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Originally published as JCO Early Release 10.1200/JCO.2003.06.039 on October 27 2003 © 2003 American Society for Clinical Oncology High-Dose Therapy and Autologous Peripheral-Blood Stem-Cell Transplantation As Salvage Treatment for HIV-Associated Lymphoma in Patients Receiving Highly Active Antiretroviral Therapy
From the Unità Semplice Dipartimentale Ematologia, Clinica di Malattie Infettive, Università di Brescia, Centro Trasfusionale, and III Laboratorio Analisi, Spedali Civili, Brescia; Divisione di Oncologia Medica A, Centro di Riferimento Oncologico, Aviano; Divisione di Ematologia, Ospedale Santi Antonio e Biagio e Cesare Arrigo, Alessandria; Divisione di Ematologia, Ospedale Niguarda; Divisione di Malattie Infettive, Ospedale Niguarda; Divisione di Malattie Infettive, Ospedale San Raffaele, Milano; Clinica I di Malattie Infettive, Policlinico Gemelli, Roma; and Centro Immunotrasfusionale ed Analisi Cliniche, Centro di Riferimento Oncologico, Aviano, Italy. Address reprint requests to Alessandro Re, MD, Divisione di Ematologia, Spedali Civili, p.le Spedali Civili, 1, 25123 Brescia, Italy; e-mail: reale{at}bshosp.osp.unibs.it.
Purpose: High-dose therapy (HDT) and peripheral-blood stem-cell transplantation (PBSCT) in HIV-associated lymphoma (HIV-Ly) has been recently reported in selected patients. We describe the results of a multi-institutional program of HDT and PBSCT as salvage therapy in HIV-Ly responsive to highly active antiretroviral therapy (HAART) in unselected patients. Patients and Methods: Patients with resistant or relapsed HIV-Ly after first-line chemotherapy (CT) underwent PBSC collection after a course of second-line CT or cyclophosphamide and granulocyte colony-stimulating factor. Patients with chemotherapy-sensitive disease received carmustine, etoposide, cytarabine, and melphalan (BEAM regimen) and PBSC reinfusion. Effective HAART was maintained during the entire program. Results: Sixteen consecutive patients entered the program. Adequate collection of PBSC was obtained in 80% of patients (median CD34+ cells 6.8 x 106/kg). Three patients had early progression. Ten patients (62%) received PBSCT with prompt engraftment in all patients (neutrophils and platelet engraftment after a median of 10 days [range, 8 to 10 days] and 13 days [range, 8 to 18 days], respectively). No patients died as a result of opportunistic or other infections or treatment-related complications. Eight of nine assessable patients achieved complete remission (one patient after radiotherapy for residual disease) and one patient achieved partial remission. Two patients experienced relapse and died at +10 and +14 months. Six patients are alive and disease free at a median of 8 months after transplantation. Conclusion: Our data confirm that HDT plus PBSCT is feasible and active as salvage therapy in HIV-Ly on a multi-institutional basis and in unselected HAART-responding patients. HIV infection should no longer preclude the opportunity of HDT in patients with lymphoma.
HIV-ASSOCIATED HODGKIN’S disease (HD) and non-Hodgkin’s lymphoma (HIV-Ly) have peculiar clinical and pathologic features and less favorable outcome compared with lymphoma occurring in HIV-negative patients.1,2 The worse prognosis is due both to the intrinsic lymphoma aggressiveness and to the patients’ characteristics related to the underlying HIV infection.3,4 Nevertheless, several experiences have shown that in HIV-Ly, high rates of complete remission (CR), and prolonged survival can be achieved with intensive regimens in a proportion of patients with good prognostic features.5–7 Patients with HIV-Ly who do not respond to or experience relapse after first-line chemotherapy (CT) have little possibility of cure with standard-dose salvage CT.8–11 High-dose therapy (HDT) with autologous peripheral-blood stem-cell transplantation (PBSCT) is widely performed as salvage therapy in HIV-negative patients with HD and non-Hodgkin’s lymphoma (NHL), and is considered the treatment of choice in chemotherapy-sensitive relapse.12,13 This aggressive treatment approach has been considered prohibitive in HIV-positive patients because of the potential toxicity and the possibility of worsening the immune defect, thereby accelerating the course of HIV infection. The introduction of highly active antiretroviral therapy (HAART) has recently changed the natural history of HIV infection, reducing HIV-related morbidity and mortality by improving immune function. This has allowed the exploration of potentially curative myeloablative therapy in HIV-infected individuals; an aggressive therapeutic approach with HDT and stem-cell support has been used in selected patients with HIV-Ly.14,15 However, the possibility of such approach in unselected patients and on a multi-institutional basis is still uncertain. We report the results of a program of HDT and PBSCT given as salvage therapy in unselected patients with HIV-Ly who were refractory or experienced relapse after intensive first-line chemotherapy.
Patients All HIV-positive patients with HD or NHL who failed to achieve CR after standard-dose first-line CT (primary refractory or in confirmed partial remission [PR]) or experienced disease relapse (first or subsequent relapse) were considered for PBSC mobilization and HDT. Patients with HD in first relapse were eligible if previous CR lasted less than 1 year. Eligibility criteria included WHO performance status less than 3, left ventricular ejection fraction more than 50%, creatinine level lower than 2 mg/dL, bilirubin level lower than 3 mg/dL, absence of active opportunistic infections (OI) or CNS lymphoma, and availability of effective HAART. Patients were excluded if the CD4 count was less than 100/µL during HAART, if not related to recent CT. Previous AIDS-defining illness was not an exclusion criterion. The study was approved by the Review Board at the Spedali Civili (Brescia, Italy) and all patients gave an informed consent according to the Declaration of Helsinki.
Treatment A minimum of 5 x 106 CD34+ cells/kg of patient weight was planned to be collected. Patients were eligible for HDT if they demonstrated sensitivity to chemotherapy, defined as at least a minor response (more than 25% decrease in measurable disease or any amelioration of assessable disease or disappearance of disease-related symptoms) to debulking treatment. Patients with disease progression during mobilization and collection procedures did not proceed to HDT but were analyzed for the study on an intention-to-treat basis. At least 1 month after stem-cell harvest, patients received HDT with carmustine 300 mg/m2 on day -7, cytarabine 200 mg/m2 on days -6 to -3, etoposide 200 mg/m2 on days -6 to -3, and melphalan 140 mg/m2 on day -2 (BEAM) as conditioning regimen16 and PBSC reinfusion. G-CSF was started at day +1 at a dose of 5 µg/kg/d. HAART was given concomitantly from the beginning of chemotherapy and throughout the entire treatment program regardless of CD4 count or HIV viral load. Patients received antibacterial, antifungal, and antiviral prophylaxis with quinolones, azoles, and acyclovir until granulocyte recovery, and trimethoprim plus sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis during conditioning treatment and after hematologic recovery. Toxicity was graded according to National Cancer Institute of Canada common toxicity grading criteria.
From September 2000 to April 2003, 16 consecutive patients were considered eligible for intensive second-line treatment and entered this program within the Italian Cooperative Group on AIDS and Tumors. All patients had refractory or relapsed disease, except one patient who was in PR after first-line treatment. Eight patients had NHL (three refractory, three first relapse, one second relapse, and one PR) and eight patients had HD (three refractory, three early first relapse, and two second relapse). Histologic subtypes of NHL were five diffuse large B cell, one Burkitt’s, one plasmablastic, and one anaplastic large-cell CD30+. Histologic subtypes of HD were two nodular sclerosis, two mixed cellularity, two lymphocyte depletion, and two unclassifiable. The presence of Epstein-Barr virus, analyzed on histologic sections with in vitro hybridization (Epstein-Barr early region protein), was detected in four of four tested patients with HD and in three of three tested patients with NHL.
The median age of patients was 39 years (range, 31 to 56 years). The patients, lymphoma characteristics, and the HIV-related features at the time of study entry are shown in Table 1
One patient had disease progression soon after debulking treatment. Fifteen patients are assessable for PBSC collection; in 12 of them (80%), an adequate number of CD34+ cells (6.8 x 106/kg; range, 4.1 to 8.3 x 106) was obtained after a median of two apheresis treatments (range, two to three). In six patients, PBSCs were collected at recovery after debulking CT, and in the others after high-dose cyclophosphamide 4 g/m2 plus G-CSF. Three patients experienced mobilization treatment failure after second-line CT and two patients also experienced treatment failure after high-dose cyclophosphamide plus G-CSF. There were no significant differences between patients who did or did not mobilize CD34+ cells; median CD4 count was 204/µL (range, 17 to 506/µL) and 138/µL (range, 35 to 193/µL; P = .17), respectively. The HIV status was not affected during mobilization and collection procedures. No significant toxicity and no OIs were seen, and the HIV viral load did not increase in any patients; the mean CD4 count at study entry and after the procedures was 251 and 188 cells/µL (P = .47), respectively. Two patients with adequate CD34 collection had rapid disease progression before receiving transplantation. One patient died soon after, whereas the other received HDT with PBSC support, achieved a short-lasting PR, and died 4 months later as a result of disease progression. The 10 remaining patients received HDT and PBSCT. Their characteristics were as follows: six patients had NHL (three refractory, one first relapse, one second relapse, and one PR) and four patients had HD (one refractory, one first relapse, and two second relapse); the median age was 37 years (range, 31 to 54 years). None of the three patients with CD4 count less than 100 cells/µL at study entry received transplant (one mobilization failure and two disease progressions). The mean CD4 count before receiving conditioning regimen was 181 cells/µL (range, 88 to 365 cells/µL). Two patients have had previous major OI (intestinal mycobacteriosis, esophagus candidosis, and cytomegalovirus encephalitis in one patient, and Mycobacterium pneumonia in one patient). Four patients had positive HCV serology. All patients were receiving HAART at the time of transplantation. Three of the 10 patients had detectable viremia at study entry and one also at transplantation (81 cp/mL). All received BEAM regimen therapy and G-CSF 5 µg/kg from day +1. Six patients underwent transplantation at the Hematology Department of Brescia (Italy), three underwent transplantation at the Aviano Cancer Center (Italy), and one underwent transplantation at the Hematology Department of Alessandria (Italy). Engraftment promptly occurred in all patients. White cell engraftment, defined as an absolute neutrophil count greater than 500/mL, occurred after a median of 10 days (range, 8 to 10 days), and platelet engraftment, defined as self-supporting platelet count greater than 20 x 109/mL, occurred after a median of 13 days (range, 8 to 18 days). Treatment toxicity included grade 2 to 3 gastrointestinal toxicity in seven patients (grade 2 stomatitis in four patients, grade 3 stomatitis in three patients, and grade 2 diarrhea in one patient) and grade 3 hepatic toxicity in two patients. One patient had a severe hypersensitivity reaction to dimethyl sulfoxide at PBSC reinfusion, with hypertension and bronchospasm, requiring parenteral medications. Infectious complications during the period of neutropenia included two sepses (from Escherichia coli and Staphylococcus epidermidis) and a Clostridium difficile colitis, which promptly responded to antimicrobials. Two episodes of febrile neutropenia were registered. No reactivation of HCV was seen.
The underlying HIV infection did not worsen significantly after the transplantation procedure. The mean CD4 count decreased after the treatment (154 and 93 cells/µL at month +1 and +3 after transplantation, respectively), but a trend toward recovery was seen as early as 6 months after transplantation (mean CD4 count 186 cells/µL at month +6; Fig 1
Nine patients are assessable for response of lymphoma (it is too early to assess response in one patient). Seven patients achieved CR and two patients achieved PR after HDT. One patient with PR subsequently achieved CR after radiotherapy on residual disease. Four patients received involved-field radiotherapy after transplantation on previous bulky disease. No patients died as a result of OI or other infections or treatment-related complications. No significant difference of CD4 count at study entry was seen between patients achieving CR and those who did not achieve CR for any reasons (mean CD4 count 253 and 208/µL, respectively; P = .492). Two patients experienced relapse at month +5 and +12 and died as a result of disease progression 10 and 14 months after transplantation, respectively. Six patients are alive in continuous CR, after a median of 8 months (range, 2 to 17 months) from the transplantation. Two of them had detectable viremia at study entry and no detectable viremia at last follow-up. The median disease-free survival of patients who underwent transplantation was 11 months and the overall survival was 18 months, compared with 6 months for patients who did not proceed to transplantation. On an intention-to-treat basis, the median survival of the entire series of 16 patients was 18 months from study entry, with a projected overall survival (OS) of 39% at 2 years (Fig 2  ).
The results of conventional-dose second-line chemotherapy for patients with resistant or relapsing HIV-Ly have been poor. The CR rate ranged from 10% to 26% and most patients eventually experienced relapse and died as a result of lymphoma; the median OS ranged from 2 to 4 months from the start of treatment.8–11 Moreover, toxicity was substantial, with treatment-related mortality in up to 12%11 and WHO grade 4 hematologic toxicity in up to 100% of patients.10 The use of HDT with marrow stem-cell rescue has been reported in occasional patients. One patient reported by Gabarre et al14 developed several OIs and died as a result of AIDS 2 years after transplantation. More recently, after the improvement of immune function obtained with HAART and the shortening of the duration of neutropenia using peripheral blood as a stem-cell source, HDT with stem-cell support has been proven feasible also in HIV-positive patients. Gabarre et al14 reported on eight patients (updated to 14 patients in abstract form17) with relapsed or refractory HIV-Ly who received HDT and PBSCT as salvage treatment; Krishnan et al15 reported on nine patients (updated to 15 patients in abstract form18) who underwent transplantation mainly in high-risk first CR or subsequent CR as consolidation treatment. In these small and selected series, successful engraftment with rapid hematologic recovery and no significant detrimental effect on HIV infection have been reported. Another small series reported in abstract form by Serrano et al19 showed some engraftment delay but no significant toxicity. Our data confirm the feasibility of this treatment approach also on a multi-institutional basis and in unselected HAART-responding patients with refractory or relapsed HIV-Ly. All patients promptly engrafted after PBSCT and time to engraftment was comparable with the HIV-negative setting. Treatment-related toxicity and infectious complications were acceptable; bacterial infections were the main complication of the procedure, as in HIV-negative patients. No patients died as a result of toxicity or HIV progression. This aggressive treatment approach, performed in patients receiving HAART, did not show clear detrimental effect on immune function in excess of that usually seen as a consequence of standard CT and concomitant antiretroviral therapy.20 HAART was well tolerated and was interrupted in three patients only for few days during HDT. On the basis of the results of pilot studies, the efficacy of HDT on HIV-Ly varied according to the status of disease at the time of transplantation, as for HIV-negative patients. Gabarre et al14 reported encouraging data in chemotherapy-sensitive disease and treatment failure in chemotherapy-resistant lymphoma; Krishnan et al18 reported excellent OS and disease-free survival in patients who had achieved CR with first-line standard CT and were considered at high risk of relapse. However, patient selection bias in these studies is unknown and might have been substantial. Our prospective study of HDT in consecutive patients with HIV-Ly allows a more proper evaluation of the feasibility and efficacy of the procedure in patients responding to HAART. It shows that HDT can be performed on approximately 60% of eligible patients, particularly because of early disease progression, which may be expected in HIV-Ly. Indeed, two patients had disease progression during debulking treatment and two had early disease progression shortly after successful PBSC collection before receiving HDT. Conversely, HIV patients did not show a reduction in mobilization capacity. The percentage of adequate CD34+ cell mobilizations and collections in our study was comparable to that in the HIV-negative population, with 80% success, even in patients heavily pretreated with intensive CT. Moreover, in no patient was HDT precluded because of progression of HIV disease. The preliminary clinical results of our study are promising both in terms of remission rate and remission duration. They confirm on a multi-institutional basis the results obtained in pilot, single-center studies and compare favorably with the results obtained with conventional-dose second-line CT in this setting.8–11 Additional studies and longer follow-up are needed to confirm these data. Given the low toxicity of the procedure, we believe that HIV status alone should no longer preclude an aggressive approach in the treatment strategy of a patient with lymphoma. In this context, because a subset of patients with HIV-Ly have a poor outcome with standard-dose, first-line CT, and because a reliable prognostic index7,21 that can predict CR and disease-free survival has been recently developed, it may be worth exploring the use of HDT and PBSCT earlier in the history of these patients, as advocated in the HIV-negative setting.
The authors indicated no potential conflicts of interest.
Supported by Instituto Superiore di Sanita and Associazione Italiana per la Ricerca sul Cancero funds.
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9. Levine AM, Tulpule A, Tessman D, et al: Mitoguazone therapy in patients with refractory or relapsed AIDS-related lymphoma: Results from a multicenter phase II trial. J Clin Oncol 15:1094–1103, 1997 10. 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[CrossRef][Medline] 11. Bi J, Espina BM, Tulpule A, et al: High-dose cytosine-arabinoside and cisplatin regimens as salvage therapy for refractory or relapsed AIDS-related non-Hodgkin’s lymphoma. J Acquir Immune Defic Syndr 28:416–421, 2001[Medline]
12. Philip T, Giglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333:1540–1545, 1995 13. Linch DC, Winfield D, Goldstone AH, et al: Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease. Lancet 341:1051–1054, 1993[CrossRef][Medline] 14. Gabarre J, Azar N, Autran B, et al: High-dose therapy and autologous haematopoietic stem-cell transplantation for HIV-1-associated lymphoma. Lancet 355:1071–1072, 2000[CrossRef][Medline]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
