BEACOPP therapeutic regimen for patients with Hodgkin’s disease and HIV infection

P. Hartmann1,2,+, U. Rehwald1, B. Salzberger2, C. Franzen2, M. Sieber1, A. Wöhrmann1 and V. Diehl1

1 Department of Internal Medicine I, University of Cologne, Cologne; 2 Department of Internal Medicine I, University of Regensburg, Regensburg, Germany

Received 14 March 2003; accepted 5 June 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Hodgkin’s disease (HD) is the most common non-AIDS-defining tumor diagnosed in HIV-infected patients. Antineoplastic treatment is difficult considering the underlying immunodeficiency caused by HIV itself and may increase the risk of opportunistic infections. The purpose of this study was to evaluate the efficacy and safety of the chemotherapeutic regimen bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (BEACOPP) in HIV-infected patients with HD (HIV-HD).

Patients and methods:

Twelve patients with HIV-HD were scheduled to receive six cycles of BEACOPP. Five patients received concomitant antiretroviral therapy. Two patients received additional radiotherapy. Restaging was carried out after three and six cycles of chemotherapy. CD4 counts and HIV RNA levels were regularly monitored during the course of chemotherapy.

Results:

Complete remission (CR) was achieved in all patients. Of 12 patients, eight patients received the intended six cycles of BEACOPP. Two patients died of opportunistic infections within the treatment period, one patient died of a relapse after 26 months. The other nine patients remain in CR for their individual follow-up period, median 49 months (range 13–108). The most commonly observed toxicity was bone marrow suppression with National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3/4 leukopenia in 75% of all cases. The mean decline of CD4+ lymphocytes was 238 ± 230/µl, with a mean recovery of 272 ± 329/µl 6 months after the last cycle. Plasma levels of HIV RNA increased moderately or even declined under chemotherapy if highly active anti-retroviral therapy was given concomitantly with BEACOPP.

Conclusions:

The BEACOPP regimen is feasible and highly effective in HIV-HD patients. With respect to its overall moderate toxicity, BEACOPP is a safe regimen even in the immunocompromised patient.

Key words: antiretroviral therapy, chemotherapy, HIV infection, Hodgkin’s disease


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Hodgkin’s disease (HD) is the most common non-AIDS-defining tumor diagnosed in HIV-infected patients. Its unusually aggressive tumor behavior includes a higher frequency of unfavorable histological subtypes, more advanced stage and extranodal involvement by the time of presentation, and poor therapeutic outcome in comparison with HD outside the HIV setting.

At the time of diagnosis, 74–92% of all HIV-infected patients with HD (HIV-HD) present with advanced disease (Ann Arbor stage III–IV). Extranodal involvement is frequent (60%) with the most common sites being bone marrow, liver and spleen. Seventy per cent to 96% of patients suffer from B symptoms, including fever, night sweats and/or weight loss of >10% of normal body weight. HD tends to develop early in the course of HIV infection, presenting in patients with a median CD4+ cell count in a range from 275 to 306/µl [17]. The classic prognostic criteria for Hodgkin’s lymphoma in the general population do not apply for HIV-HD. They need to be supplemented by host prognostic criteria in the HIV setting, namely a low CD4+ count and AIDS prior to diagnosis of HD, both of which reflect the underlying immunodeficiency [7, 8].

Antineoplastic treatment is difficult considering the underlying immunodeficiency caused by HIV itself and may increase the risk of opportunistic infections (OIs) by inducing further immunosuppression. Retrospective evaluation and prospective trials show that overall survival of patients with HIV-associated HD is short at 12–18 months and the incidence of OIs as well as treatment toxicity is increased on treatment with standard therapeutic regimens [6, 7, 914]. The bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (BEACOPP) regimen was originally developed to investigate the potential of moderate dose escalation of conventional polychemotherapy to improve the unsatisfactory results in advanced stage HD in the general population. The HD 9 trial by the German Hodgkin’s Lymphoma Study Group (GHSG) demonstrated that BEACOPP (baseline dose) attained superior failure-free survival and that dose escalation made a further marked improvement [15, 16]. Herein we report results of a pilot study on a small group of patients (n = 12) with HIV-HD who received treatment with BEACOPP (baseline dose) plus granulocyte colony-stimulating factor (G-CSF).


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
This multicenter pilot study was initiated according to the guidelines of the GHSG in March 1993. As of February 2001, 12 patients were enrolled by four different centers. The end of follow-up for all patients was February 2002. The study was carried out in accordance with the Declaration of Helsinki (Hong Kong Amendment, 1989). The protocol met the requirements of the European Good Clinical Practice Guidelines (July 1990). Eligibility criteria for the trial were as follows: (i) untreated Hodgkin’s lymphoma in HIV-positive patients; (ii) age from 18 to 65 years; and (iii) either (a) Ann Arbor stage IIB with at least one of the following risk factors: large mediastinal mass (more than one-third of the thoracic diameter), extranodal disease or massive splenic involvement, or (b) stage IIIA with at least one of the above risk factors and/or elevated erythrocyte sedimentation rate (>=50 mm/h) and/or three or more affected lymph node areas, or (c) stage IIIB or IV. All subtypes of HD were included. Histological slides were reviewed by an independent expert panel consisting of four GHSG reference pathologists. For enrollment into the study, patients also had to meet the following requirements: bidimensionally measurable disease; at least one lesion >1.5 cm in its largest diameter; and an Zubrod–ECOG Eastern Cooperative Oncology Group performance status of <=3 [17, 18]. In addition, patients had to be neither pregnant nor lactating, be using accepted birth control methods and have a life expectancy of >=3 months.

Status of HIV infection
The status of HIV infection was assessed for each patient at study entry according to the US Centers for Disease Control and Prevention 1993 Criteria [19]. In order to monitor the course of HIV disease during BEACOPP chemotherapy, the number of CD4+ T-lymphocytes was determined at study entry, days 1 and 14 of each cycle, and every 4 weeks thereafter. In patients who were enrolled in to the study later than January 1996, in addition, HIV RNA PCR was performed on day 1 of each cycle with the Roche HIV-1 AMPLICORTM 1.0 and 1.5.

Chemotherapy
In this study, patients with HIV-HD were scheduled to receive six cycles of BEACOPP (baseline dose) every 21 days (Table 1), whereas HIV-negative patients received eight cycles of BEACOPP in the initial GHSG trial [15]. The lower cumulative dose of all chemotherapeutic drugs was preferred in order to reduce hematopoietic toxicity. Each cycle was initiated in due time if sufficient hematopoietic recovery had been achieved and if G-CSF administration had been ceased at least 48 h previously. Sufficient hematopoietic recovery was defined as leukocyte and thrombocyte counts after 21 days being at least 2000 and 50 000/µl, respectively, after the nadirs had been passed. If this was not the case, therapy was postponed until these conditions were fulfilled. If the postponement amounted to >1 week, the protocol required a dose reduction of cyclophosphamide, doxorubicin, etoposide and procarbacine to 75% of the planned dose in the remaining cycles. A 50% dose reduction of these drugs was obligatory if the delay of cell recovery exceeded 14 days.


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Table 1. BEACOPP regimen
 
Additional radiotherapy (RT) was administered locally only to patients with initial bulky disease (>=5 cm diameter; 30 Gy) or residual tumor (40 Gy). RT began 2–4 weeks after the end of chemotherapy in daily fractions of 1.8–2.0 Gy.

Treatment of HIV infection
Patients with a known HIV infection before diagnosis of HD had been treated with different antiretroviral regimens before enrollment into this study. Due to the long period of patient recruitment (1993–2001), the trends in antiretroviral regimens administered reflect the time of drug licensure and recommended treatment policy in Germany. In patients who were treated before 1997, antiretroviral therapy (ART) was discontinued during the time of chemotherapy in order to reduce hematopoietic toxicity. However, ART was usually given concomitantly to chemotherapy thereafter. Drugs for prevention of OIs were administered according to the 1999 USPHS/IDSA guidelines [20].

Patient monitoring
Patients were monitored for safety and antitumor effects on days 1 and 14 of each cycle of BEACOPP, as well as monthly after completion of all scheduled cycles. Toxicity was evaluated using the National Cancer Institute’s Adult Toxicity Criteria (February 1988 guidelines). Evaluation of disease assessment included physical examination, computed tomography (CT) after completion of three and six cycles of BEACOPP, and every 3 months for 2 years thereafter. Stage of disease was determined according to the Ann Arbor classification [21]. A bone marrow biopsy was performed at baseline and at confirmation of complete remission (CR), if positive at baseline.

End points and response criteria
Patients were assessable for efficacy if they had completed at least three cycles of BEACOPP. Response criteria were those previously defined by the report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas (National Cancer Institute Sponsored International Working Group) [22].

Statistical analysis
Time to progression and duration of response were measured from day 1 of the first cycle of BEACOPP and the first observation of response, respectively. These data were analyzed by the Kaplan–Meier product-limit method. Patients were evaluable when having completed at least three cycles of BEACOPP. For the efficacy analysis, the best response achieved from the start of treatment to progressive disease was recorded. The response rates (overall objective and CR rates) are reported in rates with 95% confidence intervals (Clopper Pearson intervals) [23].


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients were treated and followed up between March 1993 and February 2002.

Demographic characteristics and features of HD
The demographic data and characteristics of HD in these patients are given in Table 2. The median age of patients was 33 years. Eleven (92%) patients had advanced stage HD III–IV. Extranodal stage IV disease affected liver (17%) and bone marrow (25%). Seven (58%) patients had lymph node involvement only. B symptoms with at least two of the features, fever, night sweats and/or weight loss, occurred in 10 (83%) patients at diagnosis of HD. Central review of pathology material was performed on 10 patients (83%). With reference to the histological subtypes, nodular slerosis HD was diagnosed in three patients (25%). Nine patients (75%) had mixed cellular HD, one of whom showed areas of lymphocyte depletion. ECOG performance status was 3 in four patients (33%), three of whom had AIDS prior to diagnosis of HD.


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Table 2. Patient demographic data and features of Hodgkin’s disease
 
Features of HIV disease at diagnosis of HD
Table 3 shows the baseline characteristics of HIV disease prior to or at diagnosis of HD. Three patients (25%) had AIDS indicators prior to their HD: Pneumocystis carinii pneumonia (PCP), Mycobacterium avium complex (MAC) and HIV encephalopathy. Eight patients (67%) were symptomatic of HIV disease having constitutional symptoms including fever >38.5°C and diarrhea lasting >4 weeks, recurrent oropharyngeal infections such as Candida spp. and non-AIDS-defining viral infections (Herpes zoster). The median CD4+ count was 205/µl (range 110–1020). Of 12 patients, five received ART prior to diagnosis of HD, three of whom received only monotherapy with zidovudine (two patients) or didanosine (one patient), whereas the other two patients received combination therapy consisting of lamivudine plus stavudine or stavudine plus abacavir plus nelfinavir, respectively.


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Table 3. Features of HIV infection at diagnosis of HD
 
Response to BEACOPP
Eight of 12 patients received the intended six cycles of BEACOPP, one of whom received extended treatment with a total of eight cycles based on his physician’s individual decision. Two patients had to discontinue treatment due to progression of AIDS after four and five cycles, respectively, and died of OIs within <1 year after their diagnosis of HD. Two patients received only five cycles of BEACOPP because of prolonged neutropenia after the fifth cycle and an excessive increase in HIV RNA, respectively. Two patients received abdominal field radiation because of initial bulky disease and residual tumor, according to the protocol.

All patients were evaluable for response. CR was achieved in all patients [100%, 95% confidence interval (CI) 73.5% to 100%]. Eleven of 12 patients (91.7%, 95% CI 61.5% to 99.8%) were in CR at the staging evaluation after three cycles of chemotherapy, whereas one patient with initial abdominal bulky disease had only achieved PR at this time point. The latter had a residual abdominal tumor after six cycles of BEACOPP, but achieved CR after additional radiation.

Toxicity and infection during chemotherapy
Among the main laboratory findings at study entry, the median hemoglobin level was 9.6 g/dl (range 5.4–16.2), absolute neutrophil count (ANC) was 2870/ml (range 670–5789) and platelets were 210 000/ml (range 38 000–467 000). The National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade of observed toxicities in 69 administered cycles of BEACOPP is given in Table 4. The most common side-effect was bone marrow suppression. As the application of G-CSF was left to the physician’s individual discretion, G-CSF was applied in 37 (54%) cycles. Nevertheless, six patients (50%) experienced grade 4 neutropenia with ANC <500/ml accounting for 17 (26%) of all administered cycles. Grade 3 neutropenia was observed in three patients (25%) accounting for 35 cycles (51%). Thus a total of nine patients (75%) developed significant neutropenia. Grade 4 and grade 3 anemia occurred in two and three patients, respectively, with hemoglobin <6.5 g/dl and 6.5–7.9 g/dl accounting for 15 (28%) and seven (10%) cycles, respectively. Thus severe anemia occurred in 42% of patients. Significant thrombocytopenia was detected in only one patient who also had bone marrow infiltration with MAC at the diagnosis of HD and therefore a low baseline thrombocyte count of 38 000/ml.


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Table 4. Treatment toxicity NCI-CTC grade
 
A delay of 1 week or interruption of chemotherapy occurred in five patients affecting eight cycles, with four cycles accounting only for the patient with bone marrow infiltration with MAC who experienced prolonged bone marrow suppression after all administered cycles. In two patients chemotherapy had to be postponed because of florid infections (esophageal candidiasis and Herpes zoster). The other two patients experienced an episode of prolonged neutropenia, both after the fifth cycle. In one case prolongation of neutropenia was so severe that chemotherapy had to be discontinued after five cycles. Dose reduction of 25% was required for one cycle in the patient with concomitant MAC infection. Two patients developed symptoms of peripheral neuropathy after the third and fourth cycle of chemotherapy, respectively. Subsequently the following cycles were administered without vincristine.

During the course of chemotherapy five episodes of febrile neutropenia with fever of unknown origin (FUO) occurred, one of which was severe (grade 4) and required intensive care. One patient developed febrile neutropenia with clinically documented pneumonia.

Course of HIV infection during chemotherapy
All patients experienced a significant decline of CD4+ cells during their treatment period. The mean decline of CD4+ lymphocytes was 238 ± 230/µl with a mean recovery of 272 ± 329/µl 6 months after the last cycle (Table 5). Of seven patients treated after 1996, four received concomitant ART. The other three refused ART because of previously experienced severe side-effects. In this small study population the courses of CD4+ counts of patients with and without ART were very similar, as shown in Figure 1. In contrast, plasma levels of HIV RNA, as measured for the eight patients treated within the past 6 years, increased only moderately or even declined under chemotherapy if HAART was given concomitantly with BEACOPP (Figure 2). With respect to the clinical course of HIV infection under BEACOPP, two patients died of progression of AIDS. One patient, who had already experienced one episode of PCP prior to diagnosis of HD, had discontinued her prophylaxis with cotrimoxazol and died of PCP 5 months after her diagnosis of HD. The other patient who was simultaneously diagnosed with MAC infection and HD died of MAC 9 months after his diagnosis of HD. Among the other patients, two had HIV-related and AIDS-defining infections, respectively (Herpes zoster, esophageal Candida spp. infection).


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Table 5. Patient-specific data on HIV infection and course during chemotherapy
 


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Figure 1. Decline and recovery of CD4+ counts (n = 12). Courses of CD4+ counts were similar in patients with (dotted line, n = 4) and without (solid line, n = 8) concomitant antiretroviral therapy.

 


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Figure 2. Increase and decline of HIV RNA (n = 7). Six months after the last cycle of bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine and prednisone (BEACOPP), patients (n = 8) reached plasma levels of HIV RNA that were close to their baseline prior to Hodgkin’s disease, regardless of whether they received concomitant antiretroviral treatment (dotted line) or whether highly active antiretroviral therapy was started shortly after the end of chemotherapy (solid line).

 
Survival
Median survival could not be calculated in our study since only three of 12 patients died within the study period. The individual survival period of each patient is given in Table 6. Survival periods range from 5 to 108 months. For clarity, Kaplan–Meier analysis, as shown in Figure 3, was limited to a period of 5 years. Overall survival and disease-free survival were virtually identical in our study. Only one patient experienced a relapse 22 months after diagnosis of HD and died of fulminant progression of HD 4 months later. In this small group of patients, survival did not correlate with the duration of HIV infection prior to diagnosis of HD.


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Table 6. Patient-specific data on Hodgkin’s disease and therapeutic outcome
 


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Figure 3. Overall survival calculated for 5 years (n = 12), tick mark indicates patient is alive.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Retrospective evaluations of treatment regimens that have been used in HIV-negative patients with advanced HD show low rates of CR, poor tolerance of chemotherapy and the necessity for dose reduction and/or delay of treatment [6, 7, 911]. Similar results have been shown in recent prospective studies. Errante et al. [12] employed a regimen of moderate bone marrow toxicity in 17 patients using epirubicin, bleomycin and vinblastine (EBV) at full dosage in patients with good prognosis disease (low risk) and at 50% dose levels in patients with poor prognostic factors, including AIDS prior to HD and poor performance status (high risk). CR was achieved in 67% of low risk patients, whereas only one of five patients (20%) with high-risk factors achieved CR. The concomitant use of zidovudine in that trial resulted in a substantial decrease of OIs. However, overall median survival was only 11 months [12].

In a consecutive trial, the regimen epirubicin, bleomycin, vinblastine and prednisone (EBVP) plus G-CSF with concomitant ART with either zidovudine or didanosine (DDI) was employed in 35 patients [13]. Neither CR nor overall median survival were significantly improved at 74% and 16 months, respectively.

The BEACOPP regimen proved to be a successful treatment of unfavorable HD in the HIV-negative population [15, 24]. Our study shows the feasibility and efficacy of the BEACOPP regimen in HIV-HD patients. CR was achieved in all 12 patients, only one relapse occurred and only three patients died. Median survival could not be calculated with 75% of patients still being alive at their last follow-up. However, as of 28 February 2002, the median follow-up time of those patients remaining in the study was 4 years (range 1–9) and suggests an overall median survival and disease-free survival that is far above that achieved with other chemotherapeutic regimens. This suggestion gains support by an overall survival of 83% at 2 years achieved in our study.

In comparison, the most recent studies of Levine et al. [25] and Spina et al. [26] achieved 66% at 2 years and 56% at 17 months, respectively. Overall toxicity of BEACOPP was moderate. Severe hematological toxicity with grade IV neutropenia occurred in 50% of patients, but was manageable and no death due to neutropenic infection occurred. As G-CSF was not given routinely in this trial, hematological toxicity may be decreased by the routine use of G-CSF. Levine et al. [25] treated 23 HIV-HD patients with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus G-CSF. CR was achieved in 43% of patients, median survival was 1.5 years and, thus, far below the results achieved with ABVD in the HIV-negative population with advanced stage HD. Despite the routine use of G-CSF, severe grade IV neutropenia occurred in 47% of patients; however, bone marrow involvement of HD was present in 57% of patients and may have contributed to the high grade of hematological toxicity. In comparison, in our study the prevalence of bone marrow involvement of HD was only 25%. Also with regard to response rate and survival, Levine’s study had a higher percentage of patients with poor prognostic factors of HIV-HD [25]. CD4 counts were <100/µl in 38% of patients at diagnosis of HD, and AIDS was present in 29% of patients. In our study none of the patients had CD4 counts <100/µl, but AIDS was present in 25%. According to the HIV-associated prognostic risk factors, three patients in our study were evaluated as high-risk patients presenting with pre-AIDS and a poor performance status at diagnosis of HD. Two of them died of progressive AIDS. BEACOPP proved to be superior to cyclophosphamide, vincristine, procarbazine and prednisone (COPP)/ABVD in HIV-negative patients with advanced stage HD [24]; therefore, the notable differences between our study population and Levine’s may have contributed less to the results in response and survival than the activity of the BEACOPP regimen itself.

A treatment approach with the Stanford V regimen (mechlorethamione, doxorubicine, vinblastine, vincristine, bleomycin, etoposide and prednisone) plus G-CSF, PCP and fungal prophylaxis and concomitant HAART was presented by Spina et al. [26]. With regard to its results reported for HIV-negative patients with unfavorable HD, the Stanford V regimen is comparable to the BEACOPP regimen [27]. Of 59 patients with HIV-HD treated in the study, 53 had an objective response—48 (81%) achieved CR and five (8%) achieved PR—six patients (10%) progressed. At a median follow-up time of 17 months, 33 (56%) patients were alive and disease free. The estimated 3-year overall survival and disease-free survival rates were 51% and 68%, respectively. The certainly considerably larger study population of Spina et al. [26] is very similar to ours with regard to the demographic data and the characteristics of HD and HIV disease. The main difference between the two studies is that half of their patients were intravenous drug users (IVDU), whereas we had none, and all of their patients received HAART concomitantly.

In both studies the courses of CD4 counts and HIV RNA are almost analogical, even though in the present study concomitant ART was employed in only 25% of patients. The other patients started or restarted ART shortly after the end of chemotherapy. However, since the feasibility of concomitant application of chemotherapy and HAART has been shown [26], this approach deserves further evaluation in future prospective trials, particularly because the impact of HAART on presentation and outcome of AIDS-related lymphoma remains a matter of controversial discussion [28, 29].

Even though this is a small group of patients, the response rate of 100%, the overall survival of 83% at 2 years and median follow-up time of 4 years suggest that BEACOPP may be as effective in HIV-HD as it is in the HIV-negative population with HD. Concomitant ART was well tolerated. Based on these promising results larger prospective trials should evaluate the use of BEACOPP plus G-CSF and concomitant use of HAART in HIV-HD patients.


    Acknowledgements
 
We are grateful to Jürgen Schölmerich for critical discussion of the manuscript.


    Footnotes
 
+ Correspondence to: Dr P. Hartmann, Department of Internal Medicine I, University Clinics Regensburg, 93042 Regensburg, Germany. Tel: +49-941-944-7050; Fax: +49-941-584-0542; E-mail: pia.hartmann{at}klinik.uni-r.de Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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