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Phase II Trial of Infusional Cyclophosphamide, Doxorubicin, and Etoposide in Patients With HIV-Associated Non-Hodgkin’s Lymphoma: An Eastern Cooperative Oncology Group Trial (E1494)

From the Albert Einstein Cancer Center/Montefiore Medical Center, Bronx; Albany Medical College, Albany, NY; Dana-Farber Cancer Institute, Boston; Eastern Cooperative Oncology Group, Brookline, MA; Mayo Clinic, Rochester, MN; Johns Hopkins Oncology Center, Baltimore, MD; University of Pennsylvania Cancer Center, Philadelphia, PA; and Northwestern University Medical Center, Chicago, IL

Address reprint requests to Joseph A. Sparano, MD, Montefiore Medical Center, Weiler Division, 1825 Eastchester Rd,/2 South, Rm 47-48, Bronx, NY 10461; e-mail: jsparano{at}montefiore.org

	ABSTRACT

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PURPOSE: To determine the effectiveness of an infusional chemotherapy regimen in patients with HIV-associated lymphoma treated before and after the use of highly active antiretroviral therapy (HAART) in routine clinical practice.

PATIENTS AND METHODS: Ninety-eight assessable patients with HIV-associated intermediate- or high-grade non-Hodgkin’s lymphoma received cyclophosphamide 200 mg/m²/d, doxorubicin 12.5 mg/m²/d, and etoposide 60 mg/m²/d (CDE) given by continuous intravenous infusion for 4 days (96 hours) every 4 weeks plus filgrastim. Concurrent antiretroviral treatment consisted of the nucleoside analog didanosine in the first 43 patients enrolled before December 1996 (pre-HAART group), or HAART in the remaining 55 patients enrolled after that time (HAART group).

RESULTS: Complete response occurred in 44 patients (45%; 95% CI, 35% to 55%). Failure-free survival and overall survival (OS) at 2 years was 36% (95% CI, 26% to 46%) and 43% (95% CI, 33% to 53%), respectively. At the time of the analysis, 30% in the pre-HAART group were alive compared with 47% in the HAART group; when adjusted for varying length of follow-up, patients in the HAART group had improved OS (P = .039). Patients in the HAART group experienced less grade 4 nonhematologic toxicity (22% v 42%; P = .037), thrombocytopenia (31% v 52%; P = .033), and anemia (9% v 27%; P = .021), and had fewer treatment-associated deaths (0% v 10%; P = .013).

CONCLUSION: Infusional CDE is an effective and potentially curative regimen for patients with HIV-associated lymphoma. Patients treated in the HAART era have less chemotherapy-associated toxicity and improved survival.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
The incidence of non-Hodgkin’s lymphoma is increased by 100-fold or more in individuals infected with the HIV.^1-3 Previous studies have indicated that patients with lymphoma and HIV infection have a poor prognosis.⁴ Features that contribute to the poor prognosis include lymphoma-specific factors (eg, aggressive histology, extranodal disease) and HIV-specific factors (eg, poor bone marrow reserve, CD4 lymphopenia, opportunistic infection), although the CD4 lymphocyte count seems to be the most important prognostic factor.^5-8 In one large, multicenter trial performed in the era before highly active antiretroviral therapy (HAART) that evaluated a commonly used chemotherapy regimen (moderate-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and etoposide) given at either a standard dose or a reduced dose, the median survival was 8 months and only approximately 10% of patients survived at least 2 years.⁹

Some preclinical¹⁰ and clinical^11-14 evidence suggests a therapeutic advantage for administering cytotoxic therapy via a protracted rather than a bolus schedule (the standard method of drug administration). These observations led to a series of studies at the Albert Einstein Cancer Center (Bronx, NY) that included cyclophosphamide, doxorubicin, and etoposide (CDE) given as a 96-hour continuous intravenous (IV) infusion. Sixty-two patients received infusional CDE or CDE in combination with the antiretroviral agents didanosine or saquinavir and stavudine.^15-19 The complete response (CR) rate was 53% and median survival was 18 months for the entire study population.

On the basis of these studies, the Eastern Cooperative Oncology Group (ECOG) initiated a multi-institutional phase II trial of infusional CDE in HIV-associated lymphoma (E1494). When the study was initiated in March 1995, concurrent antiretroviral therapy with the nucleoside analog didanosine was stipulated by the protocol because a previous study had demonstrated that combination with infusional CDE was feasible,¹⁷ and because single-agent nucleoside analog therapy at the time was an acceptable therapeutic option for advanced HIV infection. It subsequently became common practice to use combination antiretroviral therapy consisting of protease inhibitors and nucleoside analogues to maximally reduce viral burden, a treatment strategy known as HAART,²⁰ and an expert panel recommended this as standard practice beginning in 1997.²¹ This was followed by a substantial reduction in morbidity and mortality secondary to HIV infection in the United States.^22-24 In addition, other studies have indicated that HAART has been associated with a decreased likelihood of developing lymphoma,^25-27 although lymphoma as the initial manifestation of the AIDS may now be more common.²⁸ Because of the change in practice patterns and the improving prognosis for patients with HIV infection, accrual to the study was continued after achieving the initial accrual goal in December 1996, and the protocol was modified to allow antiretroviral therapy other than single-agent didanosine. We present our analysis of patients treated with infusional CDE plus concurrent didanosine (pre-HAART group) or other concurrent antiretroviral therapies (HAART group).

	PATIENTS AND METHODS

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Patient Selection
Patients were required to have biopsy or cytology-proven intermediate- or high-grade non-Hodgkin’s lymphoma, to have measurable or assessable disease, and to be HIV seropositive. Other eligibility criteria included age of at least 18 years; ECOG performance status of 0, 1, or 2; serum creatinine less than 3.1 mg/dL; serum amylase less than 1.5 x the upper limits of normal; and neutrophil count at least 1,000/µL and platelets at least 50,000/µL (unless caused by lymphomatous marrow involvement, in which case the patient was eligible). All patients were required to provide written informed consent. The protocol was approved by the institutional review board at each participating institution. Representative pathologic materials were centrally reviewed for all patients by a single hematopathologist (T.N.) using the National Cancer Institute Working Formulation, which was an accepted and commonly used classification at the time that the study was initiated.²⁹

Chemotherapy
The treatment plan and supportive care are listed in Table 1. Doxorubicin and cyclophosphamide had previously been shown to be compatible when admixed.³⁰ Treatment was repeated every 28 or more days if the absolute neutrophil count was at least 1,500/µL, platelet count was at least 50,000/µL, and the patient had satisfactorily recovered from nonhematologic toxicity. The dose of each agent in CDE was reduced in subsequent cycles if there was febrile neutropenia (neutrophil nadir less than 500/µL and fever requiring parenteral antibiotics), severe thrombocytopenia (platelet nadir 25,000/µL), or severe (grade 3 or 4) mucositis. The doses were reduced by 25% for the first dose reduction, and 10% for subsequent dose reductions. Patients with hepatic dysfunction had the dose of doxorubicin modified on the basis of the total bilirubin: 5 mg/dL, doxorubicin was withheld; 3.0 to 4.9 mg/dL, reduced 75%; and 1.6 to 2.9 mg/dL, reduced 50%. Patients with renal dysfunction had the dose of etoposide reduced proportionate to the creatinine clearance (assuming that 60 mL/min was 100%). Patients continued treatment with CDE until two cycles beyond achieving a CR for a minimum of four and a maximum of eight cycles. Patients were removed from the study if there was progressive disease, stable disease after four cycles, a life-threatening infectious complication that resulted in a treatment delay of more than 6 weeks, or a decrease in the ECOG performance status to 3 or 4 for more than 4 weeks.

CNS Prophylaxis and Therapy
CNS prophylaxis was given to patients with small noncleaved-cell lymphoma or lymphomatous bone marrow involvement. It consisted of intrathecal cytarabine 50 mg on days 1 and 4 of cycles 1 and 2. All patients underwent a lumbar puncture with analysis of the CSF for cytologic examination within 6 weeks of registration. Radiographic imaging of the CNS was performed if clinically indicated (positive CSF cytology or focal findings suggestive of meningeal disease). Patients with meningeal lymphoma at diagnosis (n = 4) received whole-brain irradiation (24 Gy in 12 fractions) plus intrathecal cytarabine 50 mg alternating with methotrexate 10 mg/m² to maximum 15 mg) three times weekly (via an Ommaya reservoir or lumbar puncture) until the CSF cytology was negative on two consecutive occasions, then twice weekly for 2 weeks, then weekly for 4 weeks, then monthly for 6 months. Citrovorum 5 mg was given orally or intravenously every 6 hours for four doses after each intrathecal methotrexate injection. Patients with parenchymal CNS involvement were not eligible.

Staging Evaluation and Evaluation of Response
All patients were required to have a chest x-ray, computed tomography of the abdomen and pelvis (within 2 weeks of registration), and a unilateral bone marrow biopsy (within 6 weeks of registration). All studies that demonstrated measurable and/or assessable disease were repeated after every two cycles of therapy. A modification of the ECOG response criteria³² that was previously used for ECOG lymphoma trials was employed. The original criteria required resolution of all sites of disease to no larger than 1 cm; if larger, sites had to be free of lymphoma on biopsy. The revised criteria for CR allowed lymph nodes of a larger size if the lymph nodes subsequently decreased or remained stable in size for at least 3 months.

Statistical Considerations
The primary objectives of the trial were to determine the CR rate and overall survival (OS). The initial accrual goal was 45 eligible patients; the probability of falsely rejecting the treatment (observing less than 22 CRs among 45 patients [49% CR rate]) was .059. The accrual goal was expanded to 110 eligible patients after achievement of the initial accrual to determine the effectiveness and toxicity of CDE in patients diagnosed and treated in the HAART era. This report represents an analysis of data performed in April 2003.

Failure-free survival (FFS) was defined as the time from registration until progression or relapse of the lymphoma, or death as a result of any cause. OS was defined as the time from registration to death. FFS and OS were estimated using the product-limit method of Kaplan and Meier.³³ A prognostic factor analysis was performed. Univariate significance for FFS and OS was assessed using the log-rank test.³⁴ Multivariate analyses were performed using the Cox proportional hazards model³⁵ to evaluate the effect of a variety of prognostic factors on FFS and OS. Fisher’s exact test was used to assess the association between two binary variables.³⁶ A multivariate model for predicting CR was developed using logistic regression.³⁷ All P values reported were for two-sided tests. OS also was compared in the pre-HAART and HAART groups; to adjust for different durations of follow-up in the two groups, patients surviving more than 50 months (equivalent to the median followup in the HAART group) were excluded (including 10 censored patients and two deaths in the pre-HAART group, and 16 censored patients in the HAART group). This resulted in 31 patients in the pre-HAART group and 39 patients in the HAART group available for this analysis.

	RESULTS

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Accrual and Reasons for Nonanalyzable Patients
One hundred thirteen patients from 17 institutions were enrolled between January 1995 and June 1999. Fifteen patients were considered nonanalyzable because of failure to meet all eligibility criteria (n = 6) or failure to confirm pathologic diagnosis on central review (n = 9). Six of 15 nonanalyzable patients had a CR (40%), including two of five in the pre-HAART group and four of 10 in the HAART group. Five patients (33%) remain alive after a median follow-up of 53.5 months (range, 24.5 to 61.0 months). Efficacy, treatment, and outcome data are reported only for analyzable patients (n = 98), whereas toxicity data are reported for all patients for whom data were available (n = 112).

Patient Characteristics of Analyzable Patients
The first 43 analyzable patients accrued between March 1995 and December 1996 were required to receive concurrent didanosine (pre-HAART group). For the next 55 analyzable patients enrolled between January 1997 and April 1999, the selection of concurrent antiretroviral therapy was left to the discretion of the treating physician; it was standard practice at the time to use HAART (HAART group). The characteristics of the 98 analyzable patients are listed in Table 2. Although the incidence of prior antiretroviral therapy was slightly higher in the HAART group (80% v 67%), patients in this group had a higher baseline median CD4 count (227 v 90/µL; P = .002) and were less likely to have a CD4 count less than 100/µL (24% v 54%), indicating the use of more effective antiretroviral therapy before developing a lymphoma diagnosis. The two groups were otherwise comparable in clinical characteristics. Approximately two thirds of all patients had at least two adverse prognostic features by the age-adjusted International Prognostic Index (IPI),³⁸ which has also been reported to have prognostic significance in HIV-associated lymphoma.³⁹

View larger version (18K): [in this window] [in a new window]   Fig 1. Failure-free survival. HAART, highly active antiretroviral therapy.

View larger version (18K): [in this window] [in a new window]   Fig 2. Overall survival. HAART, highly active antiretroviral therapy.

Toxicity
Toxicity data for 112 of 113 patients treated in the pre-HAART and HAART cohorts are listed in Table 6, including 14 of 15 patients deemed to be not analyzable for response. There was less toxicity in the HAART cohort, including grade 5 (0% v 10%; P = .013) and grade 4 nonhematologic (22% v 42%; P = .037) toxicity. It is noteworthy that although the incidence of grade 4 granulocytopenia was similar (73% v 75%), patients treated in the HAART group tended to have fewer grade 3 to 5 infections (20% v 35%; P = .137), and had significantly fewer grade 4 thrombocytopenia (31% v 52%; P = .033) and anemia (9% v 27%; P = .021). The most common grade 3 to 4 nonhematologic toxicities that occurred in at least 10% of HAART patients included infection in 20%, metabolic abnormalities in 17%, liver dysfunction in 14%, neurologic toxicity in 14%, stomatitis in 11%, and a variety of other toxicities in 17% of patients.

Five patients died as a result of treatment-associated complications, all of whom were treated in the pre-HAART group (including one ineligible patient). Causes of death included Pneumocystis carinii pneumonia after cycle 1 (CD4 count 1/µL), pulmonary aspergillosis after cycle 4 (CD4 count 22/µL), Pseudomonas bacteremia associated with neutropenia after cycle 4 (CD4 count 57/µL), culture-negative sepsis without neutropenia after cycle 1 (CD4 count 252/µL), and an acute abdomen with gastrointestinal hemorrhage after cycle 1 in a patient with gastrointestinal lymphoma (CD4 count 2/µL).

	DISCUSSION

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We report the results of a multi-institutional phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide plus filgrastim in 98 analyzable patients with HIV-associated non-Hodgkin’s lymphoma. The cytotoxic agents were given at conventional doses but were administered in an unconventional manner by protracted IV infusion over 96 hours. All patients had intermediate- or high-grade lymphoma, 67% were considered intermediate to high or high risk by the age-adjusted IPI index, and the median CD4 count was 160/µL. The CR rate was 45%, median OS was 12.8 months, and the 2-year FFS and OS were 36% and 43%, respectively. Patients in the HAART group had substantially less toxicity and had improved survival compared with the pre-HAART group, although the CR rates were similar. Our findings suggest that approximately 40% of patients with HIV-associated lymphoma treated with infusional CDE in the HAART era will benefit from prolonged remission and perhaps cure. This result is similar to a recent multicenter trial that evaluated infusional CDE in immunocompetent patients with age-adjusted poor IPI risk intermediate-grade lymphoma (having at least two adverse prognostic factors); in that study, the CR rate was 48%, 2-year FFS was 50%, and 2-year OS was 58%.⁴⁰

The prognosis for patients with advanced HIV infection has improved considerably during the last 15 years. Routine prophylaxis against Pneumocystis carinii pneumonia in the late 1980s led to substantial reductions in mortality,⁴¹ although additional refinements in infection prophylaxis against other pathogens in the early 1990s had less impact.⁴² Beginning in 1997, however, a marked reduction in morbidity and mortality was ascribed to the routine use of HAART in clinical practice.^22-24 Recent reports indicate that HAART may also improve the prognosis for patients with lymphoma and HIV infection. For example, Vaccher et al⁴³ reported that patients treated with a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like regimen in the HAART era had a lower mortality rate (38% v 85%; P = .001) compared with patients treated with the same regimen in the pre-HAART era, despite the absence of a difference in CR rate. Antinori et al⁴⁴ reported that a good virologic response to HAART therapy was associated with not only improved survival, but also improved CR rate. It is noteworthy that nearly 50% of patients treated with infusional CDE in the HAART group were alive and nearly 40% did not experience treatment failure after a median follow-up of more than 4 years. Given the multicenter nature of the study, it is likely that these findings can be generalized to patients with HIV-associated lymphoma diagnosed in the community, and indicate an improved outcome compared with previous multicenter studies conducted in the pre-HAART era that employed standard cytotoxic therapy.⁹ However, our trial does not address whether it is necessary to administer HAART concurrently with chemotherapy. Other groups have advocated discontinuation of HAART during the period of chemotherapy administration to minimize the potential for noncompliance and consequent emergence of drug-resistant virus, and decrease the potential risk of adverse drug-drug interactions.⁴⁵

It is unclear whether the improved outcome observed for patients in our study was the result of improved antiretroviral therapy and supportive care, the infusional administration of cytotoxic therapy, or a combination of factors. Other groups have provided more convincing evidence that infusional therapy is more effective than conventional IV bolus therapy. For example, Little et al⁴⁵ reported a 74% CR rate and 72% survival (after a median follow-up of 53 months) in 39 patients with HIV-associated lymphoma treated with a similar infusional regimen (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin [EPOCH]), as listed in Table 7 and contrasted with CDE. In addition, the same group reported that EPOCH resulted in a 92% CR rate and 70% OS (after a median follow-up of 62 months) in immunocompetent patients with intermediate-grade lymphoma (of whom 52% had at least two poor prognostic factors by the age-adjusted IPI index).⁴⁶ In addition, infusional therapy may represent a better platform for rituximab because of rituximab’s long half-life,⁴⁷ facilitating greater potential for therapeutic synergy.⁴⁸ Although the combination of rituximab with CHOP (R-CHOP) significantly improved CR rate and survival compared with CHOP alone in elderly patients with intermediate-grade lymphoma,⁴⁹ a preliminary analysis of a similar trial in patients with HIV-associated lymphoma demonstrated a significantly higher infectious death rate for the R-CHOP arm (15% v 2%) without improvement in the CR rate (57% v 49%).⁵⁰ Moreover, the benefit for adding rituximab in elderly patients was evident only in the two thirds of patients whose lymphoma overexpressed bcl-2.⁵¹ Although bcl-2 overexpression is uncommon in HIV-associated lymphoma,⁵² two multicenter phase II trials demonstrated a high CR rate for rituximab chemotherapy combinations in HIV-associated lymphoma without an increased risk of lethal infection, including R-CHOP (CR rate 77%)⁵³ and R-CDE (CR rate 78%)⁵⁴; among 89 patients, only one died as a result of a treatment-related infection.

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Katherine Phillips for her expert data management, and Amgen Inc for providing filgrastim for this trial.

	NOTES

 
This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service grants CA14958, CA23318, CA13650, CA 16116, CA15488, CA17145, CA66636, CA21115 from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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Submitted August 29, 2003; accepted February 2, 2004.

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