high dose therapy and autologous stem cell transplantation for human immunodeficiency...

High Dose Therapy and Autologous Stem CellTransplantation for Human Immunodeficiency Virus-Associated Non-Hodgkin Lymphoma in the Era ofHighly Active Antiretroviral Therapy

Arturo Molina, M.D., M.S.1

Amrita Y. Krishnan, M.D.1

Auayporn Nademanee, M.D.1

Rachel Zabner, M.D.2

Irena Sniecinski, M.D.3

John Zaia, M.D.4

Stephen J. Forman, M.D.1

1 Division of Hematology and Bone Marrow Trans-plantation, City of Hope National Medical Center,Duarte, California.

2 Division of Medicine (Infectious Disease), City ofHope National Medical Center, Duarte, California.

3 Division of Pathology (Transfusion Medicine), Cityof Hope National Medical Center, Duarte, Califor-nia.

4 Division of Pediatrics (Virology and InfectiousDiseases), City of Hope National Medical Center,Duarte, California.

Supported in part by United States Public Servicegrants CA30206, CA33572, and AI38592. A.M.was supported by an American Cancer SocietyClinical Oncology Career Development Award.A.Y.K. is the recipient of a Fellowship Award fromthe Lymphoma Research Foundation of America.

The authors thank Dr. Lawrence Kaplan at SanFrancisco General Hospital for referring and pro-viding follow-up clinical information on Patient 2,and Martha Gomez for secretarial assistance withthe article.

Address for reprints: Arturo Molina, M.D., M.S.,Department of Hematology and Bone MarrowTransplantation, City of Hope National MedicalCenter, 1500 E. Duarte Road, Duarte, CA 91010.

Received September 3, 1999; revisions receivedMarch 3, 2000 and April 27, 2000; accepted April27, 2000.

BACKGROUND. The advent of highly active antiretroviral therapy (HAART) has

allowed the exploration of more dose-intensive therapy such as autologous stem

cell transplantation (ASCT) in selected patients with human immunodeficiency

virus (HIV)-associated non-Hodgkin lymphoma (NHL).

METHODS. The authors report on the use of myeloablative chemotherapy with

ASCT in two HIV positive patients with NHL. The first patient underwent ASCT at

the time of first disease remission for poor risk, diffuse, large cell NHL and the

second patient had multiply recurrent, chemosensitive Burkitt lymphoma. ASCT

was performed in both patients using a transplant conditioning regimen of high

dose cyclophosphamide, carmustine, and etoposide (CBV).

RESULTS. The target dose of $ 5 3 106/kg CD34 positive peripheral blood stem

cells (PBSC) utilized for ASCT was collected using granulocyte-colony stimulating

factor (G-CSF) after chemotherapy for mobilization while both patients were

receiving concomitant HAART for HIV infection. HAART was continued during

CBV conditioning. Prompt hematopoietic recovery was observed after ASCT. Both

patients remained in clinical disease remission from their lymphoma at 28 months

and 20 months after transplant, respectively.

CONCLUSIONS. ASCT is feasible in patients with HIV-associated NHL. Adequate

numbers of CD34 positive PBSC can be procured from patients receiving HAART

and chemotherapy for NHL. Selected patients with HIV-related lymphoma can

tolerate the high dose CBV myeloablative chemotherapy regimen without in-

creased acute regimen-related toxicity. Reinfusion of G-CSF-mobilized PBSC can

lead to rapid recovery of hematologic function and sustained engraftment after

ASCT. Given the poor prognosis of patients with HIV-associated NHL treated with

conventional chemotherapy, further investigation of this approach should be

considered. Cancer 2000;89:680 –9. © 2000 American Cancer Society.

KEYWORDS: autologous stem cell transplantation, lymphoma, human immunodefi-ciency virus, highly active antiretroviral therapy, myeloablative therapy.

S ince 1985, diffuse aggressive non-Hodgkin lymphoma (NHL) hasbeen recognized as an acquired immune deficiency syndrome

(AIDS)-defining diagnosis in patients with human immunodeficiencyvirus (HIV) infection.1 The incidence of NHL is 60-fold higher inHIV-infected individuals compared with the general population.2

HIV-associated lymphomas often present in extranodal sites, such asbone marrow, the gastrointestinal tract, and the central nervous sys-tem (CNS).3

Prior to the development of antiretroviral therapy, treatment with

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conventional chemotherapy regimens, such as stan-dard dose methotrexate, bleomycin, doxorubicin, cy-clophosphamide, vincristine, and dexamethasone (m-BACOD) and CNS prophylaxis resulted in a mediansurvival rate of 11 months.4 A randomized trial per-formed by the AIDS Clinical Trials Group (ACTG)showed no difference in the response rate or in overallsurvival between standard dose and reduced dose m-BACOD.5 Treatment with the reduced doses causedsignificantly less hematologic toxicity, suggesting thatless intensive regimens are tolerated better and do notcompromise treatment outcome in this patient popu-lation.

Other investigators have reported more favorableresults with the use of conventional or intensifiedregimens in a selected subgroup of patients.6 – 8 Forexample, the French-Italian Cooperative Group used amore aggressive multiagent approach referred to asthe LNH84 regimen.7 This strategy produced a 2-yearsurvival rate of 50% in a select subgroup of 66 patientswith favorable features. Similarly, the infusional cyclo-phosphamide, doxorubicin, and etoposide (CDE) che-motherapy regimen produced an impressive completeresponse rate of 71% and an overall response rate of93%.8

Since the mid-1980s, several new nucleoside andnonnucleoside reverse transcriptase inhibitors havebeen developed for the treatment of patients withHIV.9 A few pilot studies have demonstrated that theconcomitant administration of cytotoxic chemother-apy and HIV reverse transcriptase antiretroviralmonotherapy, with or without cytokine support, isfeasible and well tolerated in patients with HIV-relatedlymphoma.10 –12 Unfortunately, overall survival doesnot appear to have been improved significantly whensingle-agent reverse transcriptase antiretroviral ther-apy is combined with standard or dose-reduced che-motherapy regimens.

The use of three- and four-drug combinationscontaining two reverse transcriptase inhibitors andone or two HIV protease inhibitors has resulted inreduced HIV-1 replication and increased CD4 positivecell counts in patients with HIV infection.13 The ad-vent of this approach, referred to as highly activeantiretroviral therapy (HAART), in conjunction withimproved supportive care, has changed the naturalhistory of HIV infection by reducing the incidence ofopportunistic infections and improving survival.14,15

Current studies are investigating the use of concomi-tant HAART and cytotoxic chemotherapy for treat-ment of HIV-related NHL. Preliminary results of thesestudies suggest that these newer chemotherapy andantiretroviral strategies are feasible and are well toler-ated in this patient population.16 –18

Patients with relapsed HIV-related lymphomahave a very poor prognosis and limited treatmentoptions. These patients rarely achieve a prolongedsecond remission with conventional type salvage reg-imens or investigational agents.19 –22 Although the useof myeloablative therapy and autologous stem celltransplantation (ASCT) improves survival in high riskand relapsed, diffuse, aggressive NHL in non-HIV pa-tients,23,24 this approach has not been used routinelyfor lymphoma patients with HIV infection primarilybecause of concern over the increased risk of hema-tologic and infectious complications.

Herein, we describe the use of high dose chemo-therapy and ASCT in two patients with HIV-relatedlymphoma. Granulocyte-colony stimulating factor (G-CSF) was used to mobilize and procure adequatenumbers of CD34 positive peripheral blood-derivedstem cells (PBSCs) after both patients received HAARTand combination chemotherapy for their HIV infec-tion and malignant lymphoma, respectively. Both pa-tients tolerated high dose myeloablative chemother-apy and were engrafted successfully after reinfusion ofunmanipulated PBSCs. This preliminary report indi-cates that treatment with high dose therapy and ASCTis feasible in selected patients who are receivingHAART and chemotherapy for HIV-related NHL. Thisstrategy represents an alternative treatment optionthat can be investigated further for patients at the timeof disease recurrence or early in the course of theirdisease (i.e., in first remission) in a fashion similar tothat used for non-HIV-infected patients with poor risk,diffuse, aggressive NHL.23,24

MATERIALS AND METHODSPatientsPatient 1A Latino male age 37 years presented with bloodydiarrhea in April 1997. Diffuse erythematous polypoidfolds with mucosal ulceration involving the cecum,hepatic flexure, descending colon, and rectum wereseen on colonoscopy. Biopsies of these lesions re-vealed histologic findings consistent with intermedi-ate grade, diffuse, large cell lymphoma. The patientwas referred to the City of Hope National MedicalCenter (COHNMC) in June 1997. A bone marrow bi-opsy and aspirate showed ' 5% involvement withatypical, large, lymphoid cells that stained positivelyfor CD20. Immunoglobulin heavy-chain gene rear-rangements were detected by polymerase chain reac-tion (PCR) analysis, providing further evidence for thepresence of a clonal B-cell population in the bonemarrow. No additional areas of lymphomatous in-volvement were seen on routine computerized tomog-raphy (CT) scans. A chemistry panel and a complete

ASCT in HIV-Related Lymphoma/Molina et al. 681

blood count showed the following abnormal values:alkaline phosphatase, 137 units/L; lactate dehydroge-nase (LDH), 780 units/L; aspartate aminotransferase(SGPT), 207 units/L; alanine aminotransferase(SGOT), 271 units/L; white blood cell (WBC) count, 2.13 109/L; hemoglobin,. 12.8 g/L; and platelets, 1183 109/L. The Eastern Cooperative Oncology Groupperformance status was 1.

Because of his cytopenias, the patient was startedon reduced dose cyclophosphamide, doxorubicin,vincristine, and prednisone (CHOP) chemotherapy inJune 1997. HIV serologic studies were sent immedi-ately before starting chemotherapy. Two days afterstarting CHOP, antibodies against HIV were reportedto be reactive, and HIV infection was confirmed byWestern blot analysis, which detected bands againstp24, p31, gp41, p51, p65, gp120, and gp160. Within afew days, he developed thrush, and prednisone wasdiscontinued. The HIV RNA viral load, which was ob-tained after recovery from the first cycle of CHOP, was1,323,013 copies/mL. After the first cycle of CHOP, hewas started on cytokine support with G-CSF and an-tibiotic therapy for treatment of neutropenia and cel-lulitis. The patient went on to receive a second cycle ofdose-modified CHOP (without prednisone) and G-CSF support, at which time he also was started onHAART with indinavir, stavudine (d4T), and lamivu-dine (3TC) at the recommended doses. Inhaled pent-amidine also was started as prophylaxis against Pneu-mocystis carinii pneumoniae (PCP). A repeat HIV viralload obtained soon after the third cycle of CHOPshowed a decreased level of 11,604 copies/mL.

The patient was admitted in early August 1997with cellulitis and bilateral pulmonary nodular infil-trates, resulting in a 6-week delay in the administra-tion of the fourth cycle of chemotherapy. A bronchos-copy showed evidence of PCP, and he was treatedsuccessfully with intravenous trimethoprim-sulfame-thoxazole (TMP-SMX) and additional antibiotics forthe cellulitis. In early September 1997, he developedprogressive right neck adenopathy, requiring incisionand drainage. Acid fast bacilli (AFB) were seen, andcultures were consistent with infection with Mycobac-terium avium intracellulare (MAI), for which he wastreated with ethambutol, clarithromycin, and levo-floxacin. The development of MAI necessitated a2-month delay in administering the fifth cycle ofCHOP; however, the patient continued taking HAARTand medications for prophylaxis against other oppor-tunistic infections.

Restaging studies performed after the completionof five cycles of chemotherapy, including CT scans ofthe chest, abdomen, and pelvis, repeat colonoscopy,and bone marrow biopsy and aspiration, showed that

the patient was in first complete remission. Threeintrathecal treatments with cytosine arabinoside(Ara-C) and methotrexate also were administered forCNS prophylaxis during the five courses of CHOP. Atthe conclusion of the sixth cycle of CHOP, a total of10.5 3 106/kg CD34 positive PBSCs were collectedusing G-CSF 10 mg/kg per day for mobilization. HIVviral load was undetectable (, 400 copies/mL) at thetime of PBSC procurement (see Fig. 1). In March 1998,he underwent ASCT in first remission using a condi-tioning regimen of cyclophosphamide, carmustine(BCNU) and etoposide (VP-16) (for details of ASCT,see below). Informed consent was obtained from thepatient prior to ASCT in accordance with COHNMCinstitutional guidelines.

Patient 2A Caucasian woman age 37 years with a 10-year his-tory of untreated HIV infection presented in October1997 with a right groin mass that, on biopsy, revealedsmall, noncleaved cell, Burkitt-like lymphoma. A bonemarrow biopsy was hypercellular (90% cellularity) andshowed extensive lymphomatous involvement; there-fore, she was classified with Stage IV disease. HIV viralload and CD4 counts at the time of diagnosis of NHLwere 27,000 copies/mL and 40/mL, respectively. Thepatient was started on low dose CHOP. HAART con-sisted of nevirapine, stavudine (d4T), ritonavir, andsaquinavir and was initiated concomitantly with che-motherapy. Intrathecal Ara-C was administered forCNS prophylaxis. Complete remission was achievedafter six cycles of CHOP, but the patient’s lymphomarecurred 2 months later with a tumor mass in the earcanal. Four cycles of salvage chemotherapy consistingof infusional ifosfamide and etoposide led to anothercomplete remission in May 1997, at which time theHIV viral load was 500 copies/mL and the CD4 countwas 64/mL. Symptoms of nausea and emesis devel-oped during this chemotherapy, resulting in poorcompliance with HAART. Subsequently, she receivedfive doses of weekly rituximab and resumed HAART.Soon after completing rituximab, she developed a bi-opsy-proven recurrence of lymphoma in the left armthat was treated with a cycle of etoposide, solumedrol,cytarabine, and cisplatin (ESHAP) chemotherapy,which resulted in a complete remission.

The patient was referred to COHNMC in October1998 for consideration of ASCT. Her HIV viral load atthat time was , 50 copies/mL, and her CD4 count was70/mL. A lumbar puncture showed no evidence of CNSlymphoma. Unilateral bone marrow biopsy was 60%cellular and was without evidence of lymphoma. Asecond cycle of ESHAP was administered, and G-CSF10 mg/kg was given for PBSC mobilization prior to

682 CANCER August 1, 2000 / Volume 89 / Number 3

apheresis. A total of 5.4 3 106/kg CD34 positive PBSCswere collected. After obtaining informed consent forASCT in accordance with COHNMC institutionalguidelines, she was admitted to our institution onNovember 8, 1998, for ASCT using a cyclophospha-mide, carmustine, and etoposide (CBV) regimen sim-ilar to that used for the first patient.

Apheresis, Processing, and Cryopreservation TechniquesA double-lumen Hickman catheter was placed in bothpatients prior to starting PBSC apheresis. Granulo-cyte-colony stimulating factor (G-CSF) was used at adose of 10 mg/kg per day for PBSC mobilization.25 Thefirst patient received a slightly intensified dose of cy-clophosphamide of 1000 mg/m2 with the sixth cycle ofCHOP followed by the G-CSF. The second patient wasstarted on G-CSF after the second cycle of ESHAP.Because of concern about the potential for bone mar-row toxicity, TMP-SMX was not given during G-CSFpriming and PBSC collection, and aerosolized penta-midine was substituted for PCP prophylaxis duringthis period.

Apheresis was started upon recovery from chemo-therapy when WBCs reached a count of 1000/mL andwas continued daily until a minimum of 5 3 106/kgCD34 positive cells were collected. PBSC apheresiswas performed using a continuous-flow cell separator,either the CS-3000 Plus with a small-volume collectionchamber (Baxter, Deerfield, IL) or the Spectra cellseparator (Cobe, Lakewood, CO). Patients were anti-

coagulated with ACD-A (Baxter, Deerfield, IL) using awhole blood to ACD-A ratio of 10:1. Approximately 9.5L of whole blood were processed during each collec-tion procedure.

CD34 positive cells were enumerated by using atwo-color immunofluorescence analysis performed onthe FACSscan flow cytometer (Beckton Dickinson, SanJose, CA) as described previously.26 After collection,the PBSC products were combined with a cytopro-tectant containing a final concentration of 10% di-methylsulfoxide (DMSO) (Research Industries, SaltLake City, UT) and cryopreserved without rate-con-trolled freezing by simple immersion at 2130 °C to2150 °C in a freezer dedicated to HIV-infected aphere-sis products.27

Preparative Regimen and PBSC ReinfusionThe conditioning regimen consisted of BCNU 450mg/m2 given in split doses over 3 consecutive days onDay 25 to Day 27, VP-16 60 mg/kg on Day 24, andcyclophosphamide 100 mg/kg on Day 22. This trans-plant-conditioning regimen has been used atCOHNMC for more than 10 years for the treatment ofpatients with low grade lymphoma, Hodgkin disease,and diffuse aggressive lymphoma.24,25,28,29 For bothpatients in this study, the doses of VP-16 and cyclo-phosphamide were calculated by using adjusted ac-tual body weight and ideal body weight, respectively.The mobilized PBSCs were reinfused 48 hours aftercompletion of cyclophosphamide on Day 0. The PBSC

FIGURE 1. Measurement of human

immunodeficiency virus (HIV) viral load

and CD4 positive cell counts before and

after autologous stem cell transplanta-

tion (ASCT) in Patient 1.


products were transported to the bedside in the vaporphase of liquid nitrogen, rapidly thawed in a water bathat 37–40 °C, and infused as described previously.27

Supportive CareBoth patients were housed in high-efficiency particu-late air-filtered rooms during the period of granulo-cytopenia. Levofloxacin was used for gastrointesti-nal decontamination. Intravenous TMP-SMX wasadministered from Day 29 to Day 22 for prophy-laxis against PCP and was reinstituted by oral admin-istration at the time of discharge. Starting on Day 21,acyclovir 250 mg/m2 was given every 12 hours untilrecovery of granulocyte function and improvement ofmucositis. Both patients received daily G-CSF 5 mg/kgstarting on Day 11 and continued until the absoluteneutrophil count remained . 1000/mL for 3 consecu-tive days. Empiric broad-spectrum antibiotics and to-tal parenteral nutrition were given as clinically indi-cated. Low dose amphotericin-B (0.1– 0.2 mg/kg) wasadministered starting on Day 11 and was continueduntil the time of discharge.30

Platelet transfusions were administered to main-tain the platelet count at . 20,000/mL at all times.Single or designated donor platelets were used whenclinically indicated. Packed red blood cell (PRBC)transfusions were given to keep the hemoglobin levelabove 8.0 gm/dL. All platelet and PRBC products wereleukodepleted by filtration to prevent alloimmuniza-tion and cytomegalovirus transmission. In addition,all blood products were irradiated with 2500 centi-grays prior to transfusion.

HIV Viral Load and CD4 CountsThe plasma HIV viral load was measured as the con-centration of HIV RNA by using a sensitive branched-DNA signal amplification assay.31 CD4 cell countswere determined by using routine flow cytometricprocedures in the Clinical Pathology Department atCOHNMC.

RESULTSPBSC CollectionThe target dose of $ 5 3 106/kg CD34 positive cellswas obtained during two apheresis procedures foreach patient. Totals of 10.5 3 106/kg and 5.4 3 106/kgCD34 positive cells were collected from Patient 1 andPatient 2, respectively.

Acute ASCT-Related ToxicitiesBoth patients developed febrile neutropenia that wastreated with broad-spectrum intravenous antibiotics.On Day 17, the Patient 1 had fever and a coagulasenegative Staphylococcus species grown from blood

cultures and was treated with intravenous vancomy-cin. He was discharged from the hospital on Day 112and continued outpatient antibiotic therapy. Patient 2had minimal mucositis; however, persistent nauseaprecluded her from taking any antiretroviral medica-tion during hospitalization. On Day 17, she developedfever and was treated with broad-spectrum antibiot-ics. Blood cultures grew out Streptococcus pneu-moniae, which required intravenous vancomycin. Shewas discharged from the hospital on Day 115, andHAART was resumed under the supervision of herprimary physician at an outside institution.

EngraftmentPatient 1 reached an absolute neutrophil count. 500/mL and a platelet count of 25,000/mL withoutany further platelet transfusions on Days 111 and 110after ASCT, respectively. He had normal blood countsat 28 months post-ASCT. Patient 2 engrafted with anabsolute neutrophil count . 500/mL on Day 111 andwas transfusion independent at discharge. A bonemarrow biopsy obtained about 2 months after ASCTshowed 50% cellularity and no evidence of lymphoma.However, 10 weeks after transplantation, her graftfunction decreased with a drop in her WBC count to1200/mL and in her platelet count to 25,000/mL. Awork-up for cytomegalovirus and parvovirus was neg-ative. Because of concern over medication-inducedmyelosuppression, TMP-SMX was discontinued tem-porarily, and she was switched to a different PCPprophylaxis regimen. At 17 months post-ASCT, hercounts had increased to a WBC count of 3000/mL anda platelet count of 111,000/mL despite resuming theuse of prophylactic TMP-SMX.

Remission StatusPatient 1 remains in complete remission from his lym-phoma at 28 months posttransplantation. A colonos-copy performed at 1 year post-ASCT showed no evi-dence of lower gastrointestinal lymphomatousinvolvement. Additional staging studies were repeatedat 1 and 2 years posttransplantation. CT scans of thechest, abdomen, and pelvis showed no adenopathy ormasses. Follow-up bone marrow biopsies and aspi-rates showed no morphologic, flow cytometric, or mo-lecular (PCR) evidence of lymphoma in the bone mar-row. Routine laboratory studies obtained 28 monthsafter ASCT also were within normal limits.

Patient 2 was restaged at 12 months posttrans-plantation with CT scans of the chest, abdomen, andpelvis that showed no evidence of lymphoma. A repeatbone marrow biopsy and aspirate was not performedas part of her annual restaging evaluation. Clinically,she remains in remission from lymphoma 20 months


after ASCT. She has been unable to take antiretroviralmedications consistently since the transplantationdue to recurrent nausea unrelated to ASCT. Extensivegastroenterologic evaluation, including upper endos-copy, was unrevealing. Ultimately, enteral feeding wasrequired. Psychiatric evaluation confirmed the diag-nosis of major depression, which contributed to hernoncompliance with medications; however, she hasrefused antidepressant medication.

HIV VIRAL LOAD AND CD4 POSITIVE COUNTSAlthough the HIV RNA plasma viral load was 1,323,013copies/mL at presentation, the Patient 1 had a goodresponse to HAART. The HIV viral load dropped to11,604 copies/mL after the third cycle of chemother-apy and reached undetectable levels by the timeCHOP was completed in December 1997. The HIVviral load remained undetectable (, 400 copies/mL)at the time of PBSC apheresis and throughout thepost-ASCT follow-up period. The first CD4 positivecell count on this patient, which was obtained afterthe second cycle of chemotherapy, was 32/mL. Subse-quent CD4 have fluctuated during the course of in-duction chemotherapy but have continued to improveduring the posttransplantation period (see Fig. 1). InMay 1998, nelfinavir was substituted for indinavir, be-cause the patient developed recurrent flank pain andnephrolithiasis, a known side effect of this particularprotease inhibitor. The most recent CD4 count, whichwas obtained 22 months post-ASCT, was 426 cells/mL.

Since her diagnosis of lymphoma, the second pa-tient’s course was notable for nausea that was multi-factorial and was related in part to her antiretroviraltherapy but also was due to psychological factors. Thiswas exacerbated during the administration of salvagechemotherapy and often precluded her from takingthe HAART regimen. At the time NHL was diagnosed,the HIV viral load was 17,560 copies/mL, and the CD4count was 33 cells/mL. HAART was then initiated andadministered during chemotherapy. Prior to trans-plantation, the viral load had decreased to undetect-able levels; however, the CD4 count remained at 70cells/mL. After transplantation, the viral load has in-creased, and the CD4 count has remained in the rangeof 10 –50 cells/mL. The patient returned to her refer-ring physician for follow-up care.

DISCUSSIONThe treatment of patients with HIV-related NHL is lesssuccessful than in the non-HIV setting, partly becauseof the increased risks of opportunistic infection asso-ciated with the use of cytotoxic chemotherapeuticagents in this patient population. The administrationof chemotherapy to patients with HIV-related lym-

phoma also is associated with a significant and sus-tained reduction in CD4 lymphocyte counts and se-vere neutropenia, leading to treatment delays despitethe use of G-CSF.32–34 Currently, issues regarding theoptimal combination chemotherapy regimen for thetreatment of patients with HIV-related NHL as well asthe dose intensity and route of administration of thechosen regimen remain largely undefined. Few studieshave assessed prospectively the impact of combinedsingle-agent antiretroviral therapy and standard che-motherapy as front-line therapy for patients with HIV-related lymphoma.10 –12 A recent innovative approachusing a combination of the anti-B4bR immunotoxinand low dose m-BACOD did not appear to offer asignificant advantage over the use of m-BACOD alone,and 43% of patients in that study died of diseaserecurrence or progression.35 Promising results fromthe National Cancer Institute using dose-adjusted eto-poside, prednisone, vincristine, cyclophosphamide,and doxorubicin (EPOCH) administered without ini-tial concomitant HAART have been reported withcomplete response rates of 70% when used as a front-line approach,36

Factors that have been shown to be predictive ofpoor survival in patients with HIV-related lymphomainclude lower CD4 counts at diagnosis, prior diagnosisof AIDS, performance status , 70%, Stage III–IV dis-ease, age . 35 years, history of intravenous drug use,elevated LDH, and bone marrow involvement.7,37–39

Two recent studies also suggest that the InternationalPrognostic Index (IPI)40 can be used as a predictor ofsurvival in patients with HIV-related lymphoma re-ceiving treatment with standard dose combinationchemotherapy.41,42 Disease recurrence is a commoncause of treatment failure in this patient population,and 35–55% of these patients ultimately die of diseaseprogression.19

For patients with recurrent HIV-related lym-phoma, the treatment options are limited and includesingle agents, such as mitoguazone or PEG-L-aspargi-nase; standard salvage combinations; or novel infu-sional chemotherapy regimens.19 –22 In the non-HIVsetting, ASCT has emerged as an acceptable treatmentfor patients with diffuse, aggressive, recurrent NHLand for patients with poor risk features in first com-plete or partial remission, as defined by the IPI.40

Because of the very high incidence of opportunisticinfections and hematologic toxicity associated withcytotoxic chemotherapy, historically, there has beenvery limited enthusiasm for the use of high dose ther-apy and ASCT for patients with HIV-related lym-phoma.

The advent of HAART therapy using triple andquadruple antiretroviral drug combinations and im-


proved supportive care has changed the clinicalcourse of patients with HIV infection.13–15 Patientsnow enjoy increased survival resulting from decreasedopportunistic infections and improved immunologicfunction. Consequently, the use of new therapeuticavenues, such as solid organ transplantation and au-tologous, allogeneic, and syngeneic stem cell trans-plantation, may be considered in patients with HIVinfection.43– 47

Recent reports indicate that it is possible to ad-minister HAART in conjunction with conventionalchemotherapy regimens.16 –18 Vaccher et al.17 treated15 patients with concomitant CHOP and HAART: Al-though the complete response rate of 33% was similarto a historic control group of HIV-related lymphomapatients who were treated with CHOP alone, the mor-tality rate and the incidence of opportunistic infec-tions were lower, and the median survival was higherin this small cohort of patients who received concom-itant CHOP and HAART. However, the group that re-ceived the combined treatment experienced a higherincidence of treatment-related anemia and neurotox-icity. Another study combining the protease inhibitorsaquinavir with CDE infusional chemotherapy re-ported a significant increase in the incidence of mu-cositis, suggesting the need for careful investigationregarding the use of HAART in combination with che-motherapy.48

Previously, we and others have reported that G-CSF can be used to mobilize PBSCs in HIV-1 infectedpatients with . 200 CD4 cells/mL without any changein the HIV RNA levels or change in clinical status.49,50

In addition, it also has been shown that the in vitroclonogenic potential of CD34 positive, Thy1 positivehematopoietic stem cells (HSC) selected by using ahigh-speed cell-sorting process from asymptomatic,HIV-1-infected individuals is comparable to G-CSF-mobilized HSC from HIV seronegative volunteers.51

Most of the patients in these studies were receivingsome type of single or double reverse transcriptaseinhibitor therapy, but none was receiving HAARTcombinations containing an HIV protease inhibitor.The demonstration that functional HSC can be mobi-lized from HIV-1-infected individuals supports thefeasibility of using stem cell-based gene therapy ap-proaches and high dose therapy with ASCT in patientswith HIV infection and associated complications, suchHIV-related NHL.

Our report of these two patients demonstratesthat it is possible to collect adequate numbers of stemcells for use in ASCT from HIV-related lymphomapatients receiving standard chemotherapy and HAARTand to sustain durable engraftment after ASCT. Inaddition, we showed that high dose chemotherapy can

be administered without excessive treatment-relatedtoxicities. In both patients, engraftment was promptand was comparable to that of patients without HIVwho have undergone ASCT for lymphoid malignanciesat our institution. Despite having suffered numerousopportunistic infections during induction chemother-apy, the first patient had an uneventful posttransplan-tation course with well-controlled HIV viral loads andrising CD4 counts (see Fig. 1). Significant nausea ofmultifactorial etiology has limited the second patient’sability to take her antiretroviral therapy after trans-plantation, leading to elevations in the HIV viral load.Notably, this patient had significant problems withnausea associated with the use of standard chemo-therapy and HAART, which preceded high dose che-motherapy and ASCT.

Defining the role of ASCT as part of initial therapyfor poor risk, diffuse, aggressive lymphoma in non-HIV patients remains an area of active investigation. Abenefit of early ASCT has not been observed in pa-tients who are slow responders or are not in a goodpartial or complete remission with initial therapy andin those who receive abbreviated or nonstandard ini-tial chemotherapy. However, there is an emergingbody of literature that supports the use of this ap-proach for non-HIV patients with IPI high-intermedi-ate risk and high risk, diffuse, aggressive lymphoma infirst remission. The previously published, randomizedFrench study was updated recently.52 With a medianfollow-up of 8 years, that study demonstrated a statis-tically significant improvement in the 8-year diseasefree survival and overall survival rates in favor of theautologous transplantation arm compared with thenontransplantation, sequential chemotherapy arm infirst remission patients with high-intermediate riskand high risk IPI scores. To clarify this issue further, aprospective trial comparing eight cycles of CHOP ver-sus five cycles of CHOP plus autologous transplanta-tion for non-HIV patients with poor risk, diffuse, ag-gressive lymphoma in first remission is underway inthe United States.

In summary, this is the first report describing theuse of G-CSF-mobilized PBSC for ASCT in HIV-relatedlymphoma patients receiving modern antiretroviraltherapy. Both patients in this study had an undetect-able viral load at the time of PBSC apheresis, therebydemonstrating the feasibility of mobilizing and pro-curing PBSC from patients with HIV-associated lym-phoma who are receiving chemotherapy and concom-itant HAART. However, the impact of ASCT on diseasefree and overall survival rates in patients with HIV-related lymphoma remains undetermined. The firstpatient was considered to have high-intermediate riskdisease at presentation with elevated LDH, Stage IV


disease, and two extranodal sites of involvement atpresentation as defined by the IPI. Because of oppor-tunistic infections, there were substantial delays in theadministration of chemotherapy. This patient had twoadditional poor risk factors that have been associatedwith a poor outcome in HIV-related lymphoma: 1)CD4 count at presentation , 100 cells/mL and 2) age. 35 years. Therefore, his chance of sustained remis-sion with standard chemotherapy was poor, even if hedid not have underlying HIV infection. The relapserates for patients with HIV-associated lymphoma whoachieve a complete response with initial chemother-apy range from 30% to 50%. At 28 months posttrans-plantation and at 37 months after the initial diagnosis,the first patient already has exceeded the anticipated31–35 week median survival of patients with HIV-related lymphoma who were treated on the random-ized ACTG m-BACOD chemotherapy study.5

The second patient in our report has remained inremission for 20 months after transplantation, whichis a longer time frame than that afforded by her priorconventional chemotherapy regimens. Generally, pa-tients with recurrent, HIV-related lymphoma have amedian survival of 2–3 months using published sal-vage treatments.19,21 Hence, our results with these twopatients are encouraging and suggest that there is apotential role for further investigation of the use ofASCT in the treatment of patients with HIV-relatedlymphoma.

Based on our preliminary results with these twopatients, we have initiated a prospective trial of ASCTfor patients with HIV-associated lymphoma in firstcomplete or partial remission with poor risk featuresat presentation as defined by the IPI (i.e., high-inter-mediate and high risk) and for patients who experi-ence disease recurrence after initial treatment.53 Con-comitant therapy with HAART to maintain an HIVviral load of less than 20,000 copies/mL is required forparticipation in this trial. As part of a companionstudy, patients who are eligible for ASCT have receiveda combination of nontransduced, CD34 positive cells(minimum of 2 3 106 CD34 positive cells/kg) andsimilar numbers of CD34 positive cells transducedwith retrovirus vectors encoding either hammerheadribozymes targeted to HIV tat and rev or neomycinphosphotransferase.54 Five additional patients withHIV-associated lymphoid malignancies have receivedASCT using genetically modified stem cells.55 We havefound that that the engraftment of gene-marked cellsis enhanced significantly after conditioning the pa-tient with high dose myeloablative therapy. Anotherpatient with chemosensitive, relapsed NHL receivedASCT with nontransduced, CD34 positive cells. Thesesix patients also tolerated CBV conditioning well and

received concomitant HAART. Results of this trial willbe presented in the future after longer follow-up isavailable.

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