Treatment of human immunodeficiency virus-related lymphoma with haematopoietic stem cell transplantation

SCT for HIV-related lymphoma

Treatment of human immunodeficiency virus-related lymphoma with haematopoietic stem cell transplantation Arturo Molina, John Zaia, Amrita Krishnan Division of Hematology and Bone Marrow Transplantation and Department of Virology, City of Hope National Medical Center, Duarte, CA, USA

Abstract The advent of highly active antiretroviral therapy (HAART) and its co-administration with chemotherapy in patients with human immunodeficiency virus (HIV)-related lymphoma has lead to the exploration of potentially curative combination chemotherapy and myeloablative therapy followed by autologous haematopoietic stem cell transplantation (ASCT). Applying the same principles used for patients with HIV-negative aggressive lymphoma, in 1998 we developed a program of high-dose therapy and ASCT at City of Hope for patients with HIV-related lymphoma and Hodgkin’s disease. Our studies have primarily included patients with chemosensitive lymphoma in relapse or first remission with poor-risk features at diagnosis. Filgrastim (G-CSF) -primed peripheral blood stem cell mobilization and apheresis have been successful while patients were receiving HAART and chemotherapy. To date, ASCT has been performed in 19 patients with HIV-related lymphoid malignancies, representing the largest single-institution experience reported to date. Most patients received a chemotherapy-based conditioning regimen consisting of high-dose carmustine, etoposide and cyclophosphamide. Early infections, namely bacteremias and neutropenic fever were similar to those observed in the HIV-negative transplant setting. Opportunistic infections were rare and easily treatable. There were three early deaths, two from relapsed lymphoma and one from multi-organ failure in an older patient. The remaining 16 patients are alive and in remission. In summary, ASCT is well tolerated, can result in long-term remissions, and is potentially curative in selected HIV-related lymphoma patients with chemosensitive relapse and high-risk disease in first remission defined by the age-adjusted International Prognostic Index criteria (i.e., two or three of the following: elevated LDH, advanced stage, and poor performance status). Acquisition of resistance to HAART remains as a potential problem for HIV-positive patients who are cured of their lymphoma.
c 2003 Elsevier Ltd. All rights reserved. KEY WORDS: lymphoma; Hodgkin’s disease; HIV; haematopoietic stem cell transplantation; highly active antiretroviral therapy (HAART)

INTRODUCTION

A

ggressive non-Hodgkin’s lymphoma (NHL) has been recognized as an acquired immune deficiency syndrome (AIDS)-defining condition since 1985.1 Early

in the AIDS epidemic, patients with HIV infection were found to have an extraordinarily increased risk of Kaposi’s sarcoma and B-cell NHL.2 The majority of patients with HIV-related lymphoma present with systemic symptoms, advanced stage disease and extranodal sites of involvement including the central nervous system and bone marrow.3–7 Hodgkin’s disease is the most common non-AIDS defining malignancy in HIV patients.8–13 In the setting of HIV infection, HD also presents with advanced stages and unique sites of extranodal dissemination. Historically, before the development of combination antiretroviral therapy, the treatment of HIV-related NHL and HD had been hampered by the high risk of opportunistic infections and cytopenias associated with combination chemotherapy. Early efforts to eradicate these malignancies focused on reduced-dose approaches to try to decrease the toxicity of treatment.14 Results of treatment with less intensive therapy were similar to results obtained with conventional dose regimens and were associated with less hematologic toxicity. Nonetheless, the outcome of reduced and standard dose chemotherapeutic approaches has been poor, resulting in median survival rates of 7–18 months.14–19 For HIV patients with relapsed lymphoma, the prognosis has also been even more dismal. Recent publications still report poor survival rates of 3–7 months with the use of conventional salvage chemotherapy regimens.20–23 Generally, the curability of HIV-associated lymphoid malignancies, particularly in patients with relapsed disease, is not discussed in the medical literature. The development of effective antiretroviral agent combinations in 1996, referred to as highly active antiretroviral therapy (HAART), has resulted in a reduced incidence of opportunistic infections, Kaposi’s sarcoma, increased CD4 counts and improved survival.2;24;25 Many studies have assessed the impact of HAART on the incidence and outcome of NHL and HD and conflicting results have been reported.26–40 Some studies suggest that there is a statistically significant decrease in the incidence of most types of lymphomas in individuals with HIV infection, particularly primary central nervous system lymphoma and small noncleaved type of systemic lymphoma26–33 whereas other reports have shown no difference in the incidence of NHL and HD in this setting.34–38 As the frequency of AIDS-defining conditions such as Kaposi’s sarcoma, pneumocystis carinii pneumonia (PCP), mycobacterium avium complex (MAC) and cytomegalovirus (CMV) has declined with the advent of HAART, lymphoma may constitute a higher percentage of AIDS-defining diagnoses in the future. Some epidemiologic investigations suggest that in the era of HAART, HIV-associated NHL is now seen in individuals with higher CD4 counts and without prior history of opportunistic infections.30 As the proportion of new AIDS cases due to opportunisitic infections has declined, the proportion of new AIDS cases due to lymphoma has increased.29 However, as HAART prolongs survival in AIDS, there are contradictory findings which show decreased median CD4 counts at the time of lymphoma diagnosis, indicating that HIV-related lymphoma is still a late manifestation of the disease.40 The discrepancies between these studies may be related to accessibility and compliance with HAART, persistence of immunologic defects despite the


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Molina et al. use of HAART, and timing of the study, with the more recent studies suggesting a decrease in the overall incidence of all HIV-related malignancies. Other questions remain in regards to the impact of HAART on the natural history and curative potential of HIV-associated lymphoid malignancies. Does the concomitant use of HAART affect the ability to deliver full or intensified doses of chemotherapy or does it improve the survival? As will be discussed below, recent studies indicate that HAART can be administered along with standard and intensified chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and Stanford V (mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone), respectively, without an increase in hematologic toxicity or opportunistic infections.41–45 By preserving immune parameters during chemotherapy, HAART might ultimately improve survival of patients with HIV lymphoma undergoing standard chemotherapy.46;47 Unfortunately, these combinations of chemotherapy and HAART are still associated with lower remission and survival rates compared to similar lymphoma patients without HIV infection.41–45 To improve the outcome of patients with HIV-related lymphoid malignancies, in 1998 we initiated an active program of high-dose myeloablative therapy and autologous tem cell transplantation (ASCT) at City of Hope National Medical Center (COHNMC) for this patient population.48;49 Gabarre et al.50 reported the first treatment of AIDS lymphoma using ASCT, and soon thereafter, the development of our program coincided with the introduction of HAART and consequent ability to better control the HIV infection in these patients. Our ASCT program paralleled the exploration and development of transplant programs at other centers, including solid organ transplantation as well as syngeneic and allogeneic stem cell transplantation.50–56 Herein, we review our rationale and approach for using ASCT in patients with HIV-related lymphoma and address some future research directions in this area.

BACKGROUND Concomitant chemotherapy and HAART Because of the improved immune function and hematologic reserve associated with the use of HAART, the oncology community has recently shown more enthusiasm for the use of standard and intensified dose chemotherapy regimens such as CHOP, ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and Stanford V as well as infusional regimens such as CDE (cyclophosphamide, doxorubicin, etoposide) plus rituximab and EPOCH (etoposide, prednisone, vincristine, doxorubicin, cyclophosphamide) in patients with HIVrelated lymphoma.41–45;57–61 Most of these studies have not shown an increased incidence of toxicity and side effects in patients receiving combination chemotherapy and HAART. Concern has been raised regarding potential overlapping side effects or interactions between HAART and specific chemotherapeutic agents. Two small studies have suggested the possibility of a higher risk of mucositis and neurotoxicity.41 Of note, some of the antiretroviral agents such as didanosine, 250

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zalcitabine, and stavudine may be associated with neurotoxicity. Overall, most studies suggest that HAART regimens containing these antiretroviral agents can be co-administered with standard chemotherapy combinations. Currently, HAART regimens that are combined with chemotherapy usually avoid the use of zidovudine (AZT), which by itself is associated with profound myelosuppression, but sometimes includes lamivudine, which also is potentially myelotoxic. The EPOCH regimen developed and tested at the National Cancer Institute suspends the use of HAART in patients with HIVassociated NHL during the administration of chemotherapy.59;61 Despite an increase in the viral load and drop in the CD4 counts during EPOCH therapy, a return to baseline was observed after the completion of chemotherapy and resumption of HAART, without any deleterious effect on the natural history of the underlying HIV infection.59 Concerns about stem cell transplantation Few research centers have attempted the use of high-dose chemotherapy or radiochemotherapy and ASCT with curative intent in patients with HIV-related NHL and HD.48;49;53;54;56 Early in course of the HIV epidemic, the major obstacles were the high mortality rate from opportunistic infection along with poor tolerability and low remission rates with combination chemotherapy. With the use of antiretroviral monotherapy, usually AZT or didanosine, the control of HIV infection and immune function remained poor. Moreover, studies demonstrated reduced mobilization of CD34+ cells in patients with poorly controlled HIV infection, raising concerns about the feasibility of procuring stem cells in this group of patients.62–64 In the era of AZT, the bone marrow toxicity of this agent precluded the successful mobilization and collection of autologous haematopoietic stem cells. Effect of HAART on hematologic function HAART appears to favorably impact hematologic reserve in patients with HIV infection with improvement of white blood cell (WBC) and platelet counts as viral loads decline.63;65 Although response rates of HIV-related lymphoma remain similar, chemotherapy regimens combined with HAART are associated with an improved survival rate compared with identical chemotherapy regimens combined with antiretroviral monotherapy.66;67 Based on this observation, HAART is now combined with most front-line and salvage regimens for HIV-related lymphoma.41–45;57;58 This clinical practice has paved the way for studies of high-dose myeloablative chemotherapy or radiochemotherapy in the treatment of HIV-related lymphoma.

CITY OF HOPE EXPERIENCE WITH ASCT Eligibility criteria At COHNMC we have developed an active ASCT program for the treatment of HIV-related lymphoma.48;49 Between March 1998 through May 2002, we performed ASCT in 19 patients.68–70 The eligibility criteria for consideration of ASCT in patients with HIV-related lymphoma has been similar to the criteria required for HIV-negative patients with diffuse aggressive lymphoma and Hodgkin’s disease. Namely, patients

SCT for HIV-related lymphoma were required to have normal renal, hepatic, pulmonary and cardiac function prior starting the ASCT process as assessed with a 24 h urine collection for creatinine clearance, comprehensive metabolic panel, pulmonary function tests and echocardiogram or MUGA scan. Evidence of chemosensitive disease was criteria for ASCT at the time of screening, although two patients with regrowth of their lymphoma immediately prior to ASCT were allowed to proceed on this study. All patients were required to receive concomitant HAART along with front-line or salvage chemotherapy for their lymphoma. Patients had to be free of opportunistic infections for one year (excluding oral thrush) prior to transplant evaluation. For the first five patients we required a CD4 count of >100/lL but subsequently eliminated that requirement. Good control of HIV infection as determined by a viral load <10,000 gc/ml was required at the time of screening.

13 of the first 15 patients, the median HIV viral load was 400 genome copies/mL (range undetectable to 320,000) and unknown in two patients during apheresis. In our initial analysis, the histologic subtypes were diffuse aggressive NHL (n ¼ 13) or HD (n ¼ 2). Most of the patients had chemosensitive disease, although two of the NHL patients had refractory or poorly controlled disease. Three patients transplanted in first remission had high-intermediate and high-risk features by International Prognostic Index (IPI) criteria71 defined by the presence of 2 or 3 of the following variables (elevated LDH, stage II or IV disease, compromised performance status); 5 patients were in first partial remission; 4 patients were in first relapse, including 2 with refractory disease (1 patient had Burkitt’s leukemia; 1 patient had CD30+ anaplastic large cell lymphoma); 2 were in second remission, and one was in third remission.

Demographics We have recently reported our analysis of the first 15 patients (male ¼ 14; female ¼ 1) transplanted at our COHNMC program between March 1998 and May 2001.68;69 Table 1 lists some of the demographic information and survival information of these 15 patients. The median age at transplantation was 43 years (range, 11–68). The median CD4 count at lymphoma diagnosis was 174/lL (range 30–500) in 11 patients and unknown in 4 patients. The median HIV viral load at lymphoma diagnosis and 7334 genome copies/mL (range undetectable – 1,300,000) in 9 patients and unknown in 6 patients. The median number of prior chemotherapy regimens was 2 (range 1–4). HIV infection was fairly well controlled in most patients at the time of stem cell collection. In

Stem cell mobilization Prior to initiating our ASCT program for HIV-related lymphoma, we conducted studies to establish the hematopoietic potential of selected CD34+ progenitor cells and demonstrated that functional granulocyte colony stimulating factor (G-CSF)-mobilized stem cells could be procured from asymptomatic HIV-positive individuals, some of whom were receiving antiretroviral therapy.72;73 For patients with HIV-associated lymphoma, we used the last cycle of salvage or induction chemotherapy as the mobilizing regimen along with filgrastim (G-CSF) at a dose of 10 lg/kg per for peripheral blood stem cell (PBSC) mobilization as previously described.48;74 Because of concern over potential, deleterious hematologic effects, we routinely

Table 1 Demographics and status of 15 HIV-lymphoma patients undergoing ASCT UPN 202 203 204 208 209 400 405 406 407 408 409 410 411 412 413

Diagnosis NHL HD NHL NHL HD NHL NHL NHL NHL NHL NHL NHL NHL NHL NHL

Disease status

HAART

Prior chemotherapy

Status

1st REL 1st REL 1st PR 1st CR 1st REL 2nd CR 1st PR 1st CR 3rd CR 1st CR 1st PR 1st PR 1st REL 1st PR 1st REL

Nf, L, S I, L, S Nf, L, S Nf, Nv, S I, L Nf, Nv, L I, L, S R, S, Nv, Sa E, L, S R, S, Sa L, A, Nf L, E, Sa S, E, Nf S, E, L L, E, S

CHOP CHOP, Ifos/VP16, ESHAP CHOP, ESHAP CHOP, ESHAP BOSE, ABVD, ESHAP POG-8617, -9517, and -9317 CHOP, ESHAP, RTX CHOP CHOP, Ifos/VP16, RTX, ESHAP CHOP CHOP, ESHAP M-BACOD, RTX, ESHAP CHOP, ESHAP/RTX CAV, AraC/MTX, CODOX-M CHOP, ESHAP, RTX

CR; 44 mo CR; 38 mo Relapse/death 4 mo CR; 32 mo CR; 33 mo Relapse/death 4 mo CR; 43 mo CR; 55 mo CR; 37 mo CR; 24 mo Death day 22 CR;26 mo CR; 27 mo CR 17 mo CR 20 mo

Abbreviations: CR, complete response (remission); E, efavirenz; I, indinavir; Ifos/VP16, ifosfamide/etoposide; L, lamivudine; Nf, nelfinavir; Nv, nevirapine; R, ritonavir; RTX, rituxan; Sa, saquinavir; S, stavudine; CHOP, cyclophosphamide, adriamycin, vincristine, prednisone; ESHAP, etoposide, cytarabine, cisplatinum, prednisone; BOSE, bleomycin, oncovin, streptozocin, etoposide; ABVD, adriamycin, bleomycin, vincristine/vinblastine, dacarbazine; POG8617, cyclophosphamide, adriamycin, cytarabine; POG9517, same plus methotrexate, Ifos, VP16; POG9317, Ifos, VP16, methotrexate, cytoarabine. CAV, cyclophosphamide 400 mg, vincristine 2 mg, adriamycin 40–60 mg. AraC/Mtx, cytarabine, methotrexate. CODOX-M, cyclophosphamide, vincristine, adriamycin, methotrexate M; BACOD, methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, cytarabine, dexamethasone. (a) All subjects received autologous stem cell transplant after cyclophosphamide, BCNU, VP16 (etoposide) (CBV); status at 2-18-02 except UPN 410 received FTBI 1200 cgy, VP16 (etoposide), cyclophosphamide.


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Molina et al. discontinue trimethoprim–sulfamethoxazole (TMP–SMX) during G-CSF priming and PBSC collections. Apheresis is initiated upon recovery from the last chemotherapy when the white blood cell count (WBC) reaches a level of 1000/lL and is continued until the target dose of cells were collected, usually a minimum of 2–5  106 /kg CD34+ cells. In the first 16 patients transplanted at City of Hope, a nonAZT-containing HAART regimen was used during chemotherapy and apheresis and all patients collected adequate numbers of CD34+ haematopoietic progenitor cells. The subsequent three patients received AZT as part of their HAART regimen. Because we experienced significant difficulty in the mobilization of stem cells and engraftment in the 17th patient who had received an AZT-containing HAART regimen, we now recommend that AZT be discontinued during stem cell mobilization and collection and during the posttransplant period (Molina et al., unpublished observations). Conditioning regimen and stem cell reinfusion Most patients (n ¼ 16) have received a myeolablative regimen of carmustine (BCNU) 450 mg/m2 given on split dose over 3 consecutive days on Day )7 to Day )5, etoposide (VP16) 60 mg/kg on Day )4, and cyclophosphamide 100 mg/kg on Day )2. Three patients have received fractionated total body irradiation (FTBI) to total dose of 1200 cGy given on Day )8 to Day )5, etoposide 60 mg/kg on Day )4 and cyclophosphamide 60 mg/kg on Day )2. The doses of etoposide and cyclophosphamide are calculated by using adjusted actual body weight and ideal body weight, respectively. On Day 0, the cryopreserved mobilized PBSC are reinfused. Both of these transplant conditioning regimens have been used at City of Hope for more than 12 years for the treatment of patients with HIV-negative relapsed and poor-risk NHL and HD.74–77 Gabarre et al.54;78 also have also reported the successful use of an FTBI-containing regimen for ASCT in HIVrelated lymphoma. Supportive care Standard supportive care interventions have been reported previously by our transplant team.48;74–76 Patients are housed in high-efficiency particulate air-filtered rooms during the period of neutropenia. Levofloxacin is used starting on Day )9 for antibacterial prophylaxis. Intravenous TMP–SMX is administered from Day )9 to Day )2 and reinstituted by oral route at the time of discharge if the blood counts have normalized. Anti-herpes simplex prophylaxis is started on Day )1, acyclovir 250 mg/m2 every 12 h, and continued until recovery from neutropenia and resolution of mucositis. All patients receive G-CSF 5 lg/kg starting on Day +1 or Day +5 and continue until the absolute neutrophil count is greater than 1000/lL for 3 consecutive days. Empiric broad spectrum intravenous antibiotics and total parental nutrition are given as clinically indicated. Low-dose amphotericin-B (0.1– 0.2 mg/kg) or fluconazole 200 mg is administered starting on Day +1 and is continued until the time of discharge. Platelet transfusions are given to maintain the platelet count at >20,000/lL. Packed red blood cell (PRBC) transfusions are administered to keep the hemoglobin level above 8.0 gm/dL. All platelet and PRBC products are leukodepleted by filtration and irradiated with 2500 centigrays prior to transfusion to 252

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prevent alloimmunization. Heparin at a dose of 100 U/kg daily by 24 h continuous infusion was given for prophylaxis against veno-occlusive disease of admission to the time of engraftment.79 We attempted to continue HARRT during the peri-transplant but 10 of the first 15 patients were unable to tolerate it due to nausea or mucositis. HAART was resumed when patients were able to tolerate oral intake of medications or upon recovery of mucositis.

Transplant-related toxicities and engraftment All patients develop pancytopenia requiring the administration of blood products according to parameters listed above. Similarly, most patients develop febrile neutropenia and require treatment with additional broad spectrum antibiotics such as cefazolin and ceftazidime. In the first 15 patients, we observed 4 gram-positive bacteremias requiring treatment with vancomycin. Opportunistic infections in this group were rare and occurred 1–3 months after ASCT. These included CMV viremia in 2 patients, CMV retinitis in one patient, PCP pneumonia in one patient who stopped prophylaxis, and disseminated herpes zoster in one patient.68;69 All opportunistic infections were successfully treated. We now routinely use acyclovir prophylaxis for one year post-ASCT in these patients. One patient developed grade 3 gastrointestinal toxicity of unclear etiology requiring intensive care monitoring, but completely recovered from this adverse event. No significant neurotoxicity was seen in any patients. One patient who was 68 years old died early from transplant-related complications including grade 4 hepatic toxicity that evolved into multi-system organ failure.68;69 Severe mucositis was seen primarily in patients receiving FTBI, which is an expected complication with this conditioning regimen. We have analyzed the engraftment data in the first 15 patients. The median time to reach an absolute neutrophil count of greater than 500/lL was 11 days (range 9–13).68;69 The median time to reach a platelet count of greater than 20,000/lL without any additional platelet transfusions was 15 days (range 7–25). These results are similar to the patterns of engraftment seen in HIV-negative patients undergoing ASCT for lymphoma and Hodgkin’s disease.74–77 Subsequently, four additional patients underwent ASCT in 2002. Three of these patients received an AZT-containing HAART regimen during chemotherapy and two during stem cell collections. It is our impression that the concomitant use of AZT in this setting resulted in impaired stem cell mobilization and possibly slower engraftment (A. Molina et al., unpublished observations). One of these patients (patient 17) also continued his AZT-containing HAART regimen after the transplant. This patient developed a CNS relapse with leptomeningeal disease requiring intrathecal chemotherapy after the stem cell reinfusion. His post-transplant course was complicated by a severe delay in hematopoietic recovery, despite cytokine support and discontinuation of his antiviral medications. As a result of delayed engraftment, this patient suffered other complications during a prolonged hospitalization, including subdural hematomas requiring neurosurgical drainage and prolonged duration of platelet transfusions. Despite these complications, the patient recovered and

SCT for HIV-related lymphoma remains in systemic and CNS remission 11 months after transplant (A. Molina et al., unpublished observations). Outcome after transplantation In our analysis of the first 15 patients undergoing ASCT for with HIV-associated lymphoma at COHNMC, 12 patients remain alive with a median follow-up of 24 months (range 16–54).69 Table 1 includes information about the current disease status of these 15 patients. There were three early deaths, one from transplant-related complications and two from early relapse of lymphoma. The two relapses were in patients who had poor control of their lymphoma (i.e., Burkitt’s leukemia and CD30+ anaplastic lymphoma) prior to ASCT. The 2-year probability of overall survival (OS) and event-free survival (EFS) is 79% (95% confidence interval, 58–100%) and 79% (95% confidence interval, 58–100%), respectively.68;69 Fig. 1 shows a Kaplan– Meier plot of OS in the first 15 patients transplanted at COHNMC. All of the surviving patients are receiving HAART and most have their HIV infection under control. At six months post-transplant the median CD4 count was 176/lL (range 13–411) and HIV viral load was 50 genome copies/mL (range undetectable – 500,000). As described above, four additional patients with HIV-related lymphoma have undergone transplantation in 2002 (A. Molina et al., unpublished observations). One of them was in first remission, one was in second remission, one was in second relapse. Another patient who was initially considered to be in second remission developed central nervous system progression with leptomeningeal disease during the high-dose chemotherapy conditioning regimen. He achieved a third remission after the transplant and with additional intrathecal therapy. These four additional patients remain alive and in remission at 14–16 months after transplantation.70 FUTURE DIRECTIONS Gene therapy Because hematopoietic stem cells are intrinsically resistant to infection by HIV, these cells are attractive targets for the use of gene therapy.64;80 In a companion study performed at

Fig. 1

Overall survival after ASCT for HIV-related lymphoma.69

City of Hope, five patients undergoing ASCT for HIV-related lymphoma have received a combination of unmanipulated CD34+ stem cells and genetically modified, positively selected, CD34+ cells transduced with retrovirus vectors encoding either hammerhead ribozymes targeted to HIV tat and rev or neomycin phosphotransferase genes.80 HSCbased gene transfer research requires marrow ablation and, as such, cannot ethically be easily applied to many segments of the community of potential research subjects, whether HIV-infected patients or persons with in-born genetic diseases. We initially piloted the AIDS lymphoma treatment program, in part, to determine if this group could benefit from therapy that was being offered with success to the non-HIV patients with lymphoma. With the initial 5 subjects treated with a retrovirus-modified autologous transplant, the full potential of this model for gene transfer research has become apparent. The treatment of the patient with poor risk AIDS lymphoma has become the platform from which newer vectors can be evaluated. In the future, the first experiences with new vectors can be made in this model system in which marrow ablation is provided for therapeutic reasons. This is an extreme situation, but if a vector cannot deliver its transgene in this setting, it is likely to fail in any other setting. Thus, the impact of this model is that it provides a method to quickly determine the potential utility of a new vector. Based on this model for stem cell gene therapy, future clinical trials at COHNMC will evaluate different vectors aimed at producing a more durable engraftment with genetically modified stem cells capable of conferring an HIV-resistant phenotype to hematopoietic stem cell progeny.64;68;80 Non-myeloabalative allogeneic stem cell transplantation A clinical protocol at the National Institutes of Health was developed for the use of non-myeloablative allogeneic transplantation for treatment of patients with refractory hematologic malignancies and concomitant HIV infection.81 Two patients were recently reported, one with acute myelogeous leukemia and another with Hodgkin’s disease. One patient received genetically modified stem cells from a sibling donor and the other received unmodified donor PBSC. Both patients tolerated the procedure well, but one patient died of relapsed Hodgkin’s disease 12 months after transplantation. Two years after transplantation, the surviving patient remains in remission with undetectable HIV levels, rising CD4 counts, and with both the therapeutic and control gene transfer vectors detectable at low levels, while receiving concomitant HAART. These results suggest an alternative approach to the treatment of HIV-related lymphoma in patients with HLA-matched sibling donors. Of note, both patients developed graft-versus-host disease (GVHD) requiring prednisone therapy in addition to cyclosporin which was used for GVHD prophylaxis.81 Similarly, both patients developed CMV antigenemia requiring antiviral therapy. Novel conditioning regimens Since lymphomas and Hodgkin’s disease are exquisitely sensitive to radiation, FTBI has been routinely employed as part


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Molina et al. of myeloablative regimens in HIV-negative patients. However, in our current transplant studies, we have been reluctant to use FTBI for most patients because of concerns over the potential toxicities of the conditioning regimens. Only 3 of the 19 patients transplanted at COHNMC have received FTBI. These 3 patients were thought to be relatively chemotherapy resistant or at very high risk of relapse even with the transplant. Recently, radioimmunotherapy (RIT) has been developed as an active agent for the treatment of indolent and histologically transformed B-cell lymphomas. Ibritumomab tiuxetan (Zevalin) is an yttrium-90 (90 Y) conjugated monoclonal antibody that was recently approved in the United States for treatment of relapsed or refractory low grade B-cell lymphoma, including low grade follicular lymphoma refractory to rituximab. In an attempt to reduce toxicity associated with FTBI and to incorporate targeted radiation using RIT, we are conducting a phase I/II using trial high-dose ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by ASCT in patients with poor-risk or relapsed B-cell NHL.82 So far, 18 patients with HIV-negative lymphoma have undergone ASCT using this novel myeloablative conditioning regimen. All patients have engrafted. Although the median follow-up is only 8 months, 92% (17 patients) are alive and in remission. We have demonstrated that high-dose ibritumomab tiuxetan can be given safely in combination with high-dose etoposide and cyclophosphamide followed by

PBSC support without increasing toxicity or delaying engraftment.82 Our initial favorable experience with ASCT for HIV-related lymphomas and high-dose ibritumomab tiuxetan/chemotherapy for HIV-negative lymphoma open the possibility of exploring the use of more effective and less toxic myeloablative regimens for the treatment of HIV-related lymphoproliferative disorders. Similarly, other efforts to decrease the risk of relapse such as post-ASCT rituximab can be incorporated into the current transplant strategies for HIV-related lymphoma.83 Resistance to HAART We believe that ASCT is potentially curative in select patients with HIV-related lymphoma and that HIV infection should not preclude the use of ASCT in this population. In surviving patients, long-term risks seem to be related primarily to the HIV infection, and the potential for developing resistance HAART. As shown in Fig. 2, the first HIV-lymphoma patient in our series illustrates the natural history of HIV after the cure of his lymphoma. When he was diagnosed with lymphoma as his AIDS-defining diagnosis in June 1997, he had an HIV viral load of >1,323,000 genome copies/mL (data not shown). The first CD4 count was obtained after the second cycle of CHOP was markedly reduced ar 32/lL. With HAART and chemotherapy, the HIV viral load promptly dropped to 11,600 genome copies/mL after the third cycle of chemotherapy and became undetectable after the completion of 5 cycles of CHOP. The

Fig. 2 Measurement of HIV viral load and CD4+ T-cells shows development of virological failure occurring 42 months after ASCT in a patient (UPN 406) with HIV related lymphoma.

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SCT for HIV-related lymphoma CD4 counts improved while receiving HAART and CHOP, decreased after ASCT, but have then improved with ongoing follow-up. Because of non-compliance, the viral load increased in May 2001, but again became transiently undetectable by November 2001 after adhering to his HAART regimen. By February 2002, he demonstrated virologic failure and the HIV viral load increased to 180,000 genome copies/mL. HIV genotyping showed that he was resistant to several of the drugs in his HAART regimen. He was then switched to a new antiretroviral regimen containing AZT. By July 2002, the viral load has decreased to 4000 genome copies/mL and there was no significant change in the CD4 counts.

DISCUSSION Highly active antiretroviral therapy has improved the survival of HIV-positive individuals, but there is still an ongoing risk of developing diffuse aggressive lymphoma and Hodgkin’s disease. Even though recent studies suggest that there is a decreasing incidence of malignancies following the development of HAART, HIV-infected individuals still have a markedly increased relative risk of developing diffuse aggressive B-cell lymphoma, Hodgkin’s disease, low grade lymphoma and Tcell lymphoma compared to the normal population.64;84 As the incidence of opportunistic infections and Kaposi’s sarcoma continues to decrease, NHL is becoming the most common AIDS-defining diagnosis in HIV-infected persons.29 Survival of HIV-related lymphoma also appears to be improving after the introduction of HAART.66;67 Instead of treating HIV-lymphoma patients with attenuated doses of chemotherapy, the introduction of HAART has allowed the medical community to treat patients with standard or intensified regimens, which are used in the HIV-negative setting. In general, HAART can be administered concomitantly with multiple chemotherapy regimens without a significant increase in side effects. Despite these improvements, relapse of lymphoma remains a vexing problem. Moreover, treatment results of concomitant HAART and chemotherapy for HIV lymphoma are still inferior to results seen in HIV-negative patients. In HIV-negative lymphoma, high-dose therapy and ASCT are routinely employed for the treatment of relapsed disease and first remission patients with poor-risk features at presentation.74–76;15–88 Because of concern over the potential toxicities associated with ASCT, this modality has not been routinely offered to patients with HIV-related lymphoma. There is limited published experience describing the use of ASCT in HIV-related lymphoma, with most reports originating from COHNMC and the French group led by Gabarre et al.48–50;54;68–70 In their most recent update, the French investigators reported results on 14 patients with HIV-related lymphoma, 13 of whom were receiving concomitant HAART.78 Although they have also demonstrated that ASCT is feasible, eight of the patients in their cohort have died, primarily from relapsed lymphoma. The patients in their study had more advanced disease at the time of transplant, suggesting that ASCT should be offered earlier in the course of poor-risk aggressive HIV-related NHL and HD. The COHMNC studies have included primarily patients with relapsed chemosensitive disease, although three patients in first remission

with poor-risk features by IPI criteria (i.e., elevated LDH, advanced stage, poor-performance status) and two patients with refractory disease were also treated. In our analysis of the first 15 patients, 12 are alive, with remissions lasting between 17 and 56 months. Four additional patients transplanted in 2002 are alive and in remission at the time of this report. In summary, ASCT is feasible and potentially curative in patients with HIV-related lymphoma. Stem cells can be mobilized and collected while patients are receiving HAART and chemotherapy. AZT-containing regimens should be avoided to prevent delayed engraftment. HIV resistance to HAART remains as a potential future problem. Close surveillance and effective treatment of HIV infection is necessary in long-term transplant survivors. ASCT for HIV lymphoma provides a model for further exploration of gene therapy, which may be one of the ways to address the problem of resistance to HAART.

Practice points •

With the use of HAART, the prognosis of HIV-related lymphoma is improving and patients can usually tolerate standard doses of chemotherapy.

•

Clinicians should focus on the potential cure of the lymphoma and consider the HIV infection to be a chronic condition treatable by HAART.

•

Stem mobilization is feasible and adequate numbers of stem cells can be collected for ASCT in patients receiving HAART and chemotherapy.

•

Sustained engraftment can be seen after ASCT for HIV-related lymphoma.

•

ASCT is potentially curative in HIV-related lymphoma patients with chemosensitive relapse and poor-risk disease in first remission.

Research agenda •

The era of AIDS lymphoma therapy with ASCT is young and many aspects of this remained incompletely explored. While early reports provide the first answers, the following questions remain:

•

Does the use of HAART during and after chemotherapy prolong the remission duration of lymphoma?

•

Will acquired resistance to HAART lead to an increased incidence of HIV-related lymphoma?

•

Should all patients with relapsed HIV-related lymphoma be offered ASCT as second-line therapy?

•

Should ASCT be used for poor-risk HIV-related lymphoma in first remission as defined by International Index criteria?

•

What is the role of gene therapy in ASCT for HIV-related lymphoma?

Correspondence to: Arturo Molina, MD MS FACP, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, USA. Tel.: +1-626-301-8974; Fax: +1-626-301-8973; E-mail: [email protected].


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Blood Reviews (2003) 17, 249–258

255

Molina et al. References 1. Centers for Disease Control. Revision of the case definition of acquired immunodeficiency syndrome for national reporting-United States. MMWR 1985; 34:373–375. 2. Goedert J. Epidemiology of acquired immune deficiency syndrome malignancies. Sem Oncol 2000; 27: 390–401. 3. Levine AM. Acquired immune deficiency syndromerelated lymphoma: clinical aspects. Sem Oncol 2000; 27: 442–453. 4. Tulpule A, Levine A. AIDS-related lymphoma. Blood Rev 1999; 13(3): 147–150. 5. Gates AE, Kaplan LD. AIDS malignancies in the era of highly-active antiretroviral therapy (first of two parts). Oncology 2002; 16: 441–451, see also pp. 456, 459. 6. Desai J, Mitnick RJ, Henry DH, Llena J, Sparano JA. Patterns of central nervous system recurrence in patients with systemic human immunodeficiency virus-associated non-Hodgkin lymphoma. Cancer 1999; 86: 1840–1847. 7. Seneviratne L, Espina BM, Nathwani BN, Chan JA, Brynes RK, Levine AM. Clinical, immunologic, and pathologic correlates of bone marrow involvement in 291 patients with acquired immunodeficiency syndrome-related lymphoma. Blood 2001; 98: 2358–2363. 8. Molina A. Is Hodgkin’s disease an AIDS-associated disease? (Commentary). Oncology 1987; 1(8): 52. 9. Hessol NA, Katz MH, Liu JY et al. Increased incidence of Hodgkin’s disease in homosexual men with HIV infection. Ann Intern Med 1992; 117: 309–311. 10. Tirelli U, Errante D, Dolcetti R et al. Hodgkin’s disease and human immunodeficiency virus infection: clinicopathologic and virologic features off 114 patients from the Italian Cooperative Group on AIDS and tumors. J Clin Oncol 1995; 13: 1758–1767. 11. Levine AM. Hodgkin’s disease in the setting of human immunodeficiency virus infection. J Natl Cancer Inst 1998; 23: 37–42. 12. Spina M, Vaccher E, Nasti G et al. Human immunodeficiency virus-associated Hodgin’s disease. Sem Oncol 2000; 27: 480–488. 13. Gates AE, Kaplan LD. AIDS malignancies in the era of highly-active antiretroviral therapy (second of two parts). Oncology 2002; 16: 657–665, discussion 669–670. 14. Kaplan LD, Straus DJ, Testa MA et al. Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin’s lymphoma associated with human immunodeficiency virus infection. N Engl J Med 1997; 336: 1641–1648. 15. Remick SC, Sedransk H, Haase RF et al. Oral combination chemotherapy in conjunction with filgrastim (G-CSF) in the treatment of AIDS-related non-Hodgkin’s lymphoma: evaluation of the role of G-CSF; quality-of-life analysis and long-term follow-up. Am J Hematol 2001; 66: 178–188. 16. Oksenhendler E, Gerard L, Dubreuil ML et al. Intensive chemotherapy (LNHIV-91 regimen) and G-CSF for HIV associated non-Hodgkin’s lymphoma. Leukemia Lymphoma 2000; 39: 87–95. 17. Bower M, Stern S, Fife K, Nelson M, Gazzard BG. Weekly alternating combination chemotherapy for good prognosis AIDS-related lymphoma. Eur J Cancer 2000; 36: 363–367. 18. Wiernik PH. Treatment of human immunodeficiency virus-related lymphoma. Sem Hematol 2001; 38(Suppl 10): 27–31.

256

Blood Reviews (2003) 17, 249–258


c 2003 Elsevier Ltd. All rights reserved.

19. Remick SC, Sedransk H, Haase RF et al. Oral combination chemotherapy in the management of AIDS-related lymphoproliferative malignancies. Drugs 1999; 58(Suppl 3): 99–107. 20. Tirelli U, Errante D, Spina M et al. Second-line chemotherapy in HIV-related non-Hodgkin’s lymphoma. Cancer 1996; 77: 2127–2131. 21. Levine A, Tupule A, Tessmman D et al. Mitoguazone therapy in patients with relapsed or refractory AIDS-related lymphoma: results from a multicenter phase II trial. J Clin Oncol 1997; 15: 1094–1103. 22. Spina M, Vaccher E, Juzbasic S et al. Human immunodeficiency virus-related non-Hodgkin lymphoma: activity of infusional cyclophosphamide, doxorubicin, and etoposied as second-line chemotherapy in 40 patients. Cancer 2001; 92: 200–206. 23. Bi J, Espina BM, Tulpule A, Boswell W, Levine AM. High-dose cytosine-arabinoside and cisplatin regimens as salvage therapy for refractory or relapse AIDS-related non-Hodgkin’s lymphoma. J Acq Immun Def Synd 2001; 28: 416–421. 24. Palella FJ, Delaney KM, Moorman AC et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV oupatient study investigators. N Engl J Med 1998; 338: 853–860. 25. Mocroft A, Sabin CA, Youle M et al. Changes in AIDS-defining illnesses in a London Clinic, 1987–1998. J Acq Immun Def Synd 1999; 21: 401–407. 26. Sparano JA, Anand K, Desai J, Mitnick RJ, Kalkut GE, Hanau LH. Effect of highly active antiretroviral therapy on the incidence of HIV-associated malignancies at an urban medical center. J Acq Immun Def Synd 1999; 21: S18–S22. 27. Grulich AE. AIDS-associated NHL in the era of highly active antiretroviral therapy. J Acq Immun Def Synd 1999; 21: S27–S30. 28. Rabkin CS, Testa MA, Huang J, Roenn JH. Kaposi’s sarcoma and non-Hodgklin’s lymphoma incidence trends in AIDS Clinical Trial Group study participants. J Acq Immun Def Synd 1999; 21: S31–S33. 29. Mocroft A, Katama C, Johnson AM et al. AIDS across Europe 1994–1998: the EuroSIDA study. Lancet 2000; 356: 291–296. 30. Clarke CA, Glasser SL. Epidemiologic trends in HIV-associated lymphomas. Curr Opin Oncol 2001; 13: 354–359. 31. Besson C, Goubar A, Gabarre J et al. Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy. Blood 2001: 2339–2344. 32. Biggar RJ. AIDS-related cancers in the era of highly active antiretroviral therapy. Oncology (Huntingt) 2001; 15: 439–448, discussion 448–449. 33. Grulich AE, Li Y, McDonald AM, Correll PK, Law MG, Kaldor JM. Decreasing rates of Kapos’s sarcoma and non-Hodgkin’s lymphoma in the era of potent combination anti-retroviral therapy. AIDS 2001; 15: 629–633. 34. Matthews GV, Bower M, Mandalia S et al. Changes in acquired immunodeficiency syndrome-related lymphoma since the introduction of highly active antiretroviral therapy. Blood 2000; 96: 2730–2734. 35. Buchbinder SP, Holmberg SD, Scheer S, Colfax G, O’Malley P, Vittinghoff E. Combination antiretroviral therapy and incidence of AIDS-related malignacies. J Acq Immun Def Synd 1999; 21: S23–S26. 36. Rabkin CS. AIDS and cancer in the era of highly active antiretroviral therapy (HAART). Eur J Cancer 2001; 37: 1316–1319.

SCT for HIV-related lymphoma 37. Levine AM, Seneviratne L, Tulpule A. Incidence and management of AIDS-related lymphoma. Oncology (Huntingt) 2001; 15: 629–639, discussion 639–640, 645–646. 38. Dal Maso L, Serraino D, Franceschi S. Epidemiology of AIDS-related tumours in developed and developing countries. Eur J Cancer 2001; 37: 1188–1201. 39. Little RF, Gutierrez M, Jaffe ES, Pau A, Horne M, Wilson W. HIV-associated non-Hodgkin’s lymphoma: incidence, presentation and prognosis. JAMA 2001; 285: 1880–1885. 40. Levine AM, Seneviratne L, Espina BM et al. Evolving characteristics of AIDS-related lymphoma. Blood 2000; 96: 4084–4090. 41. Vaccher E, Spina M, di Gennaro G et al. Concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus-related, non-Hodgkin’s lymphoma. Cancer 2001; 91: 155–163. 42. Ratner L, Lee J, Tang S et al. Chemotherapy for human immunodeficiency virus-associated non-Hodgkin’s lymphoma in combination with highly active antiretroviral therapy. J Clin Oncol 2001; 19: 2171–2178. 43. Navarro JT, Ribera JM, Oriol A et al. Influence of highly active anti-retroviral therapy on response to treatment and survival in patients with acquired immunodeficiency syndrome-related non-Hodgkin’s lymphoma treated with cyclophosphamide, hydrixydoxorubicin, vincristine and prednisone. Br J Haematol 2001; 112: 909–915. 44. Levine AM, Li P, Cheung T et al. Chemotherapy consisting of doxorubicin, bleomycin, vinblastine and dacarbazine with granulocyte-colony-stimulating factor in HIV-infected patients with newly diagnosed Hodgkin’s disease: a prospective multi-institutional AIDS clinical Trials Group Study (ACTG 149). J Acq Immun Def Synd 2000; 24: 444–450. 45. Spina M, Gabarre J, Rossi G et al. Stanford V regimen and concomitant HAART in 59 patients with Hodgkin disease and HIV infection. Blood 2002; 100: 1984–1988. 46. Antinori A, Cingolani A, Alba L et al. Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS 2001; 15: 1483–1491. 47. Powles T, Imani N, Nelson M, Gazzard BG, Bower M. Effects of combination chemotherapy and highly active antiretroviral therapy on immune parameters in HIV-1 associated lymphoma. AIDS 2002; 16: 531–536. 48. Molina A, Krishnan A, 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 2000; 89: 680–689. 49. Krishnan A, Molina A, Zaia J et al. Autologous stem cell transplantation for HIV-associated lymphoma. Blood 2001; 98: 3857–3859. 50. Gabarre L, LeBlond V, Sutton L et al. Autologous bone marrow transplantation in relapsed HIV-related non-Hodgkin’s lymphoma. Bone Marrow Transpl 1996; 18: 1195–1197. 51. Ubel PA, Caplan AL. Solid-organ transplantation in HIV-infected patients. N Engl J Med 2002; 347: 284–287. 52. Contu L, LaNasa G, Arras M et al. Allogeneic bone marrow transplantation combined with multiple anti-HIV treatments in a case of AIDS. Bone Marrow Transpl 1993; 12: 669–671. 53. Ragni MV, Dodson SF, Hunt SC, Bontempo FA, Fung JJ. Liver transplantation in a hemophilia patient with acquired immunodeficiency syndrome. Blood 1999; 93: 1113–1114.

54. Gabarre J, Azar N, Autran B et al. High-dose therapy and autologous haematopoietic stem-cell transplantation for HIV-1-associated lymphoma. Lancet 2000; 355(9209): 1071–1072. 55. Lane HC, Zunich KM, Wilson W et al. Syngeneic bone marrow transplantation and adoptive transfer of peripheral blood lymphocytes combine with zidovudine in human immunodeficiency virus (HIV) infection. Ann Intern Med 1990; 113: 512–519. 56. Campbell P, Iland H, Gibson J, Joshua D. Syngeneic stem cell transplantation for HIV-related lymphoma. Br J Haematol 1999; 105: 795–798. 57. Tirelli U, Spina M, Jaeger U et al. Infusional CDE with rituximab for the treatment of human immunodeficiency virus-associated non-Hodgkin’s lymphoma: preliminary results of a phase I/II study. Recent Results Cancer Res 2002; 159: 149–153. 58. Schmidt-Wolf IG, Rockstroh JK, Schlegel U, Pels H, Weiss R, Huhn D. New aspects in the treatment of AIDS-related lymphoma. Eur J Med Res 2002; 7: 295–303. 59. Little RF, Pearson D, Steinberg S et al. Dose-adjusted EPOCH chemotherapy in previously untreated HIV-associated non-Hodgkin’s lymphoma. Proc Am Soc Clin Oncol 1999; 18: 10a (abstract 33). 60. Gisselbrecht C, Gabarre J, Spina M. Treatment of HIV-related non-Hodgkin’s lymphoma adapted to prognostic factors. Proc Am Soc Clin Oncol 1999; 18: 16a (abstract 55). 61. Little RF, Yarchoan R, Wilson WF. Systemic chemotherapy for HIV-associated lymphoma in the era of highly active antiretroviral therapy. Curr Opin Oncol 2000; 12: 438–444. 62. Koka PS, Jamieson BD, Books DG, Zack JA. Human immunodeficiency virus type 1-induced hematopoietic inhibition is independent of productive infection of progenitor cells in vivo. J Virol 1999; 73: 9089. 63. Schooley RT, Mladenovic J, Sevin A et al. Reduced mobilization of CD34+ stem cells in advance human immunodeficiency virus type-1 disease. J Infect Dis 2000; 181: 148–157. 64. Levine AM, Scadden DT, Zaia JA, Krishnan A. Hematologic aspects of HIV/AIDS. Hematology (Am Soc Hematol Educ Program) 2001: 463–478. 65. Isgro A, Mezzaroma I, Aiuti A et al. Recovery of hematopoietic activity in bone marrow from human immunodficiency virus type-1 infected patients during highly active antiretroviral therapy. AIDS Res Hum Retrov 2000; 16: 1471. 66. Gerard L, Galicier L, Maillard A et al. Systemic non-Hodgkin lymphoma in HIV-infected patients with effective suppression of HIV replication: persistent occurrence but improved survival. J Acq Immun Def Synd 2002; 30: 478–484. 67. Baiocchi OC, Colleoni GW, Navajas EV et al. Impact of highly active antiretroviral therapy in the treatment of HIV-infected patients with systemic non-Hodgkin’s lymphoma. Acta Oncol 2002; 41: 192–196. 68. Krishnan A, Zaia JA, Molina A. Hematopoietic stem cell transplantation and gene therapy for HIV-associated lymphoma. J Hematoth Stem Cell Res 2002; 11: 765–775. 69. Krishnan A, Molina A, Zaia J, Vasquez D, Smith D, Forman SJ. Durable remissions in HIV-related lymphoma with autologous stem cell transplantation. Blood 2002; 100: 181a (abstract). 70. Krishan A, Molina A, Forman SJ. Organ transplantation in HIV-infected patients. N Engl J Med 2002; 347: 1801–1803, letter.


c 2003 Elsevier Ltd. All rights reserved.

Blood Reviews (2003) 17, 249–258

257

Molina et al. 71. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993; 329: 987–994. 72. Junker U, Moon JJ, Kalfoplou CS et al. Hematopoietic potential and retroviral transduction of CD34+Thy)1+ peripheral blood stem cells from asymptomatic human immunodeficiency virus type-1 infected individuals mobilized with granulocyte colony-stimulating factor. Blood 1997; 89: 4299–4306. 73. Bauer G, Valdez P, Kearns K et al. Inhibition of human immunodeficiency virus-1 (HIV-1) replication after transduction of granulocyte colony-stimulating factor-mobilized CD34+ cells from HIV-1-infected donors using retroviral vectors containing anti-HIV-1 genes. Blood 1997; 89: 2259–2267. 74. Nademanee A, Sniecinski I, Schmidt GM et al. High-dose therapy followed by autologous peripheral blood stem cell transplantation for patients with Hodgkin’s disease and non-Hodgkin’s lymphoma utilizing unprimed and granulocyte colony-stimulating factor ‘‘mobilized’’ peripheral blood stem cells. J Clin Oncol 1994; 12: 2176–2186. 75. Nademanee A, Molina A, O’Donnell MR et al. Results of high-dose therapy and autologous bone marrow/stem cell transplantation in poor-risk intermediate and high-grade lymphoma. International Index high and high-intermediate risk group. Blood 1997; 90: 3844–3852. 76. Nademanee A, O’Donnell MR, Snyder DS et al. High-dose chemotherapy with or without total body irradiation followed by autologous bone marrow and/or peripheral blood stem cell transplantation for patients with relapsed and refractory Hodgkin’s disease: results in 85 patients with an analysis of prognostic factors. Blood 1995; 85: 1381–1390. 77. Molina A, Popplewell L, Kashyap A, Nademanee A. Hematopoietic stem cell transplantation in the new millennium: report from City of Hope National Medical Center. Clin Transpl 2000: 317–342. 78. Gabarre J, Choquet S, Azar N et al. High-dose chemotherapy (HDC) with autologus stem cell transplantation (AST) for HIV-related lymphoma (Ly): a single center report on 14 patients (pts). Blood 2001; 98(Suppl 1): 502a (abstract 2092). 79. Attal M, Huguet F, Rubie H et al. Prevention of hepatic veno-occlusive disease after bone marrow transplantation by

258

Blood Reviews (2003) 17, 249–258


c 2003 Elsevier Ltd. All rights reserved.

80.

81.

82.

83.

84. 85.

86.

87.

88.

continuous infusion of low dose heparin: a prospective, randomized trial. Blood 1992; 79: 2834–2840. Zaia JA, Rossi JJ, Kriahnan A et al. Autologous stem cell transplantation using retrovirus-transduced peripheral blood progenitor cells in HIV-infected persons: comparison of gene marking post-engraftment with and without myeloablative therapy. Blood 1999; 94(Suppl 1) (abstract 2850). Kang EM, de Witte M, Malech H et al. Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome. Blood 2002; 99: 698–701. Nademanee A, Molina A, Forman SJ et al. A phase I/II trial of high-dose radioimmunotherapy (RIT) with Zevalin in combination with high-dose etoposide (VP-16) and cyclophosphamide (CY) followed by autologous stem cell transplantation (ASCT) in patients with poor-risk or relapsed B-cell non-Hodgkin’ lymphoma (NHL). Blood 2002; 100: 182a (abstract). Horovitz S, Negrin RS, Stockerl-Goldstein KE et al. A phase II trial of rituximab as adjuvant therapy to high dose chemotherapy and peripheral blood stem cell transplantation for relapsed and refractory aggressive non-Hodgkin’s lymphoma. Blood 2001; 98(Suppl 1): 862a (abstract 3578). Biggar RJ, Engels EZ, Frisch M, Goedert JJ. Risk of T-cell lymphomas in persons with AIDS. J Acq Immun Def Synd 2001; 26: 371–376. Philip T, Gugliermi 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 1995; 333: 1540–1545. Haioun C, Lepage E, Gisselbrecht C et al. Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin’s lymphoma: final analysis of the prospective LNH87-2 protocol – groupe d’Etude des lymphomas de l’Adulte study. J Clin Oncol 2000; 18: 3025–3030. Nademanee A, Molina A, Dagis A et al. Autologous stem cell transplantation for poor-risk and relapsed intermediate and high-grade non-Hodgkin’s lymphoma. Clin Lymphoma 2000; 1: 46–54. Molina A. Non-Hodgkin’s Lymphoma. In: Pazdur R, Coia L, Wagman L, Hoskins W, eds. Cancer Management: A Multidisciplinary Approach, fifth ed. Huntington, NY: PRR; 2001: 583–620.