixed cellularity
22 (71)
Lymphocyte depletion
3 (9.7)
Unclassified
2 (6.5)
Stage* (%) I
1 (3.3)
II
11 (36.7)
III
6 (20)
IV
12 (40)
B Symptoms (%) No
5 (16.1)
Yes
26 (83.9)
Bulky Disease (%) No
24 (77.4)
Yes
7 (22.6)
IPI† (%) Low-risk
10 (38.5)
High-risk
16 (61.5)
*Data not known in 1 patient. †Data not known in 5 patients.
Abbreviations: IPI = International Prognostic Index (high-risk denotes the presence of > 2 risk factors); IVDU = I.V. drug user
Clinical Lymphoma & Myeloma March 2007 • 365
Hodgkin Lymphoma in Patients with HIV Figure 2 Overall Survival of Patients with HIV with Hodgkin Lymphoma According to CD4 Cell Count at Diagnosis
Figure 1 Overall Survival of 31 Patients with HIV with Hodgkin Lymphoma 100
100 80
CD4 r 100 cells/mm3
60 Survival (%)
Survival (%)
80
40
60 CD4 < 100 cells/mm3 40
20 20
0
Table 2
20
40 Months
60
0
Treatment Toxicity Toxicity
Frequency n = 31 (%)
Anemia
4 (12.9)
Neutropenia
18 (58)
Thrombocytopenia
3 (9.6)
Neuropathy Mucositis
80
1 (3) 2 (6.5)
Any World Health Organization grade toxicity observed for each patient during chemotherapy.
Results Characteristics of patients are shown in Table 1. Twentyseven patients (87.1%) were men and 4 women (12.9%), with a median age of 43 years (range, 27-57 years). Risk factors for HIV infection included homosexual contact in 16 (53.3%), heterosexual contact in 10 (33.3%), and I.V. drug use in 4 (13.3%) cases. Twenty-five patients (83.3%) received HAART during lymphoma treatment; the other 6 did not receive any antiretroviral therapy. HAART consisted of 2 nucleoside reverse transcriptase inhibitors (NRTI) with 1 protease inhibitor in 14 patients (56%) or 2 NRTI with 1 non-NRTI (efavirenz) in 11 patients (44%). The median CD4 lymphocyte count at lymphoma diagnosis was 183/μL (range, 7-522/μL). Viral load data were available in 30 patients; 13 patients had undetectable viral load (< 400 copies/μL, according to the local test sensibility), and 17 patients had a median viral load of 17,900 copies/mL (range, 3400-281,000 copies/mL). Median time from the diagnosis of HIV and the onset of Hodgkin lymphoma was 7 years (range, 0-15 years). Only 1 patient had the diagnosis of HIV infection and Hodgkin lymphoma at the same time. First site of Hodgkin lymphoma involvement included cervical nodes on 19 patients (67.9%) and axillary nodes on 4 patients (14.3%). Mixed cellularity
366 • Clinical Lymphoma & Myeloma March 2007
20
40 Months
60
80
subtype was observed in 22 patients (71%) and nodular sclerosing Hodgkin lymphoma in 4 (12.9%). B symptoms were present in 26 patients (83.9%) and bulky disease in 7 patients (22.6%). Eighteen patients (60%) presented with stage III/IV disease. Of the 12 stage IV patients, 9 (75%) had bone marrow involvement and 3 (25%) had lung involvement. High-risk international prognostic index for Hodgkin disease (> 2 adverse prognostic factors) was seen in 16 patients (61.5%). Two patients had other viral infection at diagnosis, 1 had hepatitis C virus, and another had hepatitis B virus. Treatment included full-dose chemotherapy in 24 patients (77.4%) and reduced-intensity chemotherapy in 7 (22.6%). Median chemotherapy cycles delivered to all patients was 8 (range, 1-8 cycles). Radiation therapy to initial bulky sites was performed in 5 patients (16.1%). Treatment response could be evaluated in 22 patients (70.9%) who completed initial treatment; 20 (91%) reached CR, 1 had partial response, and another did not have a response. The overall response rate was 95.5% (95% confidence interval, 91.2%-99.8%). Nine patients (29.1%) were not available for response evaluation: 2 patients died because of sepsis during treatment, 5 abandoned treatment for unknown reasons, and 2 are still receiving treatment. Although all patients were treated with prophylactic granulocyte colony-stimulating factor, neutropenia of any grade was seen in 58% of patients during chemotherapy (Table 2). Ten patients (32%) had infectious episodes during treatment, which included sepsis in 2 patients, disseminated tuberculosis in 2 patients, infectious diarrhea in 2 patients, pneumonia in 2 patients, and cutaneous herpes virus infection in 1 patient. The mortality rate during treatment for the 22 patients who completed therapy was 9%. After a median follow-up of 3 years, the OS rate among all patients was 80.3% (Figure 1); median OS was not reached. On univariate analysis, only CD4 cell count at diagnosis was significantly related to survival (Table 3 and Figure 2). The OS
Paula Yurie Tanaka et al Table 3
Figure 3 Disease-Free Survival of Patients with HIV with Hodgkin Lymphoma 100
Characteristic
3-Year OS Rate (%)
P Value
Sex
80
Survival (%)
Overall Survival of the 31 Patients with HIV with Hodgkin Lymphoma
60
Female
100
Male
77.3
0.45
Ethnicity White
40
84.5
Mixed (white/black)
0.49
72
HIV Risk Factors 20
0
20
40 Months
60
80
Homosexual
69.7
IVDU
100
Heterosexual
100
CD4 Categories < 100 cells/mm3 * 100
rate was not significantly different according to the full-dose chemotherapy scheme used (AVBD vs. MOPP-ABV; P = 0.51). Median DFS among patients who exhibited CRs was not reached (> 33 months), with a mean DFS of 50 months (95% confidence interval, 39-62 months) and DFS rate in 3 years of 74% (Figure 3).
Discussion The best chemotherapy option for HL-HIV remains undefined. Many studies have been performed in pre-HAART era, using different kinds of treatment, with high-grade toxicity and poor outcome in this population.6,9 Spina et al, using Stanford V scheme, performed one of the studies in HL-HIV patients with concomitant HAART in 59 patients. Complete remission was observed in 81% of patients, with an estimated 3-year OS of 51%. The probability of OS was significantly higher (76%) in the group with International Prognostic Score of ≤ 2.11 Hoffmann et al analyzed the outcome of 57 patients with HL-HIV and the use and efficacy of HAART and other prognostic factors. The only factors independently associated with OS were HAART response, CR, and age (≤ 45 years). The median survival in patients who did not respond to HAART was comparable with those described in pre-HAART era. An improvement of survival was related to patients who have a response to HAART.10 Recently, Biggar et al linked the nationwide HIV/AIDS and cancer registry from 1980 through 2002, showing that incidence of HL-HIV was significantly higher in 1996 to 2002, especially for mixed cellularity type. Compared with the general population, the risk of Hodgkin lymphoma was 9.4-fold higher in patients with HIV/AIDS. For each subtype of Hodgkin lymphoma, the incidence decreased with lower CD4 counts than with moderate immunosuppression, suggesting that the increased incidence of Hodgkin lymphoma might be related to HAART use.12 In our study, 71% of patients had mixed cellularity subtype, and 73.3% had CD4 counts ≥ 100/μL. Twenty-five patients
0.28
cells/mm3
55
0.01
89.5
HAART Use Yes
79.3
No
77.8
0.28
Stage I/II
100
III/IV
63
0.06
B Symptoms No
100
Yes
75.2
0.29
IPI Low risk
85.7
High risk
75.6
0.36
Chemotherapy Type Full-dose
86.5
Reduced intensity
59.5
0.08
Abbreviations: IPI = International Prognostic Index (high-risk denotes the presence of > 2 risk factors); IVDU = I.V. drug user
(83.3%) received HAART during chemotherapy, with an overall response treatment rate of 95.5% and OS rate of 80.3% after a median follow-up of 3 years; on univariate analysis, only CD4 cell count at diagnosis was significantly related to survival, suggesting that the worst immunologic status would be related to poor outcome in our patients. We did not observe differences in survival according to the type of treatment received by the patients (ABVD vs. MOPP-ABV or full-dose vs. reduced-dose chemotherapy) or according to other previously described risk factors, such as disease stage and HAART use. It is important to point out that because of the small number of patients included in each of these groups, it is not possible to draw any firm conclusion about the best treatment option or the impact of those risk factors in HL-HIV.
Clinical Lymphoma & Myeloma March 2007 • 367
Hodgkin Lymphoma in Patients with HIV Conclusion This retrospective study shows that for patients with Hodgkin lymphoma–HIV in these 3 Brazilian centers, there were high CR and satisfactory OS rates using ABVD or hybrid MOPPABV scheme, comparable with results observed with more aggressive treatment regimens or for Hodgkin lymphoma in patients without HIV.
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