Treatment of human immunodeficiency virus-related lymphoma

Treatment of Human Immunodeficiency Virus-Related Lymphoma Peter H. Wiemih In newly diagnosed human immunodeficiency virus (HIV)-positive patients with non-Hodgkin’s lymphoma (NHL), standard lymphoma regimens yield approximately a 50% complete response (CR) rate and an overall median survival of 19 months. Treatment results of relapsed patients are extremely poor. Regimens that appear more effective than standard therapy have usually been investigated only in patients with relatively high CD4 counts. An exception is a regimen consisting of a continuous 96-hour infusion of cyclophosphamide, doxorubicin, and etoposide (CDE). A 62% CR rate was achieved in 21 patients with a median CD4 count of 87/$, and the median overall survival was 18 months. In another study of 25 patients, didanosine (ddl) was added to CDE and was shown to cause less myelosuppression without compromising efficacy. Other studies suggest that highly active antiretroviral therapy (HAART) can be combined with intensive chemotherapy regimens, with improved efficacy attributed to less frequent dosage reduction of chemotherapeutic agents. More recently, autologous and syngeneic bone marrow transplantation have been explored in a handful of patients with acquired immunodeficiency syndrome (AIDS)-related NHl. with promising results. Data on whether widespread use of HAART decreases the incidence of HIV-positive NHL are conflicting. Some clues from recent studies suggest we are close to an answer: (1) protease inhibitors significantly improve survival of HIV-positive patients with NHL; (2) only one of eight recent cases of HIV-positive men with NHL received HAART compared with greater than 70% of HIV-positive men free of NHL; and (3) no prior HAART independently predicted for AIDS-related NHl. development. On the other hand, Hodgkin’s disease may be increasing in frequency in HIV-positive patients as the incidence of NHL declines. It is hypothesized that more effective reconstitution of the immune system with HAART may facilitate the inversion of these incidences. Future prospective studies will hopefully answer these questions. Semin Hematol38(suppl10):27-31. Copyright 0 2001 by W.B. Saunders Company.

N

ON-HODGKIN’S lymphoma (NHL) occurs with a 60-fold increased incidence in individuals who are human immunodeficiency virus (HIV)positive compared with the general population. At least two thirds of NHL cases in such patients are of high-grade histology and the vast majority of the remainder are intermediate-grade. Furthermore, most patients have extranodal disease, usually of the CNS, and B symptoms are frequent. Poor prognostic factors include age greater than 35 years, a history of intravenous drug use, poor performance status, CD4 count less than lOO/pL, a history of acquired immunodeficiency syndrome (AIDS) prior to the development of NHL, advanced stage, and bulky disease and/or elevated serum lactate dehydrogenase (LDH) activity. Viral etiologies have been proven for endemic Burkitt’s lymphoma and for adult T-cell lymphoma. Although there is a marked increase in NHL in HIVinfected individuals, the causative factor appears related to immune system disorder rather than the HIV virus specifically. In fact, regardless of whether an immune disorder is due to immunodeficiency disease, autoimmune disease, therapeutic intervention (eg, immunosuppressive agents for transplant recipients), or HIV infection, there is an associated increase in the incidence of NHL. Seminars in Hemato@y,

Hodgkin’s disease (HD) in HIV-positive patients is much less common than NHL, but its incidence may be increasing.7 More cases have been reported from Europe than the United States, for unknown reasons. When HD does occur in HIV-positive patients, it is of unfavorable histology, and usually aggressive, poorly responsive to treatment. Hyperuricemia as a consequence of tumor lysis syndrome (TLS) is a recognized potential complication of NHL, especially in patients with bulky disease or advanced histology. It may occur spontaneously or following effective chemotherapy. TLS can lead to significant morbidity and mortality, and can delay the delivery of appropriate chemotherapy in patients with advanced-stage NHL.2 TLS and associated hyperuricemia may need to be addressed both prophylactically and therapeutically in selected NHL patients.

From Our Lady of Mercy Comprehensive Cancer Center, New York Medical College, Bronx, NY. Address reprint requests to Peter H. Wiemik, MD, OLM Comprehensive Cancer Center, 600 E 233rd St, Bronx, NY 10466. Copyright 0 2001 by W.B. Saunders Company 003 7-l 963/01/3804-l 007$35.00/O doi:10.1053/shem.2001.29020

Vol38, No 4, Suppl 10 (October),

2001: pp 27-31

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Peter H. Wiemik

Progress in Therapeutic Regimens for HIV-Related NHL Standard therapeutic regimens for HIV-positive NHL typically result in complete response (CR) rates on the order of 50% or less and a response duration of approximately 9 months or less. In HIV-positive NHL patients with two or more negative prognostic factors, the 5-year overall survival rate is usually less than 50%. Newer infusional regimens may yield response rates significantly higher than that associated with conventional bolus regimens, and can be given concurrently with highly active antiretroviral therapy (HAART).

Aggressive Bolus Chemotherapy HIV-Related NHL Patients

in

A recent study by Rossi et all’ involved 69 consecutive evaluable patients with HIV-related NHL, who were diagnosed at a single institution during a loyear period. Patients were segregated into four groups based on the International Prognostic Index (IPI): low risk (five patients; mean CD4 count, 313/ pL); low to intermediate risk (12 patients; mean CD4 count, 23O/pL); high to intermediate risk (16 patients; mean CD4 count, 151/pL>; and high risk (36 patients; mean CD4 count, 72/pL). Forty-five patients received ProMACE-CytaBOM (cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin, and prednisone) administered as bolus intravenous injections. The CR rates for the low-risk, low- to intermediate-risk, high-to intermediate-risk, and high-risk patients were lOO%, 88%, 50%, and 32%, respectively. Although the CR rate and median survival of the highrisk group in this study represent an improvement over what is classically observed in such patients, later studies have demonstrated additional incremental improvement in outcome with infusional therapy. Regimens that appear to be superior to standard therapy have generally been investigated only in patients with relatively high CD4 counts. For example, a recent study by Oksenhendler et all0 involved the use of a short, intensive regimen (LNHIV-91) for 52 patients with a median CD4 count of 276/pL. The regimen consisted of induction with three cycles of doxorubicin, cyclophosphamide, vindesine, bleomytin, and prednisolone with a fourth cycle delivered to patients in partial remission or with initial bulky disease. The induction regimen was followed by three cycles of cyclophosphamide, etoposide, and methotrexate. Granulocyte colony-stimulating factor (GCSF) was used with each cycle. A CR was achieved in 71% of patients and the median survival of all treated patients was 15 months. The authors concluded that the regimen yields a high CR rate and prolonged

survival in HIV-positive NHL patients with count greater than lOO/pL.

Infusional Chemotherapy HIV-Related NHL

a CD4

for

Studies utilizing infusional administration have, in general, demonstrated improved efficacy in patients with low CD4 counts, compared with bolus regimens. Sparano et ali5 initiated a trial of cyclophosphamide, doxorubicin, and etoposide (CDE) given as a prolonged infusional schedule in HIV-positive patients with relapsed or resistant NHL. Previously the authors reported a CR rate of 17% in such patients with these agents used either alone or in combination employing a standard bolus schedule.14 In the most recent study, cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2>, and etoposide (240 mg/m’> were administered via continuous intravenous infusion over 96 hours as first-line therapy for 21 patients (median CD4 count, 87/pL) with intermediate- or high-grade NHL associated with HIV infection. A CR was obtained in 62% of patients and a partial response in 24%. The estimated median survival of all treated patients was 18 months. Recently, Spina et ali6 confirmed the activity of this regimen in 40 patients with resistant or recurrent HIV-related NHL. They obtained a 10% CR (duration, 4 to 30+ months) and 18% partial response rate, with a median survival for responding patients of 10 months.

Addition

of Antiretroviral Chemotherapy

Therapy

to

Didanosine Myelosuppression and opportunistic infection are the predominant toxicities noted in HIV-positive patients receiving chemotherapy for NHL because that treatment further decreases both CD4 and CD8 lymphocytes. G-CSF may mute granulocytopenia in such patients but obviously does not affect lymphopenia. Didanosine (ddI), a nucleoside analog approved for the treatment of advanced HIV infection previously treated with zidovudine, significantly increases leukocyte, neutrophil, red blood cell, and platelet counts. Importantly, the principal toxicities of ddI, peripheral neuropathy, and pancreatitis, do not overlap with the toxicities of CDE. However, ddI is metabolized to uric acid and can cause hyperuricemia. Concomitant therapy with allopurinol has been associated with increased systemic exposure to ddI approximately fourfold in patients with renal functional impairment. Therefore, recombinant urate oxidase may be superior to allopurinol in the treatment of hyperuricemia in patients receiving dd1. Nevertheless, dd1 represents a logical choice for inclusion in the CDE regimen, along with G-CSF, for HIV-related

29

HIV-Related Lymphoma

NHL. Twenty-five patients with HIV-related NHL treated with CDE received ddI and G-CSF either during dosing cycles 1, 2,5, and 6 or during cycles 3, 4, 5, and 6.13 Patients who received ddI on consecutive CDE cycles 3 through 6 had less leukopenia and neutropenia, less thrombocytopenia, and received fewer red blood cell and platelet transfusions. As expected, there was no significant difference in CD4 counts between the two schedules. The regimen was well tolerated overall and may have been associated with less myelosuppression. Aviles and Halabel evaluated the impact of HAART in patients with HIV-related NHL treated with standard chemotherapeutic regimens. Twentynine patients with a median CD4 count of llS/pL receiving HAART (indinavir, 800 mg every 8 hours; lamivudine, 150 mg twice daily; and zidovudine, 300 mg twice daily) were treated with cyclophosphamide, 750 mg/m’ intravenously on day 1; vincristine, 1.4 mg/m’ intravenously on day 1; mitoxantrone, 10 mg/m2 intravenously on day 1; and bleomycin, 10 mg/m’ intravenosly on day 14. G-CSF, 5 pg/lzg/d, was started on day 5 of every cycle to mute myelosuppression. If hematologic toxicity was unacceptable, the dose of zidovudine was reduced or the drug was discontinued. A CRrate of 72% was observed and the 3-year overall survival rate was 55%. The authors concluded that HAART improved outcome of lymphoma treatment in this study by enabling the administration of adequate dose-intense chemotherapy. However, the need for antiretroviral therapy for the successful treatment of HIV-related NHL has not been established, and requires further study employing prospective, randomized trials.

Effect

of HAART on the Incidence Related Malignancies

of HIV-

A number of studies have evaluated the influence of HAART on the incidence of HIV-related NHL, with conflicting results. Sparano et all2 retrospectively reviewed the annual number of outpatient visits to the HIV clinic, inpatient admissions for HIV disease, and first admissions for patients with cancer and HIV disease at the Albert Einstein Cancer Center in New York from 1990 to 1997. Despite a continued increase in the annual number of HIV clinic visits from 1990 to 1995, the annual number of first admissions in 1997 for both Kaposi’s sarcoma or NHL and HIV infection decreased by 36% and 63%, respectively, compared with those recorded in 1995. They concluded that the data suggest a declining incidence of HIV-associated malignancies since the introduction of HAART. In contrast, Jacobson et al5 found the rates of NHL in patients with HIV infection to have increased 21% since the introduction of HAART. They analyzed data

from the Multicenter AIDS Cohort Study, a longitudinal cohort study of the history of HIV infection among 1,813 men, and compared data from 1996 to 1997 with that of 1984 to 1985. Thiessard et all7 reviewed all 101 cases of NHL prospectively diagnosed between January 1986 and December 1997 among patients followed in the Aquitaine Cohort study. Approximately 73% of patients received chemotherapy for NHL. Forty-four percent of patients received nucleoside reverse transcriptase inhibitors alone, and 18% received that therapy with a protease inhibitor. Nucleoside reverse transcriptase inhibitors alone or with protease inhibitors were associated with relative hazard ratios for lymphoma of 0.27 (95% confidence interval [CII, 0.13 to 0.53) and 0.08 (95% CI, 0.03 to 0.21), respectively. In addition, the use of HAART was found to improve the survival rate of HIV-infected patients with NHL. Matthews et als suggest that HAART therapy does not influence the incidence of AIDS-related NHL or patient survival. They reviewed clinical data on 7,840 HIV-positive patients in the United Kingdom and compared the pre-HAART era (1988 to 1995) with the HAART era (1996 to 1999). They found no change in the incidence of AIDS-related lymphoma over time or differences in lymphoma stage at presentation, presence of B symptoms, performance status, or marrow involvement between patients diagnosed in the two time intervals studied. They also found no difference in survival rates between the two time intervals, or between patients treated with or without HAART before the diagnosis of AIDS-related lymphoma. Finally, Tirelli and Bernardir8 concluded that the impact of HAART regimens on the incidence of HIVrelated NHL is still unclear, but survival of patients with HIV-related NHL has been favorably affected by the use of HAART. It is clear from the forgoing studies that whether or not HAART has had an impact on the course of AIDS-related NHL is still an open question. The question can only be conclusively answered by further observation.

Stem Cell Transplantation HIV-Related

for Patients NHL

With

Gabarre et al+ evaluated the role of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation in a small number of HIV-positive patients with NHL. Seven of eight patients evaluated received HAART for a median of 24 months (range, 12 to 30 months) before stem cell transplantation, and were continued on it during stem cell collection and transplantation as well as post-transplantation. The median CD4 count before high-dose chemotherapy was 122/pL. Four patients died and

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Peter H. Wiemik

four were alive and in CR at more than 4 to more than 15 months after treatment. Although this was a small study, the authors concluded that they demonstrated that the risk of myeloablative chemotherapy in HIVpositive patients receiving HAART is similar to that of other patients, and that HIV-related NHL can be successfully treated with this approach. Molina et al9 treated two patients with HIV-associated NHL with myeloablative chemotherapy followed by autologous peripheral blood stem cell transplantation. The conditioning regimen consisted carmustine, and etoposide of cyclophosphamide, (CBV). HAART was continued during CBV conditioning. Prompt hematopoietic recovery was observed after transplantation in both patients, who were still in CR 20 and 28 months post-transplantation. The authors concluded that adequate numbers of CD34+ peripheral blood stem cells can be obtained from patients with HIV-associated NHL while receiving HAART. Campbell et al2 described one case of an HIVpositive male with relapsed immunoblastic NHL who was successfully treated with salvage chemotherapy followed by a syngeneic peripheral blood stem cell transplant from his HIV-negative brother. The patient was in CR 15 months post-transplantation with a low viral load and an improved CD4 count. This approach deserves further study. Hodgkin’s

Lynphoma in HIV-Positive Patients

Hodgkin’s lymphoma in HIV-positive individuals is relatively rare, with less than 400 reported cases worldwide, but its incidence may be increasing.7 This complication of HIV infection appears to be more common in Europe than in the United States for unknown reasons. Patients with HIV-related Hodgkin’s disease typically present with advanced stage and histology, and B symptoms. Mediastinal involvement is, curiously, uncommon. Response to treatment is generally poor, and overall survival is usually on the order of approximately 18 months. The incidence of NHL may be decreasing in HIV+ patients as the incidence of HD increases. It is possible that both lymphomas are etiologically related and that the basic defect is expressed as NHL or HD, depending on the severity of the lesion. We are currently studying familial lymphoma and preliminary results support this hypothesis. In 12 families with multiple cases of both HD and NHL, the pedigrees demonstrate anticipation: lymphoma develops at an earlier age and in a more fulminant form in succeeding generations, perhaps due to trinucleotide repeat expansion at the site of an involved gene. In each family with both lymphomas, afflicted members of

the newest generation all have NHL and afflicted members of prior generations all have HD. Conclusion HIV-related lymphoma remains as a therapeutic challenge. Clinical trials support the use of aggressive chemotherapy in the management of these lymphomas. Concomitant administration of HAART may enable HIV-positive patients to receive intensive lymphoma treatment with less dosage reduction than otherwise, but this remains to be proven. As more aggressive therapy is employed in HIV-related lymphoma, hyperuricemia with or without other evidence of tumor lysis syndrome may become an even more prominent feature of treatment.3 There is disagreement in the literature whether the incidence of HIV-related NHL is decreasing, and if so, whether the decrease is directly related to the advent of HAART. However, there does appear to be agreement that the incidence of HIV-related HD is increasing. References 1. Aviles A, Halabe J: Improved prognosis in patients with acquired immunodeficiency syndrome-related lymphoma. Cancer Biother Radiopharm 14:349-352, 1999 2. Campbell P, Hand H, Gibson J, et al: Syngeneic stem cell transplantation for HIV-related lymphoma. Br J Haematol 105795798,1999 3. Couderc B, Dujols JP, Mokhtari F, et al: The management of adult aggressive non-Hodgkin’s lymphomas. Crit Rev Oncol Hematol 35:33-48, 2000 4. Gabarre J, Azar N, Autran B, et al: High-dose therapy and autologous haematopoietic stem-cell transplantation for HIV-l-associated lymphoma. Lancet 355:11071-1072, 2000 5. Jacobson LP, Yamashita TE, Detels R, et al: Impact of potent antiretroviral therapy on the incidence of Kaposi’s sarcoma and non-Hodgkin’s lymphoma among HIV-l-infected individuals. J Acquir Immune Defic Syndr 21:S34-541, 1999 6. Jones DP, Mahmoud H, Chesney RW: Tumor lysis syndrome: Pathogenesis and management. Pediatr Nephrol 9:206-212, 1995 7. Klepfish A, Schattner A, Shtalrid M, et al: Advanced Hodgkin’s disease in a pregnant HIV seropositive woman: favorable mother and baby outcome following combined anticancer and antiretroviral therapy. Am J Hematol 6357-58, 2000 8. Matthews GV, Bower M, Mandalia S, et al: Changes in acquired immunodeficiency syndrome-related lymphoma since the introduction of highly active antiretroviral therapy. Blood 96:2730-2734,200O 9. Molina A, Krishnan AY, Nademanee A, et al: High dose therapy and autologous stem cell transplantation for human immunodeficiency virus-associated non-Hodgkin lymphoma in the era of highly active antiretroviral therapy. Cancer 89:680-689, 2000 10. Oksenhendler E, Gerard L, Dubreuil M-L, et al: Intensive chemotherapy (LHNIV-91 regimen) and G-CSF for HIV associated non-Hodgkin’s lymphoma. Leuk Lymphoma 39:8795,200o 11. Rossi G, Donisi A, Casari S, et al: The International Prognostic Index can be used as a guide to treatment decisions

HIV-Related Lymphoma

regarding patients with human immunodeficiency virus-related systemic non-Hodgkin’s lymphoma. Cancer 86:23912397, 1999 12. Sparano JA, Anand K, Desai J, et al: Effect of highly active antiretroviral therapy on the incidence of HIV-associated malignancies at an urban medical center. J Aquir Immune Defic Syndr 21:S518-S522,1999 13. Sparano JA, Wiernik PH, Hu X, et al: Pilot trial of infusional cyclophosphamide, doxorubicin and etoposide plus didanoside and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkin’s lymphoma. J Clin Oncol 14: 3026.3035,1996 14. Sparano JA, Wiernik PH, Leaf A, et al: Infusional cyclophosphamide, doxorubicin, and etoposide in patients with relapsed and resistant non-Hodgkin’s lymphoma: Evidence for a schedule-dependent effect favoring infusional admin-

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istration of chemotherapy. J Clin Oncol 11:1071-1079, 1993 Sparano JA, Wiernik PH, Strack M, et al: Infusional cyclophosphamide, doxorubicin and etoposide in HIV-related non-Hodgkin’s lymphoma: A follow-up report of a highly active regimen. Leuk Lymphoma 14:263-271, 1994 Spina M, Vaccher E, Juzbasic S, et al: Human immunodeficiency virus-related non-Hodgkin lymphoma: activity of infusional cyclophosphamide, doxorubicin, and etoposide as second-line chemotherapy in 40 patients. Cancer 92:200-206, 2001 Thiessard F, Morlat P, Marimoutou C, et al: Prognostic factors after non-Hodgkin lymphoma in patients infected with the human immunodeficiency virus. Cancer 88:1696-1702,200O Tirelli U, Bernardi D: Impact of HAART on the clinical management of AIDS-related cancers. EurJ Cancer 37:1320-1324, 2001